MiR-144 regulates hematopoiesis and vascular development by targeting meis1 during zebrafish development.

PubMed

Su, Zhenhong; Si, Wenxia; Li, Lei; Zhou, Bisheng; Li, Xiuchun; Xu, Yan; Xu, Chengqi; Jia, Haibo; Wang, Qing K

2014-04-01

Hematopoiesis is a dynamic process by which peripheral blood lineages are developed. It is a process tightly regulated by many intrinsic and extrinsic factors, including transcriptional factors and signaling molecules. However, the epigenetic regulation of hematopoiesis, for example, regulation via microRNAs (miRNAs), remains incompletely understood. Here we show that miR-144 regulates hematopoiesis and vascular development in zebrafish. Overexpression of miR-144 inhibited primitive hematopoiesis as demonstrated by a reduced number of circulating blood cells, reduced o-dianisidine staining of hemoglobin, and reduced expression of hbαe1, hbβe1, gata1 and pu.1. Overexpression of miR-144 also inhibited definitive hematopoiesis as shown by reduced expression of runx1 and c-myb. Mechanistically, miR-144 regulates hematopoiesis by repressing expression of meis1 involved in hematopoiesis. Both real-time RT-PCR and Western blot analyses showed that overexpression of miR-144 repressed expression of meis1. Bioinformatic analysis predicts a target binding sequence for miR-144 at the 3'-UTR of meis1. Deletion of the miR-144 target sequence eliminated the repression of meis1 expression mediated by miR-144. The miR-144-mediated abnormal phenotypes were partially rescued by co-injection of meis1 mRNA and could be almost completely rescued by injection of both meis1 and gata1 mRNA. Finally, because meis1 is involved in vascular development, we tested the effect of miR-144 on vascular development. Overexpression of miR-144 resulted in abnormal vascular development of intersegmental vessels in transgenic zebrafish with Flk1p-EGFP, and the defect was rescued by co-injection of meis1 mRNA. These findings establish miR-144 as a novel miRNA that regulates hematopoiesis and vascular development by repressing expression of meis1. Copyright © 2014 Elsevier Ltd. All rights reserved.

FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells.

PubMed

Ren, Xiaomeng; Ustiyan, Vladimir; Pradhan, Arun; Cai, Yuqi; Havrilak, Jamie A; Bolte, Craig S; Shannon, John M; Kalin, Tanya V; Kalinichenko, Vladimir V

2014-09-26

Inactivating mutations in the Forkhead Box transcription factor F1 (FOXF1) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardiovascular, and gastrointestinal systems. In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis. Although FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and patients with alveolar capillary dysplasia with misalignment of pulmonary veins remain uncharacterized because of lack of mouse models with cell-restricted inactivation of the Foxf1 gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach. A novel mouse line harboring Foxf1-floxed alleles was generated by homologous recombination. Tie2-Cre and Pdgfb-CreER transgenes were used to delete Foxf1 from endothelial cells. FOXF1-deficient embryos exhibited embryonic lethality, growth retardation, polyhydramnios, cardiac ventricular hypoplasia, and vascular abnormalities in the lung, placenta, yolk sac, and retina. Deletion of FOXF1 from endothelial cells reduced endothelial proliferation, increased apoptosis, inhibited vascular endothelial growth factor signaling, and decreased expression of endothelial genes critical for vascular development, including vascular endothelial growth factor receptors Flt1 and Flk1, Pdgfb, Pecam1, CD34, integrin β3, ephrin B2, Tie2, and the noncoding RNA Fendrr. Chromatin immunoprecipitation assay demonstrated that Flt1, Flk1, Pdgfb, Pecam1, and Tie2 genes are direct transcriptional targets of FOXF1. FOXF1 is required for the formation of embryonic vasculature by regulating endothelial genes critical for vascular development and vascular endothelial growth factor signaling. © 2014 American Heart Association, Inc.

A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels.

PubMed

Hallaq, Haifa; Pinter, Emese; Enciso, Josephine; McGrath, James; Zeiss, Caroline; Brueckner, Martina; Madri, Joseph; Jacobs, Harris C; Wilson, Christine M; Vasavada, Hemaxi; Jiang, Xiaobing; Bogue, Clifford W

2004-10-01

The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and forebrain development. Hhex(-/-) mice die by mid-gestation (E14.5) and the cause of their early demise remains unclear. Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development. We show here, for the first time, that a null mutation of Hhex results in striking abnormalities of cardiac and vascular development which include: (1) defective vasculogenesis, (2) hypoplasia of the right ventricle, (3) overabundant endocardial cushions accompanied by ventricular septal defects, outflow tract abnormalities and atrio-ventricular (AV) valve dysplasia and (4) aberrant development of the compact myocardium. The dramatic enlargement of the endocardial cushions in the absence of Hhex is due to decreased apoptosis and dysregulated epithelial-mesenchymal transformation (EMT). Interestingly, vascular endothelial growth factor A (Vegfa) levels in the hearts of Hhex(-/-) mice were elevated as much as three-fold between E9.5 and E11.5, and treatment of cultured Hhex(-/-) AV explants with truncated soluble Vegfa receptor 1, sFlt-1, an inhibitor of Vegf signaling, completely abolished the excessive epithelial-mesenchymal transformation seen in the absence of Hhex. Therefore, Hhex expression in the ventral foregut endoderm and/or the endothelium is necessary for normal cardiovascular development in vivo, and one function of Hhex is to repress Vegfa levels during development.

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) with multiple vascular complications misdiagnosed as Dubowitz syndrome.

PubMed

Dieks, Jana-Katharina; Baumer, Alessandra; Wilichowski, Ekkehard; Rauch, Anita; Sigler, Matthias

2014-09-01

To date, the genetic basis of Dubowitz syndrome (short stature, microcephaly, facial abnormalities, eczema) is unknown and vascular complications are not known to be associated with this syndrome. In microcephalic osteodysplastic primordial dwarfism type II (MOPD II; disproportionate short statue, microcephaly, facial abnormalities), however, cerebral aneurysms and other vascular abnormalities are frequent complications. MOPD II is a genetic disorder caused by mutations in the pericentrin (PCNT) gene (21q22). We report on a patient who came to our attention as a 22-year-old with subarachnoid bleeding due to a ruptured cranial aneurysm. Until then, the patient was thought and published to have Dubowitz syndrome; previously, he was treated with coronary bypass surgery for extensive coronary angiopathy. Consecutive genetic testing revealed MOPD II. After clinical stabilization, the patient was discharged to a specialized rehabilitation center where he died due to re-rupture of a cranial aneurysm. In patients with short stature-especially when clinical features are accompanied by vascular complications-MOPD II should be considered as a differential diagnosis leading to consecutive genetic testing. After detection of mutations in the PCNT gene, a full vascular status including cerebral imaging and cardiac evaluation needs to be determined in order to analyze vascular abnormalities and initiate prophylactic treatment.

The vascular and neurogenic factors associated with erectile dysfunction in patients after pelvic fractures

PubMed Central

Guan, Yong; Wendong, Sun; Zhao, Shengtian; Liu, Tongyan; Liu, Yuqiang; Zhang, Xiulin; Yuan, Mingzhen

2015-01-01

ABSTRACT Erectile dysfunction (ED) is a common complication of pelvic fractures. To identify the vascular and neurogenic factors associated with ED, 120 patients admitted with ED after traumatic pelvic fracture between January 2009 and June 2013 were enrolled in this study. All patients answered the International Index of Erectile Function (IIEF-5) questionnaire. Nocturnal penile tumescence (NPT) testing confirmed the occurrence of ED in 96 (80%) patients on whom penile duplex ultrasound and neurophysiological testing were further performed. Of these ED patients 29 (30%) were demonstrated only with vascular abnormality, 41 (42.7%) were detected only with neural abnormality, 26 (27.1%) revealed mixed abnormalities. Of the 55 patients (29+26) with vascular problems, 7 patients (12.7%) with abnormal arterial response to intracavernous injection of Bimix (15mg papaverine and 1mg phentolamine), 31 (56.4%) with corporal veno-occlusive dysfunction and 17 (30.9%) had both problems. Of the 67 (41+26) patients with abnormal neurophysiological outcomes, 51 (76.1%) with abnormal bulbocavernosus reflex (BCR), 20 (29.9%) with pathological pudendal nerve evoked potentials (PDEPs) and 25 (37.3%) with abnormal posterior tibial somatosensory nerve evoked potentials (PTSSEPs). Our observation indicated that neurogenic factors are important for the generation of ED in patients with pelvic fracture; venous impotence is more common than arteriogenic ED. PMID:26689522

A Fourteen-Year Experience with Vascular Anomalies Encountered during Transaxillary Rib Resection for Thoracic Outlet Syndrome.

PubMed

Yi, Jeniann A; Johnston, Robert J; Nehler, Mark R; Gibula, Douglas R; Alix, Kristen; Glebova, Natalia O; Brantigan, Charles O

2017-04-01

Transaxillary approach to first rib resection and scalenectomy (TAFRRS) is a well-established technique for treatment of thoracic outlet syndrome (TOS). Although anatomic features encountered during TAFRRS are in general constant, vascular anomalies may be encountered but have not been described to date. Herein we describe vascular abnormalities encountered during TAFRRS. We performed a retrospective review of a prospective practice database of 224 operations for TOS performed in 172 patients from March 2000 to March 2014. We excluded 10 patients with missing operative reports, 3 reoperations on the same patient, and 8 non-transaxillary resections. We recorded vascular anomalies identified in operative reports and reviewed computed tomography imaging to delineate the nature of these abnormalities. The overall incidence of vascular anomalies was 11% (22 of 203 TAFRRS). Most patients with anomalies had venous TOS (vTOS) (9 patients, 41%), followed by 7 (32%) with neurogenic TOS (nTOS). The remainder of the patients had arterial TOS (aTOS) (6 patients, 27%). Seven patients (32%) had an abnormal subclavian artery (SCA) with 5 (23%) having an abnormal arterial course in the anterior scalene muscle (ASM); 6 patients (27%) had an abnormal internal mammary artery (IMA) originating from distal SCA; 4 (18%) had abnormalities in the supreme thoracic artery (bifurcation or duplication); 2 (9%) had an abnormal branch from the SCA with anomalous location in the operative field; and 3 (14%) had an abnormal large venous branch penetrating the ASM. In the 19 patients with arterial anomalies, 8 (42%) were recognized as arterial branches penetrating the ASM, and 11 (58%) were noticed as they had anomalous arterial locations within the operative field. Most arterial anomalies were seen in vTOS (9, 45%), followed by nTOS (7, 35%). No intraoperative vascular complications occurred. Perioperative complications included 1 occurrence of postoperative transfusion for bleeding following axillary drain discontinuation and 2 Horner's syndromes. One aberrant IMA was electively ligated to allow complete thoracic outlet decompression. Arterial anomalies during TAFRRS are encountered in 11% of operations, and may present with vessel locations in unusual areas within the operative field, or as abnormal vessels penetrating the ASM, thus making scalenectomy precarious. Careful attention must be paid to possible abnormal locations of vessels in the thoracic outlet to avoid bleeding complications. Copyright © 2016 Elsevier Inc. All rights reserved.

Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis

PubMed Central

Liang, Dong; Wang, Xia; Mittal, Ashok; Dhiman, Sonam; Hou, Shuan-Yu; Degenhardt, Karl; Astrof, Sophie

2014-01-01

Integrin α5-null embryos die in mid-gestation from severe defects in cardiovascular morphogenesis, which stem from defective development of the neural crest, heart and vasculature. To investigate the role of integrin α5β1 in cardiovascular development, we used the Mesp1Cre knock-in strain of mice to ablate integrin α5 in the anterior mesoderm, which gives rise to all of the cardiac and many of the vascular and muscle lineages in the anterior portion of the embryo. Surprisingly, we found that mutant embryos displayed numerous defects related to the abnormal development of the neural crest such as cleft palate, ventricular septal defect, abnormal development of hypoglossal nerves, and defective remodeling of the aortic arch arteries. We found that defects in arch artery remodeling stem from the role of mesodermal integrin α5β1 in neural crest proliferation and differentiation into vascular smooth muscle cells, while proliferation of pharyngeal mesoderm and differentiation of mesodermal derivatives into vascular smooth muscle cells was not defective. Taken together our studies demonstrate a requisite role for mesodermal integrin α5β1 in signaling between the mesoderm and the neural crest, thereby regulating neural crest-dependent morphogenesis of essential embryonic structures. PMID:25242040

Forskolin Modifies Retinal Vascular Development in Mrp4-Knockout Mice

PubMed Central

Matsumiya, Wataru; Kusuhara, Sentaro; Hayashibe, Keiko; Maruyama, Kazuichi; Kusuhara, Hiroyuki; Tagami, Mizuki; Schuetz, John D.; Negi, Akira

2012-01-01

Purpose. Multidrug resistance protein 4 (MRP4) effluxes a wide variety of endogenous compounds, including cyclic adenosine monophosphate (cAMP), and is exclusively expressed in vascular endothelial cells (ECs) of the retina. This study aimed to investigate the role of MRP4 in retinal vascular development. Methods. The retinal vascular phenotype of Mrp4−/− mice was examined by whole-mount immunohistochemistry at P3, P6, and P14. The retinas from P6 pups that received an intraperitoneal injection of either solvent control or forskolin, an inducer of intracellular cAMP formation, at P4 and P5 were analyzed in terms of their vascular formation (vascular length, vascular branching, vascular density, and the number of tip cells), cell proliferation and apoptosis, and vessel stability. Results. The Mrp4−/− mice exhibited no overt abnormalities in the development of the retinal vasculature, but retinal vascular development in the Mrp4−/− mice was suppressed in response to forskolin administration. There was a significant decrease in the vascular length, vascular branching, and vascular density, and inhibited tip cell formation at the vascular front. The forskolin-treated Mrp4−/− mice showed an increased number of Ki67-positive and cleaved caspase 3–positive ECs, a significant decrease in the amount of pericyte coverage, and a reduced number of empty sleeves. In pups exposed to hyperoxia (75% oxygen) from P7 to P12, the Mrp4−/− mice showed a significant increase in the unvascularized retinal area. Conclusions. Mrp4−/− mice exhibited suppressed retinal vascular development in response to forskolin treatment. Thus, Mrp4 might have protective roles in retinal vascular development by regulating the intracellular cAMP level. PMID:23154460

Forskolin modifies retinal vascular development in Mrp4-knockout mice.

PubMed

Matsumiya, Wataru; Kusuhara, Sentaro; Hayashibe, Keiko; Maruyama, Kazuichi; Kusuhara, Hiroyuki; Tagami, Mizuki; Schuetz, John D; Negi, Akira

2012-12-07

Multidrug resistance protein 4 (MRP4) effluxes a wide variety of endogenous compounds, including cyclic adenosine monophosphate (cAMP), and is exclusively expressed in vascular endothelial cells (ECs) of the retina. This study aimed to investigate the role of MRP4 in retinal vascular development. The retinal vascular phenotype of Mrp4(-/-) mice was examined by whole-mount immunohistochemistry at P3, P6, and P14. The retinas from P6 pups that received an intraperitoneal injection of either solvent control or forskolin, an inducer of intracellular cAMP formation, at P4 and P5 were analyzed in terms of their vascular formation (vascular length, vascular branching, vascular density, and the number of tip cells), cell proliferation and apoptosis, and vessel stability. The Mrp4(-/-) mice exhibited no overt abnormalities in the development of the retinal vasculature, but retinal vascular development in the Mrp4(-/-) mice was suppressed in response to forskolin administration. There was a significant decrease in the vascular length, vascular branching, and vascular density, and inhibited tip cell formation at the vascular front. The forskolin-treated Mrp4(-/-) mice showed an increased number of Ki67-positive and cleaved caspase 3-positive ECs, a significant decrease in the amount of pericyte coverage, and a reduced number of empty sleeves. In pups exposed to hyperoxia (75% oxygen) from P7 to P12, the Mrp4(-/-) mice showed a significant increase in the unvascularized retinal area. Mrp4(-/-) mice exhibited suppressed retinal vascular development in response to forskolin treatment. Thus, Mrp4 might have protective roles in retinal vascular development by regulating the intracellular cAMP level.

Oxidative and inflammatory signals in obesity-associated vascular abnormalities.

PubMed

Reho, John J; Rahmouni, Kamal

2017-07-15

Obesity is associated with increased cardiovascular morbidity and mortality in part due to vascular abnormalities such as endothelial dysfunction and arterial stiffening. The hypertension and other health complications that arise from these vascular defects increase the risk of heart diseases and stroke. Prooxidant and proinflammatory signaling pathways as well as adipocyte-derived factors have emerged as critical mediators of obesity-associated vascular abnormalities. Designing treatments aimed specifically at improving the vascular dysfunction caused by obesity may provide an effective therapeutic approach to prevent the cardiovascular sequelae associated with excessive adiposity. In this review, we discuss the recent evidence supporting the role of oxidative stress and cytokines and inflammatory signals within the vasculature as well as the impact of the surrounding perivascular adipose tissue (PVAT) on the regulation of vascular function and arterial stiffening in obesity. In particular, we focus on the highly plastic nature of the vasculature in response to altered oxidant and inflammatory signaling and highlight how weight management can be an effective therapeutic approach to reduce the oxidative stress and inflammatory signaling and improve vascular function. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Lysyl Oxidase Induces Vascular Oxidative Stress and Contributes to Arterial Stiffness and Abnormal Elastin Structure in Hypertension: Role of p38MAPK.

PubMed

Martínez-Revelles, Sonia; García-Redondo, Ana B; Avendaño, María S; Varona, Saray; Palao, Teresa; Orriols, Mar; Roque, Fernanda R; Fortuño, Ana; Touyz, Rhian M; Martínez-González, Jose; Salaices, Mercedes; Rodríguez, Cristina; Briones, Ana M

2017-09-01

Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces H 2 O 2 as a by-product. We addressed the interplay between LOX, oxidative stress, vessel stiffness, and elastin. Angiotensin II (Ang II)-infused hypertensive mice and spontaneously hypertensive rats (SHR) showed increased vascular LOX expression and stiffness and an abnormal elastin structure. Mice over-expressing LOX in vascular smooth muscle cells (TgLOX) exhibited similar mechanical and elastin alterations to those of hypertensive models. LOX inhibition with β-aminopropionitrile (BAPN) attenuated mechanical and elastin alterations in TgLOX mice, Ang II-infused mice, and SHR. Arteries from TgLOX mice, Ang II-infused mice, and/or SHR exhibited increased vascular H 2 O 2 and O 2 .- levels, NADPH oxidase activity, and/or mitochondrial dysfunction. BAPN prevented the higher oxidative stress in hypertensive models. Treatment of TgLOX and Ang II-infused mice and SHR with the mitochondrial-targeted superoxide dismutase mimetic mito-TEMPO, the antioxidant apocynin, or the H 2 O 2 scavenger polyethylene glycol-conjugated catalase (PEG-catalase) reduced oxidative stress, vascular stiffness, and elastin alterations. Vascular p38 mitogen-activated protein kinase (p38MAPK) activation was increased in Ang II-infused and TgLOX mice and this effect was prevented by BAPN, mito-TEMPO, or PEG-catalase. SB203580, the p38MAPK inhibitor, normalized vessel stiffness and elastin structure in TgLOX mice. We identify LOX as a novel source of vascular reactive oxygen species and a new pathway involved in vascular stiffness and elastin remodeling in hypertension. LOX up-regulation is associated with enhanced oxidative stress that promotes p38MAPK activation, elastin structural alterations, and vascular stiffness. This pathway contributes to vascular abnormalities in hypertension. Antioxid. Redox Signal. 27, 379-397.

Lysyl Oxidase Induces Vascular Oxidative Stress and Contributes to Arterial Stiffness and Abnormal Elastin Structure in Hypertension: Role of p38MAPK

PubMed Central

Martínez-Revelles, Sonia; García-Redondo, Ana B.; Avendaño, María S.; Varona, Saray; Palao, Teresa; Orriols, Mar; Roque, Fernanda R.; Fortuño, Ana; Touyz, Rhian M.; Martínez-González, Jose; Salaices, Mercedes

2017-01-01

Abstract Aims: Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces H2O2 as a by-product. We addressed the interplay between LOX, oxidative stress, vessel stiffness, and elastin. Results: Angiotensin II (Ang II)-infused hypertensive mice and spontaneously hypertensive rats (SHR) showed increased vascular LOX expression and stiffness and an abnormal elastin structure. Mice over-expressing LOX in vascular smooth muscle cells (TgLOX) exhibited similar mechanical and elastin alterations to those of hypertensive models. LOX inhibition with β-aminopropionitrile (BAPN) attenuated mechanical and elastin alterations in TgLOX mice, Ang II-infused mice, and SHR. Arteries from TgLOX mice, Ang II-infused mice, and/or SHR exhibited increased vascular H2O2 and O2.− levels, NADPH oxidase activity, and/or mitochondrial dysfunction. BAPN prevented the higher oxidative stress in hypertensive models. Treatment of TgLOX and Ang II-infused mice and SHR with the mitochondrial-targeted superoxide dismutase mimetic mito-TEMPO, the antioxidant apocynin, or the H2O2 scavenger polyethylene glycol-conjugated catalase (PEG-catalase) reduced oxidative stress, vascular stiffness, and elastin alterations. Vascular p38 mitogen-activated protein kinase (p38MAPK) activation was increased in Ang II-infused and TgLOX mice and this effect was prevented by BAPN, mito-TEMPO, or PEG-catalase. SB203580, the p38MAPK inhibitor, normalized vessel stiffness and elastin structure in TgLOX mice. Innovation: We identify LOX as a novel source of vascular reactive oxygen species and a new pathway involved in vascular stiffness and elastin remodeling in hypertension. Conclusion: LOX up-regulation is associated with enhanced oxidative stress that promotes p38MAPK activation, elastin structural alterations, and vascular stiffness. This pathway contributes to vascular abnormalities in hypertension. Antioxid. Redox Signal. 27, 379–397. PMID:28010122

Vascular Permeability and Remodelling Coincide with Inflammatory and Reparative Processes after Joint Bleeding in Factor VIII-Deficient Mice.

PubMed

Cooke, Esther J; Zhou, Jenny Y; Wyseure, Tine; Joshi, Shweta; Bhat, Vikas; Durden, Donald L; Mosnier, Laurent O; Drygalski, Annette von

2018-06-01

Vascular remodelling is a prominent feature of haemophilic arthropathy (HA) that may underlie re-bleeding, yet the nature of vascular changes and underlying mechanisms remain largely unknown. Here, we aimed to characterize synovial vascular remodelling and vessel integrity after haemarthrosis, as well as temporal changes in inflammatory and tissue-reparative pathways. Thirty acutely painful joints in patients with haemophilia (PWH) were imaged by musculoskeletal ultrasound with Power Doppler (MSKUS/PD) to detect vascular abnormalities and bloody effusions. Nineteen out of 30 painful joint episodes in PWH were associated with haemarthrosis, and abnormal vascular perfusion was unique to bleeding joints. A model of induced haemarthrosis in factor VIII (FVIII)-deficient mice was used for histological assessment of vascular remodelling (α-smooth muscle actin [αSMA] expression), and monitoring of in vivo vascular perfusion and permeability by MSKUS/PD and albumin extravasation, respectively. Inflammatory (M1) and reparative (M2) macrophage markers were quantified in murine synovium over a 10-week time course by real-time polymerase chain reaction. The abnormal vascular perfusion observed in PWH was recapitulated in FVIII-deficient mice after induced haemarthrosis. Neovascularization and increased vessel permeability were apparent 2 weeks post-bleed in FVIII-deficient mice, after a transient elevation of inflammatory macrophage M1 markers. These vascular changes subsided by week 4, while vascular remodelling, evidenced by architectural changes and pronounced αSMA expression, persisted alongside a reparative macrophage M2 response. In conclusion, haemarthrosis leads to transient inflammation coupled with neovascularization and associated vascular permeability, while subsequent tissue repair mechanisms coincide with vascular remodelling. Together, these vascular changes may promote re-bleeding and HA progression. Schattauer GmbH Stuttgart.

Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.

PubMed

Zhang, Lei; Kundu, Soumi; Feenstra, Tjerk; Li, Xiujuan; Jin, Chuan; Laaniste, Liisi; El Hassan, Tamador Elsir Abu; Ohlin, K Elisabet; Yu, Di; Olofsson, Tommie; Olsson, Anna-Karin; Pontén, Fredrik; Magnusson, Peetra U; Nilsson, Karin Forsberg; Essand, Magnus; Smits, Anja; Dieterich, Lothar C; Dimberg, Anna

2015-12-08

Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization. Copyright © 2015, American Association for the Advancement of Science.

EphrinA1 Inhibits Vascular Endothelial Growth Factor-Induced Intracellular Signaling and Suppresses Retinal Neovascularization and Blood-Retinal Barrier Breakdown

PubMed Central

Ojima, Tomonari; Takagi, Hitoshi; Suzuma, Kiyoshi; Oh, Hideyasu; Suzuma, Izumi; Ohashi, Hirokazu; Watanabe, Daisuke; Suganami, Eri; Murakami, Tomoaki; Kurimoto, Masafumi; Honda, Yoshihito; Yoshimura, Nagahisa

2006-01-01

The Eph receptor/ephrin system is a recently discovered regulator of vascular development during embryogenesis. Activation of EphA2, one of the Eph receptors, reportedly suppresses cell proliferation and adhesion in a wide range of cell types, including vascular endothelial cells. Vascular endothelial growth factor (VEGF) plays a primary role in both pathological angiogenesis and abnormal vascular leakage in diabetic retinopathy. In the study described herein, we demonstrated that EphA2 stimulation by ephrinA1 in cultured bovine retinal endothelial cells inhibits VEGF-induced VEGFR2 receptor phosphorylation and its downstream signaling cascades, including PKC (protein kinase C)-ERK (extracellular signal-regulated kinase) 1/2 and Akt. This inhibition resulted in the reduction of VEGF-induced angiogenic cell activity, including migration, tube formation, and cellular proliferation. These inhibitory effects were further confirmed in animal models. Intraocular injection of ephrinA1 suppressed ischemic retinal neovascularization in a dose-dependent manner in a mouse model. At a dose of 125 ng/eye, the inhibition was 36.0 ± 14.9% (P < 0.001). EphrinA1 also inhibited VEGF-induced retinal vascular permeability in a rat model by 46.0 ± 10.0% (P < 0.05). These findings suggest a novel therapeutic potential for EphA2/ephrinA1 in the treatment of neovascularization and vasopermeability abnormalities in diabetic retinopathy. PMID:16400034

Effects of heavy ion radiation on the brain vascular system and embryonic development

NASA Technical Reports Server (NTRS)

Yang, T. C.; Tobias, C. A.

1984-01-01

The present investigation is concerned with the effects of heavy-ion radiation on the vascular system and the embryonic development, taking into account the results of experiments with neonatal rats and mouse embryos. It is found that heavy ions can be highly effective in producing brain hemorrhages and in causing body deformities. Attention is given to aspects of methodology, the induction of brain hemorrhages by X-rays and heavy ions, and the effect of iron particles on embryonic development. Reported results suggest that high linear energy transfer (LET) heavy ions can be very effective in producing developmental abnormalities.

Common Leg Injuries of Long-Distance Runners

PubMed Central

Gallo, Robert A.; Plakke, Michael; Silvis, Matthew L.

2012-01-01

Context Long-distance running (greater than 3000 m) is often recommended to maintain a healthy lifestyle. Running injury rates increase significantly when weekly mileage extends beyond 40 miles cumulatively. With the development of running analysis and other diagnostic tests, injuries to the leg secondary to bone, musculotendinous, and vascular causes can be diagnosed and successfully managed. Evidence Acquisition Searches used the terms running, injuries, lower extremity, leg, medial tibial stress syndrome, compartment syndrome, stress fractures, popliteal artery entrapment, gastrocnemius soleus tears, and Achilles tendinopathy. Sources included Medline, Google Scholar, and Ovid from 1970 through January 2012. Results Tibial stress fractures and medial tibial stress syndrome can sometimes be prevented and/or treated by correcting biomechanical abnormalities. Exertional compartment syndrome and popliteal artery entrapment syndrome are caused by anatomic abnormalities and are difficult to treat without surgical correction. Conclusion Leg pain due to bone, musculotendinous, and vascular causes is common among long-distance runners. Knowledge of the underlying biomechanical and/or anatomic abnormality is necessary to successfully treat these conditions. PMID:24179587

VASCULAR ABNORMALITIES IN DIABETIC RETINOPATHY ASSESSED WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY WIDEFIELD IMAGING.

PubMed

Schaal, Karen B; Munk, Marion R; Wyssmueller, Iris; Berger, Lieselotte E; Zinkernagel, Martin S; Wolf, Sebastian

2017-11-10

To detect vascular abnormalities in diabetic retinopathy using swept-source optical coherence tomography angiography (SS-OCTA) widefield images, and to compare the findings with color fundus photographs (CFPs) using Early Treatment Diabetic Retinopathy Study severity grading. 3 mm × 3 mm and 12 mm × 12 mm scans were acquired to cover 70° to 80° of the posterior pole using a 100-kHz SS-OCTA instrument. Two masked graders assessed the presence of vascular abnormalities on SS-OCTA and the Early Treatment Diabetic Retinopathy Study level on CFP. The grading results were then compared. A total of 120 diabetic eyes (60 patients) were imaged with the SS-OCTA instrument. Cohort 1 (91 eyes; SS-OCTA grading only) showed microaneurysms in 91% (n = 83), intraretinal microvascular abnormalities in 79% (n = 72), and neovascularization in 21% (n = 19) of cases. Cohort 2 (52 eyes; CFP grading compared with SS-OCTA) showed microaneurysms on CFP in 90% (n = 47) and on SS-OCTA in 96% (n = 50) of cases. Agreement in intraretinal microvascular abnormality detection was fair (k = 0.2). Swept-source optical coherence tomography angiography detected 50% of intraretinal microvascular abnormality cases (n = 26), which were missed on CFP. Agreement in detecting neovascularization was moderate (k = 0.5). Agreement in detection of diabetic retinopathy features on CFP and SS-OCTA varies depending on the vascular changes examined. Swept-source optical coherence tomography angiography shows a higher detection rate of intraretinal microvascular abnormalities (P = 0.039), compared with Early Treatment Diabetic Retinopathy Study grading.

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces apoptotic cell death and cytochrome P4501A expression in developing Fundulus heteroclitus embryos

USGS Publications Warehouse

Toomey, B.H.; Bello, S.; Hahn, M.E.; Cantrell, S.; Wright, P.; Tillitt, D.E.; Di Giulio, R.T.

2001-01-01

Fundulus heteroclitus embryos were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early development using nanoinjection or water bath exposure. TCDD caused developmental abnormalities that included hemorrhaging, loss of vascular integrity, edema, stunted development and death. The LC50 and LD50 of TCDD for Fundulus embryos were ???19.7??9.5 pg TCDD/??l (water bath) and 0.25??0.09 ng TCDD/g embryo (nanoinjection). To identify a possible cause for these developmental abnormalities we analyzed the effects of TCDD on apoptotic cell death and cytochrome P4501A (CYP1A) expression in the embryos. TCDD exposure increased apoptotic cell death in several tissues including brain, eye, gill, kidney, tail, intestine, heart, and vascular tissue. CYP1A expression was also increased in the TCDD-exposed embryos predominantly in liver, kidney, gill, heart, intestine, and in vascular tissues throughout the embryo. There was co-occurrence of TCDD-induced apoptosis and CYP1A expression in some, but not all, cell types. In addition the dose response relationships for apoptosis and mortality were similar, while CYP1A expression appeared more sensitive to TCDD induction. Copyright ?? 2001 Elsevier Science B.V.

Vascular alterations in PDAPP mice after anti-Aβ immunotherapy: Implications for amyloid-related imaging abnormalities.

PubMed

Zago, Wagner; Schroeter, Sally; Guido, Teresa; Khan, Karen; Seubert, Peter; Yednock, Ted; Schenk, Dale; Gregg, Keith M; Games, Dora; Bard, Frédérique; Kinney, Gene G

2013-10-01

Clinical studies of β-amyloid (Aβ) immunotherapy in Alzheimer's disease (AD) patients have demonstrated reduction of central Aβ plaque by positron emission tomography (PET) imaging and the appearance of amyloid-related imaging abnormalities (ARIA). To better understand the relationship between ARIA and the pathophysiology of AD, we undertook a series of studies in PDAPP mice evaluating vascular alterations in the context of central Aβ pathology and after anti-Aβ immunotherapy. We analyzed PDAPP mice treated with either 3 mg/kg/week of 3D6, the murine form of bapineuzumab, or isotype control antibodies for periods ranging from 1 to 36 weeks and evaluated the vascular alterations in the context of Aβ pathology and after anti-Aβ immunotherapy. The number of mice in each treatment group ranged from 26 to 39 and a total of 345 animals were analyzed. The central vasculature displayed morphological abnormalities associated with vascular Aβ deposits. Treatment with 3D6 antibody induced clearance of vascular Aβ that was spatially and temporally associated with a transient increase in microhemorrhage and in capillary Aβ deposition. Microhemorrhage resolved over a time period that was associated with a recovery of vascular morphology and a decrease in capillary Aβ accumulation. These data suggest that vascular leakage events, such as microhemorrhage, may be related to the removal of vascular Aβ. With continued treatment, this initial susceptibility period is followed by restoration of vascular morphology and reduced vulnerability to further vascular leakage events. The data collectively suggested a vascular amyloid clearance model of ARIA, which accounts for the currently known risk factors for the incidence of ARIA in clinical studies. Copyright © 2013. Published by Elsevier Inc.

Diabetes mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications.

PubMed

Domingueti, Caroline Pereira; Dusse, Luci Maria Sant'Ana; Carvalho, Maria das Graças; de Sousa, Lirlândia Pires; Gomes, Karina Braga; Fernandes, Ana Paula

2016-01-01

Vascular complications are the leading cause of morbidity and mortality among patients with type 1 and type 2 diabetes mellitus. These vascular abnormalities result of a chronic hyperglycemic state, which leads to an increase in oxidative stress and inflammatory responses. This review addresses the relationships among endothelial dysfunction, hypercoagulability and inflammation and their biomarkers in the development of vascular complications in type 1 and type 2 diabetes. Inflammation, endothelial dysfunction, and hypercoagulability are correlated to each other, playing an important role in the development of vascular complications in diabetic patients. Moreover, it has been observed that several endothelial, inflammatory and pro-coagulant biomarkers, such as VWF, IL-6, TNF-α, D-dimer and PAI-1, are increased in diabetic patients who have microvascular and macrovascular complications, including nephropathy or cardiovascular disease. It is promising the clinical and laboratory use of endothelial, inflammatory and pro-coagulant biomarkers for predicting the risk of cardiovascular and renal complications in diabetic patients and for monitoring these patients. Copyright © 2016 Elsevier Inc. All rights reserved.

[Cutaneous hemangiomas and vascular malformations and associated pathology (Pascual-Castroviejo type II syndrome). Study of 41 patients].

PubMed

Pascual-Castroviejo, I; Pascual-Pascual, S I; Velázquez-Fragua, R; García, L; López-Gutiérrez, J C; Viaño-López, J; Martínez, V; Palencia, R

To describe the clinical, diagnostic and therapeutic features of this angiomatous neurocutaneous syndrome, which is the most frequent one, and to report a personal series of 41 patients. Forty one patients--31 females and 10 males--were studied during childhood and then, several patients were followed during many years, which allowed us to learn about the evolution of the abnormalities. The cutaneous lesions were classified as hemangiomas in 30 patients (73%) and as vascular malformations in 11 patients (27%). A cerebellar anomaly (unilateral hemispheric hypoplasia and Dandy-Walker malformation) was seen in 13 patients (31.5%) cerebral cortical dysplasia in 4 patients (10%), aortic arch coarctation in 6 patients (15%), and congenital cardiopathy in 5 patients (12%). The most frequent abnormalities were intracranial and/or extracranial vascular malformations. Persistence of the trigeminal artery was observed in 7 patients (17%), absence or severe hypoplasia of an internal carotid artery in 13 patients (32%), absence of a vertebral artery in 7 patients (17%), hypoplasia of intracranial arteries in 6 patients (15%) and aneurysmal enlargement of carotid or vertebral arteries in 5 patients (12%). Also were observed 4 patients (10%) with intracranial hemangioma, 2 (5%) with hemangioma in mediastinum, and 3 (7.5%) with intestinal hemangioma, all of which disappeared during the first years of life. Aneurysmal enlargement of the carotid and vertebral arteries and intracranial branches also disappeared after a process of progressive narrowing of the arterial lumen that caused complete obstruction of these arteries. At the same time the cutaneous hemangioma regressed. During this process, collateral vascularization through branches of the external carotid artery and of the non-affected branches of the contralateral intracranial arteries developed. This neurocutaneous syndrome is the most frequent one and it is associated with several types of vascular and non-vascular abnormalities which can involve any organ of the body. Internal and external hemangiomas and hemangiomatous lesions progress and tend to regress concomitantly.

New insights into insulin action and resistance in the vasculature

PubMed Central

Manrique, Camila; Lastra, Guido; Sowers, James R.

2014-01-01

Two-thirds of adults in the United States are overweight or obese, and another 26 million have type 2 diabetes. Decreased insulin sensitivity in cardiovascular tissue is an underlying abnormality in these individuals. Insulin metabolic signaling increases endothelial cell nitric oxide production. Impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation. In overweight and obese persons, as well as in those with hypertension, systemic and vascular insulin resistance often occurs in conjunction with activation of the cardiovascular tissue renin–angiotensin–aldosterone system (RAAS). Activated angiotensin II type 1 receptor and mineralocorticoid receptor signaling promote the development of vascular insulin resistance and impaired endothelial nitric oxide–mediated relaxation. Research in this area has implicated excessive serine phosphorylation and proteasomal degradation of the docking protein insulin receptor substrate and enhanced signaling through hybrid insulin/insulin-like growth factor (IGF-1) receptor as important mechanisms underlying RAAS impediment of downstream vascular insulin metabolic signaling. This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation. PMID:24650277

Tissue-specific insulin signaling, metabolic syndrome and cardiovascular disease

PubMed Central

Rask-Madsen, Christian; Kahn, C. Ronald

2012-01-01

Summary Impaired insulin signaling is central to the development of the metabolic syndrome and can promote cardiovascular disease indirectly through development of abnormal glucose and lipid metabolism, hypertension and a proinflammatory state. However, insulin action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications of diabetes. Recent advances in our understanding of the complex pathophysiology of insulin’s effects on vascular tissues offer new opportunities for preventing these cardiovascular disorders. PMID:22895666

Decidualized Human Endometrial Stromal Cells Mediate Hemostasis, Angiogenesis, and Abnormal Uterine Bleeding

PubMed Central

Lockwood, Charles J.; Krikun, Graciela; Hickey, Martha; Huang, S. Joseph; Schatz, Frederick

2011-01-01

Factor VII binds trans-membrane tissue factor to initiate hemostasis by forming thrombin. Tissue factor expression is enhanced in decidualized human endometrial stromal cells during the luteal phase. Long-term progestin only contraceptives elicit: 1) abnormal uterine bleeding from fragile vessels at focal bleeding sites, 2) paradoxically high tissue factor expression at bleeding sites; 3) reduced endometrial blood flow promoting local hypoxia and enhancing reactive oxygen species levels; and 4) aberrant angiogenesis reflecting increased stromal cell-expressed vascular endothelial growth factor, decreased Angiopoietin-1 and increased endothelial cell-expressed Angiopoietin-2. Aberrantly high local vascular permeability enhances circulating factor VII to decidualized stromal cell-expressed tissue factor to generate excess thrombin. Hypoxia-thrombin interactions augment expression of vascular endothelial growth factor and interleukin-8 by stromal cells. Thrombin, vascular endothelial growth factor and interlerukin-8 synergis-tically augment angiogenesis in a milieu of reactive oxygen species-induced endothelial cell activation. The resulting enhanced vessel fragility promotes abnormal uterine bleeding. PMID:19208784

Interactions between mural cells and endothelial cells stabilize the developing zebrafish dorsal aorta

PubMed Central

Stratman, Amber N.; Pezoa, Sofia A.; Farrelly, Olivia M.; Castranova, Daniel; Dye, Louis E.; Butler, Matthew G.; Sidik, Harwin; Talbot, William S.

2017-01-01

Mural cells (vascular smooth muscle cells and pericytes) play an essential role in the development of the vasculature, promoting vascular quiescence and long-term vessel stabilization through their interactions with endothelial cells. However, the mechanistic details of how mural cells stabilize vessels are not fully understood. We have examined the emergence and functional role of mural cells investing the dorsal aorta during early development using the zebrafish. Consistent with previous literature, our data suggest that cells ensheathing the dorsal aorta emerge from a sub-population of cells in the adjacent sclerotome. Inhibition of mural cell recruitment to the dorsal aorta through disruption of pdgfr signaling leads to a reduced vascular basement membrane, which in turn results in enhanced dorsal aorta vessel elasticity and failure to restrict aortic diameter. Our results provide direct in vivo evidence for a functional role for mural cells in patterning and stabilization of the early vasculature through production and maintenance of the vascular basement membrane to prevent abnormal aortic expansion and elasticity. PMID:27913637

Oxidative injury of the pulmonary circulation in the perinatal period: Short- and long-term consequences for the human cardiopulmonary system

PubMed Central

de Wijs-Meijler, Daphne P.; Duncker, Dirk J.; Tibboel, Dick; Schermuly, Ralph T.; Weissmann, Norbert; Merkus, Daphne; Reiss, Irwin K.M.

2017-01-01

Development of the pulmonary circulation is a complex process with a spatial pattern that is tightly controlled. This process is vulnerable for disruption by various events in the prenatal and early postnatal periods. Disruption of normal pulmonary vascular development leads to abnormal structure and function of the lung vasculature, causing neonatal pulmonary vascular diseases. Premature babies are especially at risk of the development of these diseases, including persistent pulmonary hypertension and bronchopulmonary dysplasia. Reactive oxygen species play a key role in the pathogenesis of neonatal pulmonary vascular diseases and can be caused by hyperoxia, mechanical ventilation, hypoxia, and inflammation. Besides the well-established short-term consequences, exposure of the developing lung to injurious stimuli in the perinatal period, including oxidative stress, may also contribute to the development of pulmonary vascular diseases later in life, through so-called “fetal or perinatal programming.” Because of these long-term consequences, it is important to develop a follow-up program tailored to adolescent survivors of neonatal pulmonary vascular diseases, aimed at early detection of adult pulmonary vascular diseases, and thereby opening the possibility of early intervention and interfering with disease progression. This review focuses on pathophysiologic events in the perinatal period that have been shown to disrupt human normal pulmonary vascular development, leading to neonatal pulmonary vascular diseases that can extend even into adulthood. This knowledge may be particularly important for ex-premature adults who are at risk of the long-term consequences of pulmonary vascular diseases, thereby contributing disproportionately to the burden of adult cardiovascular disease in the future. PMID:28680565

Extent of BOLD Vascular Dysregulation Is Greater in Diffuse Gliomas without Isocitrate Dehydrogenase 1 R132H Mutation.

PubMed

Englander, Zachary K; Horenstein, Craig I; Bowden, Stephen G; Chow, Daniel S; Otten, Marc L; Lignelli, Angela; Bruce, Jeffrey N; Canoll, Peter; Grinband, Jack

2018-06-01

Purpose To determine the effect that R132H mutation status of diffuse glioma has on extent of vascular dysregulation and extent of residual blood oxygen level-dependent (BOLD) abnormality after surgical resection. Materials and Methods This study was an institutional review board-approved retrospective analysis of an institutional database of patients, and informed consent was waived. From 2010 to 2017, 39 treatment-naïve patients with diffuse glioma underwent preoperative echo-planar imaging and BOLD functional magnetic resonance imaging. BOLD vascular dysregulation maps were made by identifying voxels with time series similar to tumor and dissimilar to healthy brain. The spatial overlap between tumor and vascular dysregulation was characterized by using the Dice coefficient, and areas of BOLD abnormality outside the tumor margins were quantified as BOLD-only fraction (BOF). Linear regression was used to assess effects of R132H status on the Dice coefficient, BOF, and residual BOLD abnormality after surgical resection. Results When compared with R132H wild-type (R132H-) gliomas, R132H-mutated (R132H+) gliomas showed greater spatial overlap between BOLD abnormality and tumor (mean Dice coefficient, 0.659 ± 0.02 [standard error] for R132H+ and 0.327 ± 0.04 for R132H-; P < .001), less BOLD abnormality beyond the tumor margin (mean BOF, 0.255 ± 0.03 for R132H+ and 0.728 ± 0.04 for R132H-; P < .001), and less postoperative BOLD abnormality (residual fraction, 0.046 ± 0.0047 for R132H+ and 0.397 ± 0.045 for R132H-; P < .001). Receiver operating characteristic curve analysis showed high sensitivity and specificity in the discrimination of R132H+ tumors from R132H- tumors with calculation of both Dice coefficient and BOF (area under the receiver operating characteristic curve, 0.967 and 0.977, respectively). Conclusion R132H mutation status is an important variable affecting the extent of tumor-associated vascular dysregulation and the residual vascular dysregulation after surgical resection. © RSNA, 2018 Online supplemental material is available for this article.

Fluid shear stress as a regulator of gene expression in vascular cells: possible correlations with diabetic abnormalities

NASA Technical Reports Server (NTRS)

Papadaki, M.; Eskin, S. G.; Ruef, J.; Runge, M. S.; McIntire, L. V.

1999-01-01

Diabetes mellitus is associated with increased frequency, severity and more rapid progression of cardiovascular diseases. Metabolic perturbations from hyperglycemia result in disturbed endothelium-dependent relaxation, activation of coagulation pathways, depressed fibrinolysis, and other abnormalities in vascular homeostasis. Atherosclerosis is localized mainly at areas of geometric irregularity at which blood vessels branch, curve and change diameter, and where blood is subjected to sudden changes in velocity and/or direction of flow. Shear stress resulting from blood flow is a well known modulator of vascular cell function. This paper presents what is currently known regarding the molecular mechanisms responsible for signal transduction and gene regulation in vascular cells exposed to shear stress. Considering the importance of the hemodynamic environment of vascular cells might be vital to increasing our understanding of diabetes.

Lack of sensitivity of measurements of Vd/Vt at rest and during exercise in detection of hemodynamically significant pulmonary vascular abnormalities in collagen vascular disease.

PubMed

Mohsenifar, Z; Tashkin, D P; Levy, S E; Bjerke, R D; Clements, P J; Furst, D

1981-05-01

Wasted ventilation fraction (Vd/Vt) normally declines substantially during exercise in persons without lung disease. Failure of Vd/Vt to decrease during exercise has been reported to be one of the earliest abnormalities in patients with dyspnea caused by pulmonary vaso-occlusive disease, suggesting that measurement of Vd/Vt at rest and during exercise are useful in the diagnosis of pulmonary vascular disorders. We studied pulmonary hemodynamic and Vd/Vt responses to exercise in 11 patients in the supine position with suspected pulmonary vascular involvement caused by progressive systemic sclerosis, systemic lupus erythematosus, or recurrent pulmonary emboli, 10 of whom had dyspnea at rest and/or on exertion. In contrast to previous reports of no change or an increase in Vd/Vt during exercise in patients with pulmonary vascular disease, we found Vd/Vt to decrease significantly during exercise in 8 of 9 patients in whom mean pulmonary artery pressures were abnormally elevated at rest and/or during exercise. Our findings suggest that normal responses of Vd/Vt to exercise do not exclude hemodynamically significant pulmonary vaso-occlusive disease.

Using impedance cardiography to detect asymptomatic cardiovascular disease in prehypertensive adults with risk factors.

PubMed

DeMarzo, Arthur P

2013-06-01

Early detection of cardiovascular disease (CVD) in prehypertension could initiate appropriate treatment and prevent progression. Impedance cardiography (ICG) is a noninvasive technology that can be used to assess cardiovascular function. This study used ICG waveform analysis with postural change to detect CVD in asymptomatic prehypertensive adults over 40 years of age with no history of CVD and at least 2 cardiovascular risk factors: cigarette smoking, poor diet, physical inactivity, central obesity, family history of premature CVD, elevated blood glucose, and dyslipidemia. A study group of 25 apparently healthy adults was tested by ICG in standing and supine positions. Criteria for an age-matched control group of 16 healthy subjects included an active lifestyle, no risk factor, and no history of CVD. In addition to hemodynamic measurements of systemic vascular resistance (SVR) and cardiac index (CI), ICG used SVR to assess vascular resistive load, an index of arterial compliance and a widening of the systolic waveform to assess vascular pulsatile load, and waveform analysis and measured wave amplitude to detect ventricular dysfunction. All subjects in the study group had some abnormal ICG data, with an average of 2.9 ± 1.5 abnormalities per person. ICG indicated that 24 (96%) had elevated vascular load, 13 (52%) had some type of ventricular dysfunction, and 12 (48%) had abnormal hemodynamics. For the control group, ICG showed none (0%) with elevated vascular load, none (0%) with ventricular dysfunction, and 7 (44%) with high CI. Prehypertensives over 40 years of age with multiple risk factors have different cardiovascular abnormalities. This ICG test could be used as part of a prevention program for early detection of CVD. An abnormal ICG test could expedite the initiation of customized treatment that targets the subclinical CVD.

Role of splenic reservoir monocytes in pulmonary vascular monocyte accumulation in experimental hepatopulmonary syndrome

PubMed Central

Wu, Wei; Zhang, Junlan; Yang, Wenli; Hu, Bingqian

2016-01-01

Abstract Background and Aim Pulmonary monocyte infiltration plays a significant role in the development of angiogenesis in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Hepatic monocytes are also increased after CBDL, but the origins remain unclear. Splenic reservoir monocytes have been identified as a major source of monocytes that accumulate in injured tissues. Whether splenic monocytes contribute to monocyte alterations after CBDL is unknown. This study evaluates monocyte distributions and assesses effects of splenectomy on monocyte levels and pulmonary vascular and hepatic abnormalities in experimental HPS. Methods Splenectomy was performed in CBDL animals. Monocyte levels in different tissues and circulation were assessed with CD68. Pulmonary alterations of HPS were evaluated with vascular endothelial growth factor‐A (VEGF‐A) levels, angiogenesis, and alveolar–arterial oxygen gradient (AaPO2). Liver abnormalities were evaluated with fibrosis (Sirius red), bile duct proliferation (CK‐19), and enzymatic changes. Results Monocyte levels increased in the lung and liver after CBDL and were accompanied by elevated circulating monocyte numbers. Splenectomy significantly decreased monocyte accumulation, VEGF‐A levels, and angiogenesis in CBDL animal lung and improved AaPO2 levels. In contrast, hepatic monocyte levels, fibrosis, and functional abnormalities were further exacerbated by spleen removal. Conclusions Splenic reservoir monocytes are a major source for lung monocyte accumulation after CBDL, and spleen removal attenuates the development of experimental HPS. Liver monocytes may have different origins, and accumulation is exacerbated after depletion of splenic reservoir monocytes. Tissue specific monocyte alterations, influenced by the spleen reservoir, have a significant impact on pulmonary complications of liver disease. PMID:27029414

MR Imaging of the Diabetic Foot.

PubMed

McCarthy, Eoghan; Morrison, William B; Zoga, Adam C

2017-02-01

Abnormalities of the peripheral nervous, vascular, and immune systems contribute to the development of numerous foot and ankle pathologies in the diabetic population. Although radiographs remain the most practical first-line imaging tool, magnetic resonance (MR) is the tertiary imaging modality of choice, allowing for optimal assessment of bone and soft tissue abnormalities. MR allows for the accurate distinction between osteomyelitis/septic arthritis and neuropathic osteoarthropathy. Furthermore, it provides an excellent presurgical anatomic road map of involved tissues and devitalized skin to ensure successful limited amputations when required. Signal abnormality in the postoperative foot aids in the diagnosis of recurrent infection. Copyright © 2016 Elsevier Inc. All rights reserved.

Using impedance cardiography with postural change to stratify patients with hypertension.

PubMed

DeMarzo, Arthur P

2011-06-01

Early detection of cardiovascular disease in patients with hypertension could initiate appropriate treatment to control blood pressure and prevent the progression of cardiovascular disease. The goal of this study was to show how impedance cardiography waveform analysis with postural change can be used to detect subclinical cardiovascular disease in patients with high blood pressure. Patients with high blood pressure had impedance cardiography data obtained in two positions, standing upright and supine. In 50 adults, impedance cardiography indicated that all patients had abnormal data, with 44 (88%) having multiple abnormalities. Impedance cardiography showed 32 (64%) had ventricular dysfunction, 48 (96%) had vascular load abnormalities, 34 (68%) had hemodynamic abnormalities, 2 (4%) had hypovolemia, and 3 (6%) had hypervolemia. Hypertensive patients have diverse cardiovascular abnormalities that can be quantified by impedance cardiography. By stratifying patients with ventricular, vascular, and hemodynamic abnormalities, treatment could be customized based on the abnormal underlying mechanisms with the potential to rapidly control blood pressure, prevent progression of cardiovascular disease, and possibly reverse remodeling.

CAPILLARY NETWORK ANOMALIES IN BRANCH RETINAL VEIN OCCLUSION ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PubMed

Rispoli, Marco; Savastano, Maria Cristina; Lumbroso, Bruno

2015-11-01

To analyze the foveal microvasculature features in eyes with branch retinal vein occlusion (BRVO) using optical coherence tomography angiography based on split spectrum amplitude decorrelation angiography technology. A total of 10 BRVO eyes (mean age 64.2 ± 8.02 range between 52 years and 76 years) were evaluated by optical coherence tomography angiography (XR-Avanti; Optovue). The macular angiography scan protocol covered a 3 mm × 3 mm area. The focus of angiography analysis were two retinal layers: superficial vascular network and deep vascular network. The following vascular morphological congestion parameters were assessed in the vein occlusion area in both the superficial and deep networks: foveal avascular zone enlargement, capillary non-perfusion occurrence, microvascular abnormalities appearance, and vascular congestion signs. Image analyses were performed by 2 masked observers and interobserver agreement of image analyses was 0.90 (κ = 0.225, P < 0.01). In both superficial and deep network of BRVO, a decrease in capillary density with foveal avascular zone enlargement, capillary non-perfusion occurrence, and microvascular abnormalities appearance was observed (P < 0.01). The deep network showed the main vascular congestion at the boundary between healthy and nonperfused retina. Optical coherence tomography angiography in BRVO allows to detect foveal avascular zone enlargement, capillary nonperfusion, microvascular abnormalities, and vascular congestion signs both in the superficial and deep capillary network in all eyes. Optical coherence tomography angiography technology is a potential clinical tool for BRVO diagnosis and follow-up, providing stratigraphic vascular details that have not been previously observed by standard fluorescein angiography. The normal retinal vascular nets and areas of nonperfusion and congestion can be identified at various retinal levels. Optical coherence tomography angiography provides noninvasive images of the retinal capillaries and vascular networks.

Comprehensive automatic assessment of retinal vascular abnormalities for computer-assisted retinopathy grading.

PubMed

Joshi, Vinayak; Agurto, Carla; VanNess, Richard; Nemeth, Sheila; Soliz, Peter; Barriga, Simon

2014-01-01

One of the most important signs of systemic disease that presents on the retina is vascular abnormalities such as in hypertensive retinopathy. Manual analysis of fundus images by human readers is qualitative and lacks in accuracy, consistency and repeatability. Present semi-automatic methods for vascular evaluation are reported to increase accuracy and reduce reader variability, but require extensive reader interaction; thus limiting the software-aided efficiency. Automation thus holds a twofold promise. First, decrease variability while increasing accuracy, and second, increasing the efficiency. In this paper we propose fully automated software as a second reader system for comprehensive assessment of retinal vasculature; which aids the readers in the quantitative characterization of vessel abnormalities in fundus images. This system provides the reader with objective measures of vascular morphology such as tortuosity, branching angles, as well as highlights of areas with abnormalities such as artery-venous nicking, copper and silver wiring, and retinal emboli; in order for the reader to make a final screening decision. To test the efficacy of our system, we evaluated the change in performance of a newly certified retinal reader when grading a set of 40 color fundus images with and without the assistance of the software. The results demonstrated an improvement in reader's performance with the software assistance, in terms of accuracy of detection of vessel abnormalities, determination of retinopathy, and reading time. This system enables the reader in making computer-assisted vasculature assessment with high accuracy and consistency, at a reduced reading time.

Coexistence of pheochromocytoma with uncommon vascular lesions

PubMed Central

Kota, Sunil Kumar; Kota, Siva Krishna; Meher, Lalit Kumar; Jammula, Sruti; Panda, Sandip; Modi, Kirtikumar D.

2012-01-01

Background: Pheochromocytoma/paragangliomas have been described to be associated with rare vascular abnormalities like renal artery stenosis. Coexistence of physiologically significant renal artery lesions is a compounding factor that alters management and prognosis of pheochromocytoma patients. Apart from individual case reports, data on such association in Indian population is not available. The aim of this study is to find the nature and prevalence of associated vascular abnormalities. Materials and Methods: From 1990 to 2010, a total of 50 patients were diagnosed with pheochromocytoma/paragangliomas. Hospital charts of these patients were reviewed retrospectively to identify those with unusual vascular abnormalities. Available literature was also reviewed. Results: Of the 50 patients with pheochromocytoma, 7 (14%) had coexisting vascular lesions including renal artery stenosis in 4, aortoarteritis in 1, aortic aneurysm in 1 and inferior vena cava thrombosis in 1. Pheochromocytoma was adrenal in 42 and extra adrenal in 8. Laparoscopic adrenalectomy was done in the patients. One patient with renal artery stenosis due to intimal fibrosis was subjected to percutaneous balloon angioplasty; the other three improved after adrenalectomy and lysis of fibrous adhesive bands. The patient with aortoarteritos was treated with oral steroids. Inferior vena cava thrombosis was reversed with anticoagulants. The patient with abdominal aortic aneurysm was advised for annual follow-up on account of its size of 4.5 cm and asymptomatic presentation. Conclusion: There are multiple mechanisms that can lead to renal artery stenosis and other vascular abnormalities in a case of pheochromocytoma. A high index of suspicion is necessary to enable both entities to be diagnosed preoperatively and allow proper planning of surgical therapy. Incomplete diagnosis may lead to persistent hypertension postoperatively in a case of associated renal artery stenosis. PMID:23226643

Dysphagia lusorium in elderly: A case report

PubMed Central

Kantarceken, Bulent; Bulbuloglu, Ertan; Yuksel, Murvet; Cetinkaya, Ali

2004-01-01

AIM: Late unset of dysphagia due to vascular abnormalities is a rare condition. We aimed to present a case of right subclavian artery abnormalities caused dysphagia in the elderly. METHODS: A 68-year-old female was admitted with dysphagia seven months ago. Upper endoscopic procedures and routine examinations could not demonstrate any etiology. Multislice computed thorax tomography was performed for probable extra- esophagial lesions. RESULTS: Multislice computed thorax tomography showed right subclavian artery abnormality and esophagial compression with this aberrant artery. CONCLUSION: Causes of dysphagia in the elderly are commonly malignancies, strictures and/or motility disorders. If routine examinations and endoscopic procedures fail to show any etiology, rare vascular abnormalities can be considered in such patients. Multislice computed tomography is a usefull choice in such conditions. PMID:15285045

Small vessel disease, neurovascular regulation and cognitive impairment: post-mortem studies reveal a complex relationship, still poorly understood.

PubMed

Love, Seth; Miners, J Scott

2017-07-15

The contribution of vascular disease to cognitive impairment is under-recognized and the pathogenesis is poorly understood. This information gap has multiple causes, including a lack of post-mortem validation of clinical diagnoses of vascular cognitive impairment (VCI) or vascular dementia (VaD), the exclusion of cases with concomitant neurodegenerative disease when diagnosing VCI/VaD, and a lack of standardization of neuropathological assessment protocols for vascular disease. Other contributors include a focus on end-stage destructive lesions to the exclusion of more subtle types of diffuse brain injury, on structural abnormalities of arteries and arterioles to the exclusion of non-structural abnormalities and capillary damage, and the use of post-mortem sampling strategies that are biased towards the identification of neurodegenerative pathologies. Recent studies have demonstrated the value of detailed neuropathology in characterizing vascular contributions to cognitive impairment (e.g. in diabetes), and highlight the importance of diffuse white matter changes, capillary damage and vasoregulatory abnormalities in VCI/VaD. The use of standardized, evidence-based post-mortem assessment protocols and the inclusion of biochemical as well as morphological methods in neuropathological studies should improve the accuracy of determination of the contribution of vascular disease to cognitive impairment and clarify the relative contribution of different pathogenic processes to the tissue damage. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Pathogenesis of arteriovenous malformations in the absence of endoglin.

PubMed

Mahmoud, Marwa; Allinson, Kathleen R; Zhai, Zhenhua; Oakenfull, Rachael; Ghandi, Pranita; Adams, Ralf H; Fruttiger, Marcus; Arthur, Helen M

2010-04-30

Arteriovenous malformations (AVMs) result in anomalous direct blood flow between arteries and veins, bypassing the normal capillary bed. Depending on size and location, AVMs may lead to severe clinical effects including systemic cyanosis (pulmonary AVMs), hemorrhagic stroke (cerebral AVMs) and high output cardiac failure (hepatic AVMs). The factors leading to AVM formation are poorly understood, but patients with the familial disease hereditary hemorrhagic telangiectasia (HHT) develop AVMs at high frequency. As most HHT patients have mutations in ENG (endoglin) or ACVRL1 (activin receptor-like kinase 1), a better understanding of the role of these genes in vascular development is likely to reveal the etiology of AVM formation. Using a mouse with a conditional mutation in the Eng gene, we investigated the sequence of abnormal cellular events occurring during development of an AVM. In the absence of endoglin, subcutaneous Matrigel implants in adult mice were populated by reduced numbers of new blood vessels compared with controls, and resulted in local venous enlargement (venomegaly). To investigate abnormal vascular responses in more detail, we turned to the more readily accessible vasculature of the neonatal retina. Endoglin-deficient retinas exhibited delayed remodeling of the capillary plexus, increased proliferation of endothelial cells and localized AVMs. Muscularization of the resulting arteriovenous shunts appeared to be a secondary response to increased blood flow. AVMs develop when an angiogenic stimulus is combined with endoglin depletion. Moreover, AVM formation appears to result from the combination of delayed vascular remodeling and an inappropriate endothelial cell proliferation response in the absence of endoglin.

Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling

PubMed Central

Makino, Ayako; Firth, Amy L.; Yuan, Jason X.-J.

2017-01-01

The pulmonary circulation is a low resistance and low pressure system. Sustained pulmonary vasoconstriction and excessive vascular remodeling often occur under pathophysiological conditions such as in patients with pulmonary hypertension. Pulmonary vasoconstriction is a consequence of smooth muscle contraction. Many factors released from the endothelium contribute to regulating pulmonary vascular tone, while the extracellular matrix in the adventitia is the major determinant of vascular wall compliance. Pulmonary vascular remodeling is characterized by adventitial and medial hypertrophy due to fibroblast and smooth muscle cell proliferation, neointimal proliferation, intimal, and plexiform lesions that obliterate the lumen, muscularization of precapillary arterioles, and in situ thrombosis. A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction, while increased release of mitogenic factors, upregulation (or downregulation) of ion channels and transporters, and abnormalities in intracellular signaling cascades are key to the remodeling of the pulmonary vasculature. Changes in the expression, function, and regulation of ion channels in PASMC and pulmonary arterial endothelial cells play an important role in the regulation of vascular tone and development of vascular remodeling. This article will focus on describing the ion channels and transporters that are involved in the regulation of pulmonary vascular function and structure and illustrating the potential pathogenic role of ion channels and transporters in the development of pulmonary vascular disease. PMID:23733654

Vascular anomalies of the head and neck.

PubMed

Donald, P J

2001-02-01

Vascular abnormalities of the head and neck are relatively uncommon lesions. An understanding of these anomalies based on their pathogenesis and natural history clearly divides them into hemangiomas and vascular malformations. Treatment strategies that are reasonable and predictable can then be devised based on the aforementioned factors.

Arteriovenous malformations of the uterus.

PubMed

Cura, M; Martinez, N; Cura, A; Dalsaso, T J; Elmerhi, F

2009-09-01

Arterial venous malformations (AVM) of the uterus are uncommon entities and should be considered in patients who present with profuse genital bleeding. There are two types of uterine AVM: acquired and congenital. Acquired uterine AVMs are conformed by communications between the uterine arteries and the myometrial veins, and are caused by an iatrogenic event or a pathological condition. Congenital AVMs are the result of abnormal development of primitive vessels that result in connections between pelvic arteries and veins in the uterus without an interconnecting capillary bed. Ultrasonography is a noninvasive diagnostic method able to demonstrate and characterize AVMs of the uterus. AVM in the pelvis may be noted incidentally by computed tomography (CT) of the pelvis, and magnetic resonance imaging (MRI) is frequently used to confirm and further characterize the sonographic findings of uterine AVM. Catheter angiography and embolization are very effective in defining the vascular anatomy and treating uterine vascular abnormalities.

A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration.

PubMed

Chavali, Venkata R M; Khan, Naheed W; Cukras, Catherine A; Bartsch, Dirk-Uwe; Jablonski, Monica M; Ayyagari, Radha

2011-05-15

Late-onset retinal macular degeneration (L-ORD) is an autosomal dominant inherited disorder caused by a single missense mutation (S163R) in the CTRP5/C1QTNF5 protein. Early phenotypic features of L-ORD include: dark adaptation abnormalities, nyctalopia, and drusen deposits in the peripheral macular region. Apart from posterior segment abnormalities, these patients also develop abnormally long anterior lens zonules. In the sixth decade of life the rod and cone function declines, accompanied by electroretinogram (ERG) abnormalities. Some patients also develop choroidal neovascularization and glaucoma. In order to understand the disease pathology and mechanisms involved in retinal dystrophy, we generated a knock-in (Ctrp5(+/-)) mouse model carrying the disease-associated mutation in the mouse Ctrp5/C1QTNF5 gene. These mice develop slower rod-b wave recovery consistent with early dark adaptation abnormalities, accumulation of hyperautofluorescence spots, retinal pigment epithelium abnormalities, drusen, Bruch's membrane abnormalities, loss of photoreceptors, and retinal vascular leakage. The Ctrp5(+/-) mice, which have most of the pathological features of age-related macular degeneration, are unique and may serve as a valuable model both to understand the molecular pathology of late-onset retinal degeneration and to evaluate therapies.

A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration

PubMed Central

Chavali, Venkata R.M.; Khan, Naheed W.; Cukras, Catherine A.; Bartsch, Dirk-Uwe; Jablonski, Monica M.; Ayyagari, Radha

2011-01-01

Late-onset retinal macular degeneration (L-ORD) is an autosomal dominant inherited disorder caused by a single missense mutation (S163R) in the CTRP5/C1QTNF5 protein. Early phenotypic features of L-ORD include: dark adaptation abnormalities, nyctalopia, and drusen deposits in the peripheral macular region. Apart from posterior segment abnormalities, these patients also develop abnormally long anterior lens zonules. In the sixth decade of life the rod and cone function declines, accompanied by electroretinogram (ERG) abnormalities. Some patients also develop choroidal neovascularization and glaucoma. In order to understand the disease pathology and mechanisms involved in retinal dystrophy, we generated a knock-in (Ctrp5+/−) mouse model carrying the disease-associated mutation in the mouse Ctrp5/C1QTNF5 gene. These mice develop slower rod-b wave recovery consistent with early dark adaptation abnormalities, accumulation of hyperautofluorescence spots, retinal pigment epithelium abnormalities, drusen, Bruch's membrane abnormalities, loss of photoreceptors, and retinal vascular leakage. The Ctrp5+/−mice, which have most of the pathological features of age-related macular degeneration, are unique and may serve as a valuable model both to understand the molecular pathology of late-onset retinal degeneration and to evaluate therapies. PMID:21349921

Effect of a High-sucrose Diet on Abdominal Aortic Aneurysm Development in a Hypoperfusion-induced Animal Model.

PubMed

Miyamoto, Chie; Kugo, Hirona; Hashimoto, Keisuke; Sawaragi, Ayaka; Zaima, Nobuhiro; Moriyama, Tatsuya

2018-05-01

Abdominal aortic aneurysm (AAA) is a vascular disease that results in rupture of the abdominal aorta. The risk factors for the development of AAA include smoking, male sex, hypertension, and age. AAA has a high mortality rate, but therapy for AAA is restricted to surgery in cases of large aneurysms. Clarifying the effect of dietary food on the development of AAA would be helpful for patients with AAAs. However, the relationship between dietary habits and the development of AAA is largely unknown. In our previous study, we demonstrated that adipocytes in vascular wall can induce the rupture of AAA. Therefore, we focused on the diet-induced abnormal triglyceride metabolism, which has the potential to drive AAA development. In this study, we have evaluated the effects of a high-sucrose diet on the development of AAA in a vascular hypoperfusion-induced animal model. A high sucrose diet induced high serum TG level and fatty liver. However, the AAA rupture risk and the AAA diameter were not significantly different between the control and high-sucrose groups. The intergroup differences in the elastin degradation score and collagen-positive area were insignificant. Moreover, matrix metalloproteinases, macrophages, and monocyte chemoattractant protein-1-positive areas did not differ significantly between groups. These results suggest that a high-sucrose diet does not affect the appearance of vascular adipocyte and AAA development under the vascular hypoperfusion condition.

The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy

PubMed Central

Tal, Reshef; Segars, James H.

2014-01-01

Background It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology. Methods Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed. Results Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms. Conclusions Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroid's abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess the potential of anti-angiogenic treatment strategies for uterine fibroids. PMID:24077979

[Anomalous systemic arterial supply to normal basal segments of the left lung (Pryce type I)].

PubMed

Ryu, Chusei; Sawada, Takahiro; Machino, Ryusuke

2013-03-01

Patient 1 was a 54-year-old female diagnosed with anomalous systemic arterial supply to normal basal segments of the left lung discovered as an abnormality on chest X-ray radiography. Patient 2 was a 47-year-old male in whom the disease was diagnosed by close examination of bloody sputum. Division of the abnormal artery and left lower lobectomy were performed in patient 1. Arterial congestion and serpentine distribution were noted in the basal segments of the lung, which was the region perfused by the abnormal artery, on histopathological examination. Arteriosclerotic changes were noted in the vascular wall, but no abnormal vascular wall or alveolar structure was noted in S6, which was not included in theperfused region. Based on the above findings, division of the abnormal artery and left basal segmentectomy were performed in patient 2. Bloody sputum disappeared, and activity of daily living( ADL) were not impaired after surgery.

Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development.

PubMed

Zhao, Xiaofeng; Peng, Xu; Sun, Shaogang; Park, Ann Y J; Guan, Jun-Lin

2010-06-14

Focal adhesion kinase (FAK) is essential for vascular development as endothelial cell (EC)-specific knockout of FAK (conditional FAK knockout [CFKO] mice) leads to embryonic lethality. In this study, we report the differential kinase-independent and -dependent functions of FAK in vascular development by creating and analyzing an EC-specific FAK kinase-defective (KD) mutant knockin (conditional FAK knockin [CFKI]) mouse model. CFKI embryos showed apparently normal development through embryonic day (E) 13.5, whereas the majority of CFKO embryos died at the same stage. Expression of KD FAK reversed increased EC apoptosis observed with FAK deletion in embryos and in vitro through suppression of up-regulated p21. However, vessel dilation and defective angiogenesis of CFKO embryos were not rescued in CFKI embryos. ECs without FAK or expressing KD FAK showed increased permeability, abnormal distribution of vascular endothelial cadherin (VE-cadherin), and reduced VE-cadherin Y658 phosphorylation. Together, our data suggest that kinase-independent functions of FAK can support EC survival in vascular development through E13.5 but are insufficient for maintaining EC function to allow for completion of embryogenesis.

Placental disease and abnormal umbilical artery Doppler waveforms in trisomy 21 pregnancy: A case-control study.

PubMed

Corry, Edward; Mone, Fionnuala; Segurado, Ricardo; Downey, Paul; McParland, Peter; McAuliffe, Fionnuala M; Mooney, Eoghan E

2016-11-01

The objectives of this study were firstly to determine the proportion of placental pathology in fetuses affected by trisomy 21 (T21) using current pathological descriptive terminology and secondly to examine if a correlation existed between the finding of an abnormal umbilical artery Doppler (UAD) waveform, the presence of T21 and defined placental pathological categories. This case-control study assessed singleton fetuses with karyotypically confirmed trisomy 21 where placental histopathology had been conducted from 2003 to 2015 inclusive, within a university tertiary obstetric centre. This was compared with unselected normal singleton control pregnancies matched within a week of gestation at delivery. Data included birthweight centiles and placental histopathology. Comparisons of Doppler findings across placental pathological categories were performed using statistical analysis. 104 cases were analysed; 52 cases of trisomy 21 and 52 controls. Fetal vascular malperfusion (48.1% vs. 5.8%, p = 0.001) and maturation defects (39.2% vs. 15.7%, p = 0.023) were more common in trisomy 21 placentas. Compared with controls, trisomy 21 fetuses were more likely to have shorter umbilical cords (p = 0.001) and had more UAD abnormalities. Amongst T21 pregnancies, umbilical artery Doppler abnormalities are associated with the presence of maternal vascular malperfusion. Fetal vascular malperfusion and maturation defects are more common in trisomy 21 placentas. Abnormal umbilical artery Doppler waveforms are more common in T21 and are associated with maternal vascular malperfusion. Placental disease may explain the increased rate of intrauterine death in T21. Copyright © 2016 Elsevier Ltd. All rights reserved.

New insights into diabetic retinopathy by OCT angiography.

PubMed

Liu, Guodong; Xu, Ding; Wang, Fang

2018-06-04

Diabetic retinopathy (DR) is one of the most common diabetic complications, which has become a leading cause for vision loss, mainly because of macular edema and vitreous hemorrhage. Optical coherence tomography (OCT) angiography is a novel technique to visualize vascular changes including microaneurysm, non-perfusion area, intraretinal microvascular abnormalities, and neovascularization. Recently, it is possible to quantify vascular density, foveal avascular zone area, non-perfusion area objectively using OCT angiography. In addition, OCT angiography also provides an alternative method to evaluate the effect of anti-vascular endothelial growth factor (VEGF) treatments by providing high resolution images of macular microcirculatory abnormalities. Thus OCT angiography is an effective method to investigate the vascular changes of the disease, and can also be potentially applied in the diagnosis, treatment, and follow up of DR. Copyright © 2018 Elsevier B.V. All rights reserved.

NORMALIZATION OF THE VASCULATURE FOR TREATMENT OF CANCER AND OTHER DISEASES

PubMed Central

Goel, Shom; Duda, Dan G.; Xu, Lei; Munn, Lance L.; Boucher, Yves; Fukumura, Dai; Jain, Rakesh K.

2012-01-01

New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a “normalization” of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more “mature” or “normal” phenotype. This “vascular normalization” is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Here, we review the pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases. PMID:21742796

Analysis of perfusion, microcirculation and drug transport in tumors. A computational study.

NASA Astrophysics Data System (ADS)

Zunino, Paolo; Cattaneo, Laura

2013-11-01

We address blood flow through a network of capillaries surrounded by a porous interstitium. We develop a computational model based on the Immersed Boundary method [C. S. Peskin. Acta Numer. 2002.]. The advantage of such an approach relies in its efficiency, because it does not need a full description of the real geometry allowing for a large economy of memory and CPU time and it facilitates handling fully realistic vascular networks [L. Cattaneo and P. Zunino. Technical report, MOX, Department of Mathematics, Politecnico di Milano, 2013.]. The analysis of perfusion and drug release in vascularized tumors is a relevant application of such techniques. Blood vessels in tumors are substantially leakier than in healthy tissue and they are tortuous. These vascular abnormalities lead to an impaired blood supply and abnormal tumor microenvironment characterized by hypoxia and elevated interstitial fluid pressure that reduces the distribution of drugs through advection [L.T. Baxter and R.K. Jain. Microvascular Research, 1989]. Finally, we discuss the application of the model to deliver nanoparticles. In particular, transport of nanoparticles in the vessels network, their adhesion to the vessel wall and the drug release in the surrounding tissue will be addressed.

Automated measurement of retinal blood vessel tortuosity

NASA Astrophysics Data System (ADS)

Joshi, Vinayak; Reinhardt, Joseph M.; Abramoff, Michael D.

2010-03-01

Abnormalities in the vascular pattern of the retina are associated with retinal diseases and are also risk factors for systemic diseases, especially cardiovascular diseases. The three-dimensional retinal vascular pattern is mostly formed congenitally, but is then modified over life, in response to aging, vessel wall dystrophies and long term changes in blood flow and pressure. A characteristic of the vascular pattern that is appreciated by clinicians is vascular tortuosity, i.e. how curved or kinked a blood vessel, either vein or artery, appears along its course. We developed a new quantitative metric for vascular tortuosity, based on the vessel's angle of curvature, length of the curved vessel over its chord length (arc to chord ratio), number of curvature sign changes, and combined these into a unidimensional metric, Tortuosity Index (TI). In comparison to other published methods this method can estimate appropriate TI for vessels with constant curvature sign and vessels with equal arc to chord ratios, as well. We applied this method to a dataset of 15 digital fundus images of 8 patients with Facioscapulohumeral muscular dystrophy (FSHD), and to the other publically available dataset of 60 fundus images of normal cases and patients with hypertensive retinopathy, of which the arterial and venous tortuosities have also been graded by masked experts (ophthalmologists). The method produced exactly the same rank-ordered list of vessel tortuosity (TI) values as obtained by averaging the tortuosity grading given by 3 ophthalmologists for FSHD dataset and a list of TI values with high ranking correlation with the ophthalmologist's grading for the other dataset. Our results show that TI has potential to detect and evaluate abnormal retinal vascular structure in early diagnosis and prognosis of retinopathies.

Natural history of splenic vascular abnormalities after blunt injury: A Western Trauma Association multicenter trial.

PubMed

Zarzaur, Ben L; Dunn, Julie A; Leininger, Brian; Lauerman, Margaret; Shanmuganathan, Kathirkamanthan; Kaups, Krista; Zamary, Kirellos; Hartwell, Jennifer L; Bhakta, Ankur; Myers, John; Gordy, Stephanie; Todd, Samuel R; Claridge, Jeffrey A; Teicher, Erik; Sperry, Jason; Privette, Alicia; Allawi, Ahmed; Burlew, Clay Cothren; Maung, Adrian A; Davis, Kimberly A; Cogbill, Thomas; Bonne, Stephanie; Livingston, David H; Coimbra, Raul; Kozar, Rosemary A

2017-12-01

Following blunt splenic injury, there is conflicting evidence regarding the natural history and appropriate management of patients with vascular injuries of the spleen such as pseudoaneurysms or blushes. The purpose of this study was to describe the current management and outcomes of patients with pseudoaneurysm or blush. Data were collected on adult (aged ≥18 years) patients with blunt splenic injury and a splenic vascular injury from 17 trauma centers. Demographic, physiologic, radiographic, and injury characteristics were gathered. Management and outcomes were collected. Univariate and multivariable analyses were used to determine factors associated with splenectomy. Two hundred patients with a vascular abnormality on computed tomography scan were enrolled. Of those, 14.5% were managed with early splenectomy. Of the remaining patients, 59% underwent angiography and embolization (ANGIO), and 26.5% were observed. Of those who underwent ANGIO, 5.9% had a repeat ANGIO, and 6.8% had splenectomy. Of those observed, 9.4% had a delayed ANGIO, and 7.6% underwent splenectomy. There were no statistically significant differences between those observed and those who underwent ANGIO. There were 111 computed tomography scans with splenic vascular injuries available for review by an expert trauma radiologist. The concordance between the original classification of the type of vascular abnormality and the expert radiologist's interpretation was 56.3%. Based on expert review, the presence of an actively bleeding vascular injury was associated with a 40.9% risk of splenectomy. This was significantly higher than those with a nonbleeding vascular injury. In this series, the vast majority of patients are managed with ANGIO and usually embolization, whereas splenectomy remains a rare event. However, patients with a bleeding vascular injury of the spleen are at high risk of nonoperative failure, no matter the strategy used for management. This group may warrant closer observation or an alternative management strategy. Prognostic study, level III.

PHACE syndrome misdiagnosed as a port-wine stain

PubMed Central

Thomson, Jason; Greig, Aina; Lloyd, Claire; Morrison, Danny; Flohr, Carsten

2015-01-01

We present the case of a boy born with a large macular, segmental vascular anomaly over the left face, initially diagnosed as a capillary malformation (port-wine stain) by the postnatal paediatric team. The vascular anomaly in the face then grew rapidly during the first few weeks of life and started to occlude the left eye, causing parental concerns about the infant's vision. A dermatological opinion established that the lesion was a segmental infantile haemangioma (IH). This, in combination with the posterior fossa malformation previously detected on antenatal scanning and confirmed by an MRI postnatally, satisfied the criteria for Posterior fossa abnormalities, Haemangiomas, Arterial abnormalities, Cardiac abnormalities and Eye abnormalities (PHACE) syndrome: a rare cutaneous neurovascular syndrome. This case highlights the diagnostic challenge posed by early phenotypes of haemangiomas as well as the importance of correctly diagnosing PHACE syndrome. PMID:26177999

Effects of vascularization on cancer nanochemotherapy outcomes

NASA Astrophysics Data System (ADS)

Paiva, L. R.; Ferreira, S. C.; Martins, M. L.

2016-08-01

Cancer therapy requires anticancer agents capable of efficient and uniform systemic delivery. One promising route to their development is nanotechnology. Here, a previous model for cancer chemotherapy based on a nanosized drug carrier (Paiva et al., 2011) is extended by including tissue vasculature and a three-dimensional growth. We study through computer simulations the therapy against tumors demanding either large or small nutrient supplies growing under different levels of tissue vascularization. Our results indicate that highly vascularized tumors demand more aggressive therapies (larger injected doses administrated at short intervals) than poorly vascularized ones. Furthermore, nanoparticle endocytic rate by tumor cells, not its selectivity, is the major factor that determines the therapeutic success. Finally, our finds indicate that therapies combining cytotoxic agents with antiangiogenic drugs that reduce the abnormal tumor vasculature, instead of angiogenic drugs that normalize it, can lead to successful treatments using feasible endocytic rates and administration intervals.

A Cross-Sectional Cohort Study of Cerebrovascular Disease and Late Effects After Radiation Therapy for Craniopharyngioma.

PubMed

Lo, Andrea C; Howard, A Fuchsia; Nichol, Alan; Hasan, Haroon; Martin, Monty; Heran, Manraj; Goddard, Karen

2016-05-01

The study objective was to describe radiation-induced vascular abnormalities, stroke prevalence, and stroke risk factors in survivors of childhood craniopharyngioma. Twenty survivors of childhood craniopharyngioma who received radiotherapy (RT) were included in the study. A clinical history, quality of life assessment, cognitive functioning assessment, magnetic resonance angiogram or computed tomography angiogram, fasting lipid profile, and fasting glucose or hemoglobin A1c test were obtained. Median age at diagnosis was 10.3 years and median age at time of study was 29.0 years. Vascular abnormalities were detected in six (32%) of 19 patients' angiograms (vascular stenosis, decreased artery size, aneurysm, cavernoma, and small vessel disease). Five (25%) of 20 patients experienced a stroke after RT. Median time since RT was 27.8 versus 9.1 years in patients with versus without vascular abnormalities (P = 0.02). A low level of high-density lipoproteiin (HDL) was present in 100% (5/5) of patients who had a post-RT stroke as compared with 13% (2/15) of patients who did not have any post-RT stroke (P = 0.02). Previous stroke had occurred in 0% (0/5) of patients receiving growth hormone (GH) replacement at the time of study, compared to 40% (6/15) of patients who were not receiving GH replacement (P = 0.09). Patients with craniopharyngioma treated with RT have a high prevalence of stroke and vascular abnormalities, particularly those with low HDL and longer duration of time since RT. There is a trend to suggest that continual GH replacement may reduce the risk of stroke. These patients should undergo careful monitoring and aggressive modification of stroke risk factors. © 2016 Wiley Periodicals, Inc.

[Hepatopulmonary syndrome and portopulmonary hypertension].

PubMed

Marcu, Cristina; Schiffer, Eduardo; Aubert, John-David; Vionnet, Julien; Yerly, Patrick; Deltenre, Pierre; Marot, Astrid

2017-08-30

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are two frequent pulmonary complications of liver disease. Portal hypertension is a key element in the pathogenesis of both disorders, which are however distinct in terms of pathogenesis, diagnosis and treatment. HPS corresponds to an abnormal arterial oxygenation in relation with the development of intrapulmonary vascular dilatations. POPH is a pulmonary arterial hypertension in the setting of portal hypertension and elevated pulmonary vascular resistance. As both diseases are associated with an increased risk of morbidity and mortality, it is important to screen and evaluate the severity of these two disorders particularly in liver transplant candidates.

S1P1 inhibits sprouting angiogenesis during vascular development.

PubMed

Ben Shoham, Adi; Malkinson, Guy; Krief, Sharon; Shwartz, Yulia; Ely, Yona; Ferrara, Napoleone; Yaniv, Karina; Zelzer, Elazar

2012-10-01

Coordination between the vascular system and forming organs is essential for proper embryonic development. The vasculature expands by sprouting angiogenesis, during which tip cells form filopodia that incorporate into capillary loops. Although several molecules, such as vascular endothelial growth factor A (Vegfa), are known to induce sprouting, the mechanism that terminates this process to ensure neovessel stability is still unknown. Sphingosine-1-phosphate receptor 1 (S1P(1)) has been shown to mediate interaction between endothelial and mural cells during vascular maturation. In vitro studies have identified S1P(1) as a pro-angiogenic factor. Here, we show that S1P(1) acts as an endothelial cell (EC)-autonomous negative regulator of sprouting angiogenesis during vascular development. Severe aberrations in vessel size and excessive sprouting found in limbs of S1P(1)-null mouse embryos before vessel maturation imply a previously unknown, mural cell-independent role for S1P(1) as an anti-angiogenic factor. A similar phenotype observed when S1P(1) expression was blocked specifically in ECs indicates that the effect of S1P(1) on sprouting is EC-autonomous. Comparable vascular abnormalities in S1p(1) knockdown zebrafish embryos suggest cross-species evolutionary conservation of this mechanism. Finally, genetic interaction between S1P(1) and Vegfa suggests that these factors interplay to regulate vascular development, as Vegfa promotes sprouting whereas S1P(1) inhibits it to prevent excessive sprouting and fusion of neovessels. More broadly, because S1P, the ligand of S1P(1), is blood-borne, our findings suggest a new mode of regulation of angiogenesis, whereby blood flow closes a negative feedback loop that inhibits sprouting angiogenesis once the vascular bed is established and functional.

Hepatopulmonary syndrome: update on pathogenesis and clinical features.

PubMed

Zhang, Junlan; Fallon, Michael B

2012-09-01

Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 5-32% of patients with cirrhosis. The presence of HPS markedly increases mortality. No effective medical therapies are currently available and liver transplantation is the only established treatment option for HPS. The definition and diagnosis of HPS are established by the presence of a triad of liver disease with intrapulmonary vascular dilation that causes abnormal arterial gas exchange. Experimental biliary cirrhosis induced by common bile duct ligation in the rat reproduces the pulmonary vascular and gas exchange abnormalities of human HPS and serves as a pertinent animal model. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental HPS, and thus might underlie HPS in humans. Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. This Review focuses on the current understanding of the pathogenesis, clinical features and management of HPS.

A Mutant Receptor Tyrosine Phosphatase, CD148, Causes Defects in Vascular Development

PubMed Central

Takahashi, Takamune; Takahashi, Keiko; St. John, Patricia L.; Fleming, Paul A.; Tomemori, Takuya; Watanabe, Toshio; Abrahamson, Dale R.; Drake, Christopher J.; Shirasawa, Takuji; Daniel, Thomas O.

2003-01-01

Vascularization defects in genetic recombinant mice have defined critical roles for a number of specific receptor tyrosine kinases. Here we evaluated whether an endothelium-expressed receptor tyrosine phosphatase, CD148 (DEP-1/PTPη), participates in developmental vascularization. A mutant allele, CD148ΔCyGFP, was constructed to eliminate CD148 phosphatase activity by in-frame replacement of cytoplasmic sequences with enhanced green fluorescent protein sequences. Homozygous mutant mice died at midgestation, before embryonic day 11.5 (E11.5), with vascularization failure marked by growth retardation and disorganized vascular structures. Structural abnormalities were observed as early as E8.25 in the yolk sac, prior to the appearance of intraembryonic defects. Homozygous mutant mice displayed enlarged vessels comprised of endothelial cells expressing markers of early differentiation, including VEGFR2 (Flk1), Tal1/SCL, CD31, ephrin-B2, and Tie2, with notable lack of endoglin expression. Increased endothelial cell numbers and mitotic activity indices were demonstrated. At E9.5, homozygous mutant embryos showed homogeneously enlarged primitive vessels defective in vascular remodeling and branching, with impaired pericyte investment adjacent to endothelial structures, in similarity to endoglin-deficient embryos. Developing cardiac tissues showed expanded endocardial projections accompanied by defective endocardial cushion formation. These findings implicate a member of the receptor tyrosine phosphatase family, CD148, in developmental vascular organization and provide evidence that it regulates endothelial proliferation and endothelium-pericyte interactions. PMID:12588999

Emerging role of thalidomide in the treatment of gastrointestinal bleeding.

PubMed

McFarlane, Michael; O'Flynn, Lauren; Ventre, Rachel; Disney, Benjamin R

2018-04-01

Thalidomide was initially synthesised in 1954 and marketed as a sedative and antiemetic for morning sickness. It was withdrawn in 1961 due to the realisation that it was teratogenic with over 10 000 children born with congenital abnormalities. Since then it has been used for treatment of dermatological and oncological conditions, including myeloma. In 1994, it was found to have a potent antiangiogenic effect via downregulation of vascular endothelial growth factor (VEGF). This has led to its use in gastrointestinal bleeding, as vascular abnormalities such as angiodysplasia have been found to have elevated VEGF levels. This article will review the current evidence of the use of thalidomide in bleeding associated with gastrointestinal vascular malformations, including angiodysplasia, gastric cancer and radiation-induced proctitis.

A Review of Vascular Abnormalities of the Spine.

PubMed

Singh, Rahul; Lucke-Wold, Brandon; Gyure, Kymberly; Boo, Sohyun

2016-01-01

Patients with spinal vascular lesions present with unique symptoms and have important anatomical and physiologic changes that must be considered prior to treatment. In this mini-review, we provide an overview of normal spinal vascular anatomy and discuss several key spinal vascular lesions. We provide an overview of cavernous malformations, intradural arteriovenous malformations, perimedullary arteriovenous fistulas, and dural arteriovenous fistulas. Important considerations are addressed in terms of pathologic characterization, specific imaging findings, and treatment approaches.

Involvement of the VEP1 gene in vascular strand development in Arabidopsis thaliana.

PubMed

Jun, Ji Hyung; Ha, Chan Man; Nam, Hong Gil

2002-03-01

A dominant mutant line characterized by abnormal leaf venation pattern was isolated from a transgenic Arabidopsis plant pool that was generated with Agrobacterium culture harboring an Arabidopsis antisense cDNA library. In the mutant line, the phenotype was due to antisense suppression of a gene we named VEP1 (Vein Patterning). The predicted amino acid sequence of the gene contained a motif related to the mammalian death domain that is found in the apoptotic machinery. Reduced expression of the VEP1 gene resulted in the reduced complexity of the venation pattern of the cotyledons and foliar leaves, which was mainly due to the reduced number of the minor veins and their incomplete connection. The analysis of mutant embryos indicated that the phenotype was originated, at least in part, from a defect in the procambium patterning. In the mutant, the stem and root were thinner than those in wild type. This phenotype was associated with reduced vascular development. The promoter activity of the VEP1 gene was detected preferentially in the vascular regions. We propose that the death domain-containing protein VEP1 functions as a positive element required for vascular strand development in Arabidopsis thaliana.

Pulse oximetry in the evaluation of peripheral vascular disease.

PubMed

Jawahar, D; Rachamalla, H R; Rafalowski, A; Ilkhani, R; Bharathan, T; Anandarao, N

1997-08-01

The role of pulse oximetry in the evaluation of peripheral vascular disease (PVD) was investigated. In addition, the value of elevating the limb to improve the sensitivity of detection of PVD by the pulse oximeter was also determined. Pulse oximetry reading in the toes were obtained in 40 young, healthy volunteers and in 40 randomly selected patients referred to the vascular investigation laboratory over a period of two months. All 40 healthy volunteers had normal pulse oximetry readings. Normal pulse oximetry reading in the toes was defined as > 95% O2 Sat and +/-2 of finger pulse oximetry reading. In all 40 patients, pulse oximetry readings were either normal or not detected at all. Since there was no gradation in decrease in the pulse oximetry reading with severity of disease or with elevation of the patient's lower extremity, an absent or no reading was considered as an abnormal result from the test. The frequency of abnormal pulse oximetry readings increased significantly in groups with abnormal ankle-brachial pressure index (ABPI) and also varied significantly with elevation of the patients' lower limbs. In patients with no PVD detected by Doppler (ABPI > 0.9), pulse oximetry readings were normal in all. However, in patients with moderate PVD (ABPI, 0.5-0.9), 84% of the patients' lower limbs had normal pulse oximetry readings and 16% had an abnormal reading at baseline level (flat). An additional 12% of the lower limbs in this group had an abnormal reading on elevation of the limb to 12 inches. In patients with severe PVD (ABPI < 0.5), 54% of the patients' lower limbs had an abnormal reading at baseline and an additional 23% had an abnormal reading at elevation of the limb to 12 inches. In conclusion, pulse oximetry was not a sensitive test for detecting early PVD.

Predictive factors for the occurrence of idiopathic menorrhagia: evidence for a hereditary trait.

PubMed

Kuzmina, Natalia; Palmblad, Jan; Mints, Miriam

2011-01-01

The aim of the present study was to assess predictive factors for occurrence of idiopathic menorrhagia (IM), a disease characterized by abnormal endometrial blood vessel morphology. It was hypothesized that IM exhibits familial clustering (suggesting inheritance) and is associated with other vascular abnormalities, primarily cutaneous hemangiomas. Women with IM (n=152) and healthy, regularly menstruating (n=56) women answered a questionnaire concerning menstrual pattern, susceptibility to bleeding and family history of abnormal gynecological bleeding. Factor analysis with principal component extraction was used to separate predictive factors that may be associated with IM. A total of 35 different items were analyzed. A strong association was found between IM and a family history of heavy menstrual bleeding (r=0.68), but not with cutaneous vascular abnormalities. Our results revealed that a family history of heavy menstrual bleeding may have the highest predictive value for the diagnosis of IM, indicating a hereditary trait.

PHACE syndrome misdiagnosed as a port-wine stain.

PubMed

Thomson, Jason; Greig, Aina; Lloyd, Claire; Morrison, Danny; Flohr, Carsten

2015-07-15

We present the case of a boy born with a large macular, segmental vascular anomaly over the left face, initially diagnosed as a capillary malformation (port-wine stain) by the postnatal paediatric team. The vascular anomaly in the face then grew rapidly during the first few weeks of life and started to occlude the left eye, causing parental concerns about the infant's vision. A dermatological opinion established that the lesion was a segmental infantile haemangioma (IH). This, in combination with the posterior fossa malformation previously detected on antenatal scanning and confirmed by an MRI postnatally, satisfied the criteria for Posterior fossa abnormalities, Haemangiomas, Arterial abnormalities, Cardiac abnormalities and Eye abnormalities (PHACE) syndrome: a rare cutaneous neurovascular syndrome. This case highlights the diagnostic challenge posed by early phenotypes of haemangiomas as well as the importance of correctly diagnosing PHACE syndrome. 2015 BMJ Publishing Group Ltd.

Maternal hemodynamics, fetal biometry and Dopplers in pregnancies followed up for suspected fetal growth restriction.

PubMed

Roberts, Llinos A; Ling, Hua Zen; Poon, Liona; Nicolaides, Kypros H; Kametas, Nikos A

2018-04-01

To assess whether in a cohort of patients with small for gestational age (SGA) foetuses with estimated fetal weight ≤10 th percentile, maternal hemodynamics, fetal biometry and Dopplers at presentation, can predict the subsequent development of abnormal fetal Dopplers or delivery with birthweight <3 rd percentile. The study population comprised of 86 singleton pregnancies with SGA fetuses presenting at a median gestational age of 32 (range 26-35) weeks. We measured maternal cardiac function with a non-invasive transthoracic bioreactance monitor (NICOM, Cheetah), mean arterial pressure, fetal biometry, umbilical artery (UA), middle cerebral artery (MCA) and uterine artery (UT) pulsatility index (PI) and the deepest vertical pool (DVP) of amniotic fluid. Z-scores of these variables were calculated based on reported reference ranges and the values were compared between those with evidence of abnormal fetal Dopplers at presentation (group 1), those that developed abnormal Dopplers in subsequent visits (group 2) and those who did not develop abnormal Dopplers throughout pregnancy (group 3). Abnormal fetal Dopplers were defined as UAPI >95 th percentile, or MCA PI <5 th percentile. Differences in measured variables at presentation were also compared between pregnancies delivering a baby with birthweight <3 rd and ≥3 rd percentile. Multivariate logistic regression analysis was used to determine significant predictors of birthweight <3 rd percentile and evolution from normal fetal Dopplers to abnormal fetal Dopplers in groups 2 and 3. In the study population 14 (16%) cases were in group 1, 19 (22%) in group 2 and 53 (62%) in group 3. The birthweight was <3 rd percentile in 39 (45%) cases and ≥3 rd percentile in 47 (55%). In the study groups, compared to normal populations, there was decreased cardiac output and stroke volume and increased peripheral vascular resistance and mean arterial pressure (MAP) and the deviations from normal were most marked in group 1. Pregnancies with a birthweight <3 rd , compared to those ≥3 rd percentile, had higher deviations from normal in fetal biometry, maternal cardiac output, stroke volume, heart rate and peripheral vascular resistance and UT-PI. Multivariate logistic regression analysis demonstrated that in the prediction of birth weight ≤3 rd percentile, maternal hemodynamics provided significant improvement to the prediction provided by maternal demographics, fetal biometry and UT-PI, UA-PI and MCA-PI (difference between AUCs 0.18, 95% CI 0.06-0.29, p=0.002). In contrast, there was no significant independent contribution from maternal hemodynamics in the prediction of subsequent abnormal fetal Dopplers. In pregnancies with SGA fetuses there is decreased maternal cardiac output and stroke volume and increased peripheral vascular resistance and MAP and the deviations from normal are most marked in cases of redistribution in the fetal circulation and reduced amniotic fluid volume. This article is protected by copyright. All rights reserved.

New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk.

PubMed

Waelchli, R; Aylett, S E; Robinson, K; Chong, W K; Martinez, A E; Kinsler, V A

2014-10-01

Facial port-wine stains (PWSs) are usually isolated findings; however, when associated with cerebral and ocular vascular malformations they form part of the classical triad of Sturge-Weber syndrome (SWS). To evaluate the associations between the phenotype of facial PWS and the diagnosis of SWS in a cohort with a high rate of SWS. Records were reviewed of all 192 children with a facial PWS seen in 2011-13. Adverse outcome measures were clinical (seizures, abnormal neurodevelopment, glaucoma) and radiological [abnormal magnetic resonance imaging (MRI)], modelled by multivariate logistic regression. The best predictor of adverse outcomes was a PWS involving any part of the forehead, delineated at its inferior border by a line joining the outer canthus of the eye to the top of the ear, and including the upper eyelid. This involves all three divisions of the trigeminal nerve, but corresponds well to the embryonic vascular development of the face. Bilateral distribution was not an independently significant phenotypic feature. Abnormal MRI was a better predictor of all clinical adverse outcome measures than PWS distribution; however, for practical reasons guidelines based on clinical phenotype are proposed. Facial PWS distribution appears to follow the embryonic vasculature of the face, rather than the trigeminal nerve. We propose that children with a PWS on any part of the 'forehead' should have an urgent ophthalmology review and a brain MRI. A prospective study has been established to test the validity of these guidelines. © The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish.

PubMed

Teraoka, Hiroki; Ogawa, Akira; Kubota, Akira; Stegeman, John J; Peterson, Richard E; Hiraga, Takeo

2010-08-15

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). The AHR also plays important roles in normal development in mice, and AHR(-/-) mice show abnormal development of vascular structures in various blood vessels. Our previous studies revealed that Ahr type 2 (Ahr2) activation by TCDD and beta-naphthoflavone (BNF) caused a significant decrease in blood flow in the dorsal midbrain of zebrafish embryos. Here we report effects of TCDD exposure on the morphology of some blood vessels in the head of developing zebrafish. TCDD caused concentration-dependent anatomical rearrangements in the shape of the prosencephalic artery in zebrafish larvae. In contrast, no major vascular defects were recognized in the trunk and tail regions following exposure to TCDD at least at the concentrations used. Essentially, the same observations were also confirmed in BNF-exposed larvae. Knock-down of either Ahr2 or Ahr nuclear translocator type 1 (Arnt1) by morpholino oligonucleotides (MOs) protected larvae against abnormal shape of the prosencephalic artery caused by TCDD and BNF. On the other hand, knock-down of Ahr2 or Arnt1 in vehicle-exposed zebrafish larvae had no clear effect on morphology of the prosencephalic artery or trunk vessels. Ascorbic acid, an antioxidant, protected against the TCDD-induced decrease in blood flow through the prosencephalic artery, but not the abnormal morphological changes in the shape of this artery. These results indicate that activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish. (c) 2010 Elsevier B.V. All rights reserved.

Current drug therapies for rosacea: a chronic vascular and inflammatory skin disease.

PubMed

Feldman, Steven R; Huang, William W; Huynh, Tu T

2014-06-01

Rosacea is a chronic skin disorder that presents with abnormal vascular and inflammatory conditions. Clinical manifestations include flushing, facial erythema, inflammatory papules and pustules, telangiectasias, edema, and watery or irritated eyes. To discuss the evolving pathophysiology of rosacea, factors involved in promoting the chronic vascular and inflammatory abnormalities seen in rosacea, and the available drug therapies for the condition. Chronic inflammation and vascular changes are believed to be underlying factors in the pathophysiology of rosacea. Aberrant cathelicidin expression, elevated kallikrein 5 (KLK5) proteolytic activity, and altered toll-like receptor 2 (TLR2) expression have been reported in rosacea skin leading to the production of proinflammatory cytokines. Until recently, drug therapies only targeted the inflammatory lesions (papules and pustules) and transient erythema associated with these inflammatory lesions of rosacea. Brimonidine tartrate gel 0.5% was recently approved for the treatment of persistent (nontransient) facial erythema of rosacea, acting primarily on the cutaneous vascular component of the disease. Rosacea is a chronic vascular and inflammatory skin disease. Understanding the role of factors that trigger the onset of rosacea symptoms and exacerbate the condition is crucial in treating this skin disease.

Nrf2/Keap1 system regulates vascular smooth muscle cell apoptosis for vascular homeostasis: role in neointimal formation after vascular injury

PubMed Central

Ashino, Takashi; Yamamoto, Masayuki; Numazawa, Satoshi

2016-01-01

Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after a vascular injury is a key event in developing neointimal hyperplasia. To maintain vascular function, proliferation and apoptosis of VSMCs is tightly controlled during vascular remodeling. NF-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) system, a key component of the oxidative stress response that acts in maintaining homeostasis, plays an important role in neointimal hyperplasia after a vascular injury; however, the role of Nrf2/Keap1 in VSMC apoptosis has not been clarified. Here we report that 14 days after arterial injury in mice, TUNEL-positive VSMCs are detected in both the neointimal and medial layers. These layers contain cells expressing high levels of Nrf2 but low Keap1 expression. In VSMCs, Keap1 depletion induces features of apoptosis, such as positive TUNEL staining and annexin V binding. These changes are associated with an increased expression of nuclear Nrf2. Simultaneous Nrf2 depletion inhibits Keap1 depletion-induced apoptosis. At 14 days after the vascular injury, Nrf2-deficient mice demonstrated fewer TUNEL-positive cells and increased neointimal formation in the neointimal and medial areas. The results suggest that the Nrf2/Keap1 system regulates VSMC apoptosis during neointimal formation, thereby inhibiting neointimal hyperplasia after a vascular injury. PMID:27198574

A Review of Vascular Abnormalities of the Spine

PubMed Central

Singh, Rahul; Lucke-Wold, Brandon; Gyure, Kymberly; Boo, Sohyun

2017-01-01

Patients with spinal vascular lesions present with unique symptoms and have important anatomical and physiologic changes that must be considered prior to treatment. In this mini-review, we provide an overview of normal spinal vascular anatomy and discuss several key spinal vascular lesions. We provide an overview of cavernous malformations, intradural arteriovenous malformations, perimedullary arteriovenous fistulas, and dural arteriovenous fistulas. Important considerations are addressed in terms of pathologic characterization, specific imaging findings, and treatment approaches. PMID:28191502

Trkb signaling in pericytes is required for cardiac microvessel stabilization.

PubMed

Anastasia, Agustin; Deinhardt, Katrin; Wang, Shiyang; Martin, Laura; Nichol, Donna; Irmady, Krithi; Trinh, Jasmine; Parada, Luis; Rafii, Shahin; Hempstead, Barbara L; Kermani, Pouneh

2014-01-01

Pericyte and vascular smooth muscle cell (SMC) recruitment to the developing vasculature is an important step in blood vessel maturation. Brain-derived neurotrophic factor (BDNF), expressed by endothelial cells, activates the receptor tyrosine kinase TrkB to stabilize the cardiac microvasculature in the perinatal period. However, the effects of the BDNF/TrkB signaling on pericytes/SMCs and the mechanisms downstream of TrkB that promote vessel maturation are unknown. To confirm the involvement of TrkB in vessel maturation, we evaluated TrkB deficient (trkb (-/-)) embryos and observed severe cardiac vascular abnormalities leading to lethality in late gestation to early prenatal life. Ultrastructural analysis demonstrates that trkb(-/-) embryos exhibit defects in endothelial cell integrity and perivascular edema. As TrkB is selectively expressed by pericytes and SMCs in the developing cardiac vasculature, we generated mice deficient in TrkB in these cells. Mice with TrkB deficiency in perivascular cells exhibit reduced pericyte/SMC coverage of the cardiac microvasculature, abnormal endothelial cell ultrastructure, and increased vascular permeability. To dissect biological actions and the signaling pathways downstream of TrkB in pericytes/SMCs, human umbilical SMCs were treated with BDNF. This induced membranous protrusions and cell migration, events dependent on myosin light chain phosphorylation. Moreover, inhibition of Rho GTPase and the Rho-associated protein kinase (ROCK) prevented membrane protrusion and myosin light chain phosphorylation in response to BDNF. These results suggest an important role for BDNF in regulating migration of TrkB-expressing pericytes/SMCs to promote cardiac blood vessel ensheathment and functional integrity during development.

Trkb Signaling in Pericytes Is Required for Cardiac Microvessel Stabilization

PubMed Central

Wang, Shiyang; Martin, Laura; Nichol, Donna; Irmady, Krithi; Trinh, Jasmine; Parada, Luis; Rafii, Shahin; Hempstead, Barbara L.; Kermani, Pouneh

2014-01-01

Pericyte and vascular smooth muscle cell (SMC) recruitment to the developing vasculature is an important step in blood vessel maturation. Brain-derived neurotrophic factor (BDNF), expressed by endothelial cells, activates the receptor tyrosine kinase TrkB to stabilize the cardiac microvasculature in the perinatal period. However, the effects of the BDNF/TrkB signaling on pericytes/SMCs and the mechanisms downstream of TrkB that promote vessel maturation are unknown. To confirm the involvement of TrkB in vessel maturation, we evaluated TrkB deficient (trkb −/−) embryos and observed severe cardiac vascular abnormalities leading to lethality in late gestation to early prenatal life. Ultrastructural analysis demonstrates that trkb−/− embryos exhibit defects in endothelial cell integrity and perivascular edema. As TrkB is selectively expressed by pericytes and SMCs in the developing cardiac vasculature, we generated mice deficient in TrkB in these cells. Mice with TrkB deficiency in perivascular cells exhibit reduced pericyte/SMC coverage of the cardiac microvasculature, abnormal endothelial cell ultrastructure, and increased vascular permeability. To dissect biological actions and the signaling pathways downstream of TrkB in pericytes/SMCs, human umbilical SMCs were treated with BDNF. This induced membranous protrusions and cell migration, events dependent on myosin light chain phosphorylation. Moreover, inhibition of Rho GTPase and the Rho-associated protein kinase (ROCK) prevented membrane protrusion and myosin light chain phosphorylation in response to BDNF. These results suggest an important role for BDNF in regulating migration of TrkB-expressing pericytes/SMCs to promote cardiac blood vessel ensheathment and functional integrity during development. PMID:24498100

Development of syndrome of inappropriate antidiuretic hormone secretion (SIADH) after Onyx embolisation of a cavernous carotid fistula

PubMed Central

Chen, Tsinsue; Kalani, M Yashar S; Ducruet, Andrew F; Albuquerque, Felipe C; McDougall, Cameron G

2016-01-01

Patients with cavernous carotid fistulas (CCFs) can present with pituitary hypoperfusion and hypopituitarism; however, there are no previous reports of pituitary or hormonal abnormalities developing after CCF embolisation in an asymptomatic patient. We describe a patient with no hormonal abnormalities who developed syndrome of inappropriate antidiuretic hormone (SIADH) secretion after CCF embolisation. The patient had bilateral indirect CCFs, which were completely embolised via a transvenous approach, and was neurologically stable postoperatively and discharged. In the subsequent 2 weeks the patient was readmitted twice for acute hyponatraemia and a tonic-clonic seizure. Laboratory studies revealed severe SIADH. Clinical status and sodium levels improved after treatment. One year later the patient was weaned off all medications and remained neurologically stable. SIADH may be a delayed phenomenon after CCF embolisation. Given the proximity of embolised vessels to the pituitary's vascular supply, CCF treatment may result in flow disturbance, ischaemia and hormonal abnormalities. PMID:27001597

Expression of the Growth Factor Progranulin in Endothelial Cells Influences Growth and Development of Blood Vessels: A Novel Mouse Model

PubMed Central

Toh, Huishi; Cao, Mingju; Daniels, Eugene; Bateman, Andrew

2013-01-01

Progranulin is a secreted glycoprotein that regulates cell proliferation, migration and survival. It has roles in development, tumorigenesis, wound healing, neurodegeneration and inflammation. Endothelia in tumors, wounds and placenta express elevated levels of progranulin. In culture, progranulin activates endothelial proliferation and migration. This suggested that progranulin might regulate angiogenesis. It was, however, unclear how elevated endothelial progranulin levels influence vascular growth in vivo. To address this issue, we generated mice with progranulin expression targeted specifically to developing endothelial cells using a Tie2–promoter/enhancer construct. Three Tie2-Grn mouse lines were generated with varying Tie2-Grn copy number, and were called GrnLo, GrnMid, and GrnHi. All three lines showed increased mortality that correlates with Tie2-Grn copy number, with greatest mortality and lowest germline transmission in the GrnHi line. Death of the transgenic animals occurred around birth, and continued for three days after birth. Those that survived beyond day 3 survived into adulthood. Transgenic neonates that died showed vascular abnormalities of varying severity. Some exhibited bleeding into body cavities such as the pericardial space. Smaller localized hemorrhages were seen in many organs. Blood vessels were often dilated and thin-walled. To establish the development of these abnormalities, we examined mice at early (E10.5–14.5) and later (E15.5–17.5) developmental phases. Early events during vasculogenesis appear unaffected by Tie2-Grn as apparently normal primary vasculature had been established at E10.5. The earliest onset of vascular abnormality was at E15.5, with focal cerebral hemorrhage and enlarged vessels in various organs. Aberrant Tie2-Grn positive vessels showed thinning of the basement membrane and reduced investiture with mural cells. We conclude that progranulin promotes exaggerated vessel growth in vivo, with subsequent effects in the formation of the mural cell layer and weakening of vessel integrity. These results demonstrate that overexpression of progranulin in endothelial cells influences normal angiogenesis in vivo. PMID:23741441

Expression of the growth factor progranulin in endothelial cells influences growth and development of blood vessels: a novel mouse model.

PubMed

Toh, Huishi; Cao, Mingju; Daniels, Eugene; Bateman, Andrew

2013-01-01

Progranulin is a secreted glycoprotein that regulates cell proliferation, migration and survival. It has roles in development, tumorigenesis, wound healing, neurodegeneration and inflammation. Endothelia in tumors, wounds and placenta express elevated levels of progranulin. In culture, progranulin activates endothelial proliferation and migration. This suggested that progranulin might regulate angiogenesis. It was, however, unclear how elevated endothelial progranulin levels influence vascular growth in vivo. To address this issue, we generated mice with progranulin expression targeted specifically to developing endothelial cells using a Tie2-promoter/enhancer construct. Three Tie2-Grn mouse lines were generated with varying Tie2-Grn copy number, and were called GrnLo, GrnMid, and GrnHi. All three lines showed increased mortality that correlates with Tie2-Grn copy number, with greatest mortality and lowest germline transmission in the GrnHi line. Death of the transgenic animals occurred around birth, and continued for three days after birth. Those that survived beyond day 3 survived into adulthood. Transgenic neonates that died showed vascular abnormalities of varying severity. Some exhibited bleeding into body cavities such as the pericardial space. Smaller localized hemorrhages were seen in many organs. Blood vessels were often dilated and thin-walled. To establish the development of these abnormalities, we examined mice at early (E10.5-14.5) and later (E15.5-17.5) developmental phases. Early events during vasculogenesis appear unaffected by Tie2-Grn as apparently normal primary vasculature had been established at E10.5. The earliest onset of vascular abnormality was at E15.5, with focal cerebral hemorrhage and enlarged vessels in various organs. Aberrant Tie2-Grn positive vessels showed thinning of the basement membrane and reduced investiture with mural cells. We conclude that progranulin promotes exaggerated vessel growth in vivo, with subsequent effects in the formation of the mural cell layer and weakening of vessel integrity. These results demonstrate that overexpression of progranulin in endothelial cells influences normal angiogenesis in vivo.

Mixed vascular nevus syndrome: a report of four new cases and a literature review.

PubMed

Ruggieri, Martino; Polizzi, Agata; Strano, Serena; Schepis, Carmelo; Morano, Massimiliano; Belfiore, Giuseppe; Palmucci, Stefano; Foti, Pietro Valerio; Pirrone, Concetta; Sofia, Vito; David, Emanuele; Salpietro, Vincenzo; Mankad, Kshitij; Milone, Pietro

2016-10-01

Mixed vascular nevus (or nevus vascularis mixtus) represents an admixture of cutaneous vascular malformations of the telangiectatic type and angiospastic spots of nevus anemicus. It can occur as an purely cutaneous trait or as a hallmark of a neurocutaneous phenotype (mixed vascular nevus syndrome) characterised by the combination of: (I) paired vascular (telangiectatic and anemic) twin nevi and brain abnormalities of the Dyke-Davidoff-Masson type (i.e., crossed cerebral/cerebellar hemiatrophy with hypoplasia of the ipsilateral cerebral vessels and homolateral hypertrophy of the skull and sinuses (hyperpneumatisation) with contralateral hemispheric hypertrophy); or (II) paired vascular twin nevi and brain malformations of the Dyke-Davidoff-Masson type in association with systemic abnormalities consisting in facial asymmetry, skeletal anomalies (i.e., Legg-Calvé-Perthes-like disease) and disorders of autoimmunity (i.e., diabetes, thyroiditis). In 2014, Happle proposed to name the syndrome with the eponym Ruggieri-Leech syndrome. Review of the existing literature on nevus vascularis mixtus and information on our personal experience on new cases and follow-up of previously reported cases by some of us. The existing literature revealed 4 previous studies including 33 cases with an inferred purely cutaneous trait and 3 cases with a combination of paired vascular twin nevi and brain malformation of the Dyke-Davidoff-Masson type. Our personal experience includes 4 unpublished patients (1 female and 3 males; currently aged 2 to 34 years) seen and followed-up at our Institutions in Italy who had: paired vascular nevi involving either the face (n=2) or the face and parts of the body (n=2); facial asymmetry (n=4); mild to moderate facial dysmorphic features (n=2); developmental delay (n=3); seizures/stroke-like episodes and associated hemiplegia (n=4); muscular hypotrophy (n=2); mild to moderate hemispheric atrophy (n=4); skull osseous hypertrophy (n=4); hyperpneumatisation of the sinuses (n=2); hypoplastic brain vessels (n=4); colpocephaly and malformation of cortical development (n=2). Follow-up data on our previous 2 cases revealed that the vascular abnormalities in the skin and nervous system were stable over years without neurological progression or deterioration. Pathogenically, this complex phenotype suggests that embryonic pairing and somatic recombination of recessive (didymotic) alleles controlling the balance between constriction (i.e., nevus anemicus) and dilatation (i.e., nevus telangiectaticus) of blood vessels could be the primary event causing the phenomena of cutaneous and brain vascular twin spotting and the paired phenomena of skull hyperpneumatisation vs . hypertrophy and brain megalencephaly/colpocephaly vs . cortical dysplasia. This association is likely more frequent than previously thought and should be investigated by means of: (I) brain and spinal cord imaging (combination of CT and MRI studies); (II) skeletal X-ray studies (when dictated by clinical findings); (III) systemic ultrasound studies; (IV) neurophysiologic studies (EEG); (V) psychomotor testing; (VI) and laboratory investigation (including immune-mediated dysfunction).

Mixed vascular nevus syndrome: a report of four new cases and a literature review

PubMed Central

Polizzi, Agata; Strano, Serena; Schepis, Carmelo; Morano, Massimiliano; Belfiore, Giuseppe; Palmucci, Stefano; Foti, Pietro Valerio; Pirrone, Concetta; Sofia, Vito; David, Emanuele; Salpietro, Vincenzo; Mankad, Kshitij; Milone, Pietro

2016-01-01

Background Mixed vascular nevus (or nevus vascularis mixtus) represents an admixture of cutaneous vascular malformations of the telangiectatic type and angiospastic spots of nevus anemicus. It can occur as an purely cutaneous trait or as a hallmark of a neurocutaneous phenotype (mixed vascular nevus syndrome) characterised by the combination of: (I) paired vascular (telangiectatic and anemic) twin nevi and brain abnormalities of the Dyke-Davidoff-Masson type (i.e., crossed cerebral/cerebellar hemiatrophy with hypoplasia of the ipsilateral cerebral vessels and homolateral hypertrophy of the skull and sinuses (hyperpneumatisation) with contralateral hemispheric hypertrophy); or (II) paired vascular twin nevi and brain malformations of the Dyke-Davidoff-Masson type in association with systemic abnormalities consisting in facial asymmetry, skeletal anomalies (i.e., Legg-Calvé-Perthes-like disease) and disorders of autoimmunity (i.e., diabetes, thyroiditis). In 2014, Happle proposed to name the syndrome with the eponym Ruggieri-Leech syndrome. Methods Review of the existing literature on nevus vascularis mixtus and information on our personal experience on new cases and follow-up of previously reported cases by some of us. Results The existing literature revealed 4 previous studies including 33 cases with an inferred purely cutaneous trait and 3 cases with a combination of paired vascular twin nevi and brain malformation of the Dyke-Davidoff-Masson type. Our personal experience includes 4 unpublished patients (1 female and 3 males; currently aged 2 to 34 years) seen and followed-up at our Institutions in Italy who had: paired vascular nevi involving either the face (n=2) or the face and parts of the body (n=2); facial asymmetry (n=4); mild to moderate facial dysmorphic features (n=2); developmental delay (n=3); seizures/stroke-like episodes and associated hemiplegia (n=4); muscular hypotrophy (n=2); mild to moderate hemispheric atrophy (n=4); skull osseous hypertrophy (n=4); hyperpneumatisation of the sinuses (n=2); hypoplastic brain vessels (n=4); colpocephaly and malformation of cortical development (n=2). Follow-up data on our previous 2 cases revealed that the vascular abnormalities in the skin and nervous system were stable over years without neurological progression or deterioration. Conclusions Pathogenically, this complex phenotype suggests that embryonic pairing and somatic recombination of recessive (didymotic) alleles controlling the balance between constriction (i.e., nevus anemicus) and dilatation (i.e., nevus telangiectaticus) of blood vessels could be the primary event causing the phenomena of cutaneous and brain vascular twin spotting and the paired phenomena of skull hyperpneumatisation vs. hypertrophy and brain megalencephaly/colpocephaly vs. cortical dysplasia. This association is likely more frequent than previously thought and should be investigated by means of: (I) brain and spinal cord imaging (combination of CT and MRI studies); (II) skeletal X-ray studies (when dictated by clinical findings); (III) systemic ultrasound studies; (IV) neurophysiologic studies (EEG); (V) psychomotor testing; (VI) and laboratory investigation (including immune-mediated dysfunction). PMID:27942471

Evidence for a possible role of oxygen free radicals in the abnormal functional arterial vasomotion in insulin dependent diabetes.

PubMed

Ceriello, A; Quatraro, A; Caretta, F; Varano, R; Giugliano, D

1990-01-01

A functional arterial spasm, revealed by reduced post-ischemic response, is present in diabetic subjects with no overt evidence of vascular damage. The administration of three different antioxidant agents, vitamin C, thiopronine and glutathione, produces an increase of basal blood flow in both diabetic and normal subjects, and ameliorates significantly the vascular functional response in diabetes. These data suggest that free radicals may play a role in the regulation of arterial resistance in humans, and that a de-regulation of their action may be involved in the development of arterial dysfunction in diabetes.

RNCR3: A regulator of diabetes mellitus-related retinal microvascular dysfunction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shan, Kun; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing

Retinal microvascular abnormality is an important pathological feature of diabetic retinopathy. Herein, we report the role of lncRNA-RNCR3 in diabetes mellitus-induced retinal microvascular abnormalities. We show that RNCR3 is significantly up-regulated upon high glucose stress in vivo and in vitro. RNCR3 knockdown alleviates retinal vascular dysfunction in vivo, as shown by decreased acellular capillaries, decreased vascular leakage, and reduced inflammatory response. RNCR3 knockdown decreases retinal endothelial cell proliferation, and reduces cell migration and tube formation in vitro. RNCR3 regulates endothelial cell function through RNCR3/KLF2/miR-185-5p regulatory network. RNCR3 inhibition may be a treatment option for the prevention of diabetes mellitus-induced retinal microvascular abnormalities. - Highlights:more » • RNCR3 expression is significantly up-regulated upon high glucose stress. • RNCR3 knockdown alleviates retinal vascular dysfunction in vivo. • RNCR3 regulates retinal endothelial cell function in vitro. • RNCR3 regulates retinal endothelial cell function via RNCR3/KLF2/miR-185-5p pathway.« less

The role of capillaroscopy and thermography in the assessment and management of Raynaud's phenomenon.

PubMed

Herrick, Ariane L; Murray, Andrea

2018-05-01

Most patients with Raynaud's phenomenon (RP) have "benign" primary RP (PRP), but a minority have an underlying cause, for example a connective tissue disease such as systemic sclerosis (SSc). Secondary RP can be associated with structural as well as functional digital vascular changes and can be very severe, potentially progressing to digital ulceration or gangrene. The first step in management is to establish why the patient has RP. This short review discusses the role of nailfold capillaroscopy and thermography in the assessment of RP. Nailfold capillaroscopy examines microvascular structure, which is normal in PRP but abnormal in most patients with SSc: the inclusion of abnormal nailfold capillaries into the 2013 classification criteria for SSc behoves clinicians diagnosing connective tissue disease to be familiar with the technique. For those without access to the gold standard of high magnification videocapillaroscopy, a low magnification dermatoscope or USB microscope can be used. Thermography measures surface temperature and is therefore an indirect measure of blood blow, assessing digital vascular function (abnormal in both PRP and SSc). Until now, the use of thermography has been mainly confined to specialist centres and used mainly in research: this may change with development of mobile phone thermography. Copyright © 2018 Elsevier B.V. All rights reserved.

A mouse model for Costello syndrome reveals an Ang II–mediated hypertensive condition

PubMed Central

Schuhmacher, Alberto J.; Guerra, Carmen; Sauzeau, Vincent; Cañamero, Marta; Bustelo, Xosé R.; Barbacid, Mariano

2008-01-01

Germline activation of H-RAS oncogenes is the primary cause of Costello syndrome (CS), a neuro-cardio-facio-cutaneous developmental syndrome. Here we describe the generation of a mouse model of CS by introduction of an oncogenic Gly12Val mutation in the mouse H-Ras locus using homologous recombination in ES cells. Germline expression of the endogenous H-RasG12V oncogene, even in homozygosis, resulted in hyperplasia of the mammary gland. However, development of tumors in these mice was rare. H-RasG12V mutant mice closely phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. These mice also displayed alterations in the homeostasis of the cardiovascular system, including development of systemic hypertension, extensive vascular remodeling, and fibrosis in both the heart and the kidneys. This phenotype was age dependent and was a consequence of the abnormal upregulation of the renin–Ang II system. Treatment with captopril, an inhibitor of Ang II biosynthesis, prevented development of the hypertension condition, vascular remodeling, and heart and kidney fibrosis. In addition, it partially alleviated the observed cardiomyopathies. These mice should help in elucidating the etiology of CS symptoms, identifying additional defects, and evaluating potential therapeutic strategies. PMID:18483625

Association Between Increased Vascular Density and Loss of Protective RAS in Early-Stage NPDR

NASA Technical Reports Server (NTRS)

Radhakrishnan, Krishnan; Raghunandan, Sneha; Vyas, Ruchi J.; Vu, Amanda C.; Bryant, Douglas; Yaqian, Duan; Knecht, Brenda E.; Grant, Maria B.; Chalam, K . V.; Parsons-Wingerter, Patricia

2016-01-01

Our hypothesis predicts that retinal blood vessels increase in density during early-stage progression to moderate nonproliferative diabetic retinopathy (NPDR). The prevailing paradigm of NPDR progression is that vessels drop out prior to abnormal, vision-impairing regrowth at late-stage proliferative diabetic retinopathy (DR). However, surprising results for our previous preliminary study 1 with NASA's VESsel GENeration Analysis (VESGEN) software showed that vessels proliferated considerably during moderate NPDR compared to drop out at both mild and severe NPDR. Validation of our hypothesis will support development of successful early-stage regenerative therapies such as vascular repair by circulating angiogenic cells (CACs). The renin-angiotensin system (RAS)is implicated in the pathogenesis of DR and in the function of CACs, a critical bone marrow-derived population that is instrumental in vascular repair.

Modeling human endothelial cell transformation in vascular neoplasias

PubMed Central

Wen, Victoria W.; MacKenzie, Karen L.

2013-01-01

Endothelial cell (EC)-derived neoplasias range from benign hemangioma to aggressive metastatic angiosarcoma, which responds poorly to current treatments and has a very high mortality rate. The development of treatments that are more effective for these disorders will be expedited by insight into the processes that promote abnormal proliferation and malignant transformation of human ECs. The study of primary endothelial malignancy has been limited by the rarity of the disease; however, there is potential for carefully characterized EC lines and animal models to play a central role in the discovery, development and testing of molecular targeted therapies for vascular neoplasias. This review describes molecular alterations that have been identified in EC-derived neoplasias, as well as the processes that underpin the immortalization and tumorigenic conversion of ECs. Human EC lines, established through the introduction of defined genetic elements or by culture of primary tumor tissue, are catalogued and discussed in relation to their relevance as models of vascular neoplasia. PMID:24046386

Nonselective inhibition of prostaglandin-endoperoxide synthase by naproxen ameliorates hepatic injury in animals with acute or chronic liver injury

PubMed Central

Bahde, Ralf; Kapoor, Sorabh; Gupta, Sanjeev

2014-01-01

The rising prevalence of hepatic injury due to toxins, metabolites, viruses, etc., necessitates development of further mechanisms for protecting the liver and for treating acute or chronic liver diseases. To examine whether inhibition of inflammation directed by cyclo-oxygenase pathways, we performed animal studies with naproxen, which inhibits prostaglandin-endoperoxide synthases 1 and 2 and is in extensive clinical use. We administered carbon tetrachloride to induce acute liver injury and ligated the common bile duct to induce chronic liver injury in adult rats. These experimental manipulations produced abnormalities in liver tests, tissue necrosis, compensatory hepatocyte or biliary proliferation, and onset of fibrosis, particularly after bile duct ligation. After carbon tetrachloride-induced acute injury, naproxen decreased liver test abnormalities, tissue necrosis and compensatory hepatocellular proliferation. After bile duct ligation-induced chronic injury, naproxen decreased liver test abnormalities, tissue injury and compensatory biliary hyperplasia. Moreover, after bile duct ligation, naproxen-treated rats showed more periductular oval liver cells, which have been classified as hepatic progenitor cells. In naproxen-treated rats, we found greater expression in hepatic stellate cells and mononuclear cells of cytoprotective factors, such as vascular endothelial growth factor. The ability of naproxen to induce expression of vascular endothelial growth factor was verified in cell culture studies with CFSC-8B clone of rat hepatic stellate cells. Whereas assays for carbon tetrachloride toxicity using cultured primary hepatocytes established that naproxen was not directly cytoprotective, we found conditioned medium containing vascular endothelial growth factor from naproxen-treated CFSC-8B cells protected hepatocytes from carbon tetrachloride toxicity. Therefore, naproxen was capable of ameliorating toxic liver injury, which involved naproxen-induced release of physiological cytoprotective factors in nonparenchymal liver cells. Such drug-induced release of endogenous cytoprotectants will advance therapeutic development for hepatic injury. PMID:24220607

New therapies for vascular anomalies of the gastrointestinal tract.

PubMed

Fox, Victor L

2018-06-01

Vascular anomalies are a morphologically and biologically diverse group of vascular channel abnormalities that are often congenital but may evolve or change over time in the developing child. Classification is based on a combination of physical and biological properties and clinical behavior that differentiate primarily between tumors and malformations and includes a few provisionally unclassified lesions. Anomalies of the gastrointestinal (GI) tract may present clinically with GI bleeding, abdominal pain, high-output cardiac failure, and malabsorption. This review focuses on new therapies for the treatment of GI bleeding. Important new pharmacological therapies include treatment of hemangioma with non-selective and selective beta-antagonist agents, propranolol and atenolol, and treatment of blue rubber bleb nevus syndrome and cutaneo-visceral angiomatosis with thrombocytopenia (also known as multifocal lymphangioendotheliomatosis with thrombocytopenia) with sirolimus, an inhibitor of the mammalian target of rapamycin. Therapeutic endoscopy may offer an effective alternative to bowel resection for colonic varices and other focal vascular anomalies of the GI tract that fail to respond to pharmacological therapy.

COMPARISON OF REAL-TIME MICROVASCULAR ABNORMALITIES IN PEDIATRIC AND ADULT SICKLE CELL ANEMIA PATIENTS

PubMed Central

Cheung, Anthony T.W.; Miller, Joshua W.; Craig, Sarah M.; To, Patricia L.; Lin, Xin; Samarron, Sandra L.; Chen, Peter C.Y.; Zwerdling, Theodore; Wun, Ted; Li, Chin-Shang; Green, Ralph

2010-01-01

The conjunctival microcirculation in 14 pediatric and 8 adult sickle cell anemia (SCA) patients was studied using computer-assisted intravital microscopy. The bulbar conjunctiva in SCA patients in both age groups exhibited a blanched/avascular appearance characterized by decreased vascularity. SCA patients from both age groups had many of the same abnormal morphometric {vessel diameter, vessel distribution, morphometry (shape), tortuosity, arteriole:venule (A:V) ratio, and hemosiderin deposits} and dynamic {vessel sludging/sludged flow, boxcar blood (trickled) flow and abnormal flow velocity} abnormalities. A severity index (SI) was computed to quantify the degree of vasculopathy for comparison between groups. The severity of vasculopathy differed significantly between the pediatric and adult patients (SI: 4.2 ± 1.8 vs 6.6 ± 2.4; p=0.028), indicative of a lesser degree of overall severity in the pediatric patients. Specific abnormalities that were less prominent in the pediatric patients included abnormal vessel morphometry and tortuosity. Sludged flow, abnormal vessel distribution, abnormal A:V ratio, and boxcar flow, appeared in high prevalence in both age groups. The results indicate that SCA microvascular abnormalities develop in childhood and the severity of vasculopathy likely progresses with age. Intervention and effective treatment/management modalities should target pediatric patients to ameliorate, slow down or prevent progressive microvascular deterioration. PMID:20872552

Pulmonary Vascular Congestion: A Mechanism for Distal Lung Unit Dysfunction in Obesity.

PubMed

Oppenheimer, Beno W; Berger, Kenneth I; Ali, Saleem; Segal, Leopoldo N; Donnino, Robert; Katz, Stuart; Parikh, Manish; Goldring, Roberta M

2016-01-01

Obesity is characterized by increased systemic and pulmonary blood volumes (pulmonary vascular congestion). Concomitant abnormal alveolar membrane diffusion suggests subclinical interstitial edema. In this setting, functional abnormalities should encompass the entire distal lung including the airways. We hypothesize that in obesity: 1) pulmonary vascular congestion will affect the distal lung unit with concordant alveolar membrane and distal airway abnormalities; and 2) the degree of pulmonary congestion and membrane dysfunction will relate to the cardiac response. 54 non-smoking obese subjects underwent spirometry, impulse oscillometry (IOS), diffusion capacity (DLCO) with partition into membrane diffusion (DM) and capillary blood volume (VC), and cardiac MRI (n = 24). Alveolar-capillary membrane efficiency was assessed by calculation of DM/VC. Mean age was 45±12 years; mean BMI was 44.8±7 kg/m2. Vital capacity was 88±13% predicted with reduction in functional residual capacity (58±12% predicted). Despite normal DLCO (98±18% predicted), VC was elevated (135±31% predicted) while DM averaged 94±22% predicted. DM/VC varied from 0.4 to 1.4 with high values reflecting recruitment of alveolar membrane and low values indicating alveolar membrane dysfunction. The most abnormal IOS (R5 and X5) occurred in subjects with lowest DM/VC (r2 = 0.31, p<0.001; r2 = 0.34, p<0.001). Cardiac output and index (cardiac output / body surface area) were directly related to DM/VC (r2 = 0.41, p<0.001; r2 = 0.19, p = 0.03). Subjects with lower DM/VC demonstrated a cardiac output that remained in the normal range despite presence of obesity. Global dysfunction of the distal lung (alveolar membrane and distal airway) is associated with pulmonary vascular congestion and failure to achieve the high output state of obesity. Pulmonary vascular congestion and consequent fluid transudation and/or alterations in the structure of the alveolar capillary membrane may be considered often unrecognized causes of airway dysfunction in obesity.

[Orbito-palpebral vascular pathology].

PubMed

Heran Dreyfus, F; Galatoire, O; Koskas, P; Lafitte, F; Nau, E; Bergès, O

2016-11-01

Orbito-palpebral vascular pathology represents 10% of all the diseases of this area. The lesion may be discovered during a brain CT scan or MRI, or because it causes clinical symptoms such as orbital mass, visual or oculomotor alteration, pain, proptosis, or acute bleeding due to a complication of the lesion (hemorrhage, thrombosis). We present these lesions using an anatomical, clinical, imaging and therapeutic approach. We distinguish four different entities. Vascular tumors have common imaging characteristics (hypersignal on T2 sequence, contrast enhancement, abnormal vascularization well depicted with ultrasound and Doppler, and possible bleeding). The main lesions are cavernous hemangiomas, the most frequent lesion of that type during adulthood; infantile hemangiomas, the most frequent vascular tumor in children; and more seldomly, hemangioperitcytomas. True vascular malformations are divided according to their flow. Low flow lesions are venous (orbital varix), capillarovenous or lymphatic (lymphangioma). High flow malformations, more rare, are either arteriovenous or arterial malformations (aneurisms). Complex malformations include both low and high flow elements. Lesions leading to modifications of the orbito-palpebral blood flow are mainly due to cavernous sinus abnormalities, either direct carotid-cavernous fistula affecting young adults after severe head trauma, or dural fistula, more insidious, found in older adults. The last section is devoted to congenital syndromic vascular malformations (Sturge-Weber, Rendu-Olser…). This classification allows for a better understanding of these pathologies and their specific imaging features. Copyright © 2016. Published by Elsevier Masson SAS.

The influence of the telomere-telomerase system on diabetes mellitus and its vascular complications.

PubMed

Qi Nan, Wu; Ling, Zhang; Bing, Chen

2015-06-01

The telomere-telomerase system plays an important role in the pathogenesis and disease progression of diabetes mellitus as well as in its vascular complications. Recent studies suggest that telomere shortening and abnormal telomerase activity occur in patients with diabetes mellitus, and targeting the telomere-telomerase system has become a prospective treatment for diabetes mellitus and its vascular complications. This review highlights the significance of the telomere-telomerase system and supports its role as a possible therapeutic target for patients with diabetes mellitus and its vascular complications Areas covered: This review covers the advances in understanding the telomere-telomerase system over the last 30 years and its significance in diabetes mellitus. In addition, it provides knowledge regarding the significance of the telomere-telomerase system in diabetes mellitus and its vascular complications as well as its role and mechanisms in oxidative stress, cell therapy and antioxidant activity Expert opinion: The telomere-telomerase system may be a potential therapeutic target that can protect against DNA damage and apoptosis in patients with diabetes mellitus and its vascular complications. DNA damage and apoptosis are associated with oxidative stress and are involved in the dysfunction of pancreatic β cells, insulin resistance, and its vascular complications. Abnormalities in the telomere-telomerase system may be associated with diabetes mellitus and its vascular complications. Therapies targeting telomere-telomerase system, telomerase reverse transcriptase transfection and alterative telomere lengthening must be identified before gene therapy can commence.

The mechanical properties of infrainguinal vascular bypass grafts: their role in influencing patency.

PubMed

Sarkar, S; Salacinski, H J; Hamilton, G; Seifalian, A M

2006-06-01

When autologous vein is unavailable, prosthetic graft materials, particularly expanded polytetrafluoroethylene are used for peripheral arterial revascularisation. Poor long term patency of prosthetic materials is due to distal anastomotic intimal hyperplasia. Intimal hyperplasia is directly linked to shear stress abnormalities at the vessel wall. Compliance and calibre mismatch between native vessel and graft, as well as anastomotic line stress concentration contribute towards unnatural wall shear stress. High porosity reduces graft compliance by causing fibrovascular infiltration, whereas low porosity discourages the development of an endothelial lining and hence effective antithrombogenicity. Therefore, consideration of mechanical properties is necessary in graft development. Current research into synthetic vascular grafts concentrates on simulating the mechanical properties of native arteries and tissue engineering aims to construct a new biological arterial conduit.

Vascular alterations underlie developmental problems manifested in cloned cattle before or after birth.

PubMed

Maiorka, Paulo Cesar; Favaron, Phelipe Oliveira; Mess, Andrea Maria; dos Santos, Caio Rodrigues; Alberto, Miryan Lanca; Meirelles, Flavio Vieira; Miglino, Maria Angelica

2015-01-01

Although assisted reproductive techniques are commonly applied in humans and animals, they are frequently associated with major developmental deficits and reduced viability. To explore abnormalities associated with cloning or nuclear transfer (NT) as the most invasive of these methods, we used a bovine model to characterize abnormalities. Detailed necropsy examinations were done on 13 calves that died soon after birth; in addition, we included data from embryos and fetuses (produced by NT) that terminated prematurely. Bovine clones that survived until the neonatal period differed quantitatively and qualitatively from in-vivo-derived cattle. Although alterations affected a variety of organs (e.g. heart, lung and liver), there was a clear association with abberant vascular developmental during the early intrauterine phase. Therefore, we concluded that vascular problems were key alterations induced by cloning (presumably via epigenetic modifications).

Vascular Alterations Underlie Developmental Problems Manifested in Cloned Cattle before or after Birth

PubMed Central

Favaron, Phelipe Oliveira; dos Santos, Caio Rodrigues; Alberto, Miryan Lanca; Meirelles, Flavio Vieira; Miglino, Maria Angelica

2015-01-01

Although assisted reproductive techniques are commonly applied in humans and animals, they are frequently associated with major developmental deficits and reduced viability. To explore abnormalities associated with cloning or nuclear transfer (NT) as the most invasive of these methods, we used a bovine model to characterize abnormalities. Detailed necropsy examinations were done on 13 calves that died soon after birth; in addition, we included data from embryos and fetuses (produced by NT) that terminated prematurely. Bovine clones that survived until the neonatal period differed quantitatively and qualitatively from in-vivo-derived cattle. Although alterations affected a variety of organs (e.g. heart, lung and liver), there was a clear association with abberant vascular developmental during the early intrauterine phase. Therefore, we concluded that vascular problems were key alterations induced by cloning (presumably via epigenetic modifications). PMID:25584533

Vascular, inflammatory, and metabolic factors associated with cognition in aging persons with chronic epilepsy.

PubMed

Hermann, Bruce P; Sager, Mark A; Koscik, Rebecca L; Young, Kate; Nakamura, Keith

2017-11-01

We examined cognition in aging persons with chronic epilepsy; characterized targeted vascular, inflammatory, and metabolic risk factors associated with abnormal cognitive aging in the general population; and examined associations between cognition and vascular, inflammatory, and metabolic health. Participants included 40 persons with chronic localization-related epilepsy and 152 controls, aged 54.6 and 55.3, respectively. Participants underwent neuropsychological assessment, clinical examination, and fasting blood evaluation for quantification of vascular status (systolic and diastolic blood pressure, obesity/body mass index [BMI], total and high-density lipoprotein [HDL] cholesterol level, and homocysteine), inflammatory markers (high sensitivity C-reactive protein [hs-CRP], and interleukin-6 [IL-6]), and metabolic status (insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], glucose). Epilepsy participants exhibited impairment across all cognitive factor scores (all p's < 0.0001); abnormalities in BMI (p = 0.049), hs-CRP (p = 0.046), HOMA-IR (p = 0.0040), and fasting glucose (p = 0.03), with significant relationships between higher HOMA-IR with poorer Immediate Memory (p = 0.03) and Visuospatial Ability (0.03); elevated hs-CRP with poorer Visuospatial (p = 0.035) and Verbal Ability (p = 0.06); elevated BMI with poorer Speed/Flexibility (p = 0.04), Visuospatial (p = 0.001) and Verbal Ability (p = 0.02); and lower HDL with poorer Verbal Learning/Delayed Memory (p = 0.01), Speed/Flexibility (p = 0.043), and Working Memory (p = 0.008). Aging persons with chronic epilepsy exhibit multiple abnormalities in metabolic, inflammatory, and vascular health that are associated with poorer cognitive function. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Poland syndrome associated with an aberrant subclavian artery and vascular abnormalities of the retina in a child exposed to misoprostol during pregnancy.

PubMed

Rosa, Rafael Fabiano Machado; Travi, Giovanni M; Valiatti, Fabiana; Zen, Paulo Ricardo Gazzola; Pinto, Louise Lapagesse; Kiss, Andrea; Graziadio, Carla; Paskulin, Giorgio Adriano

2007-06-01

Poland syndrome has been attributed to a process of vascular disruption, and exposure to misoprostol at 6-8 weeks of gestation has been shown to produce defects attributed to vascular disruption. Herein we report the first case of a patient with Poland syndrome associated with an aberrant subclavian artery and vascular abnormalities of the retina, whose mother used misoprostol during pregnancy. A White boy of 1 year and 7 months of age, whose mother used misoprostol during the second month of pregnancy, presented with bilateral epicanthal folds, aplasia of the sternocostal head of the pectoralis major muscle with a hypoplastic nipple on the right side, and asymmetry between the upper limbs. The results of an angiotomographic study showed the presence of an aberrant right subclavian artery. Ultrasonographic evaluation showed turbulence and a high peak in the diastolic velocity in both carotid arteries, suggesting stenosis. Ophthalmologic assessment disclosed an intense bilateral tortuosity of the retinal blood vessels, with arterialnarrowing and rarefaction of the retinal pigment epithelium. This case suggests that the mechanism of vascular disruption of misoprostol could be related to the aberrant subclavian artery and the observed Poland syndrome. His retinal findings are different from those in cases described thus far in the literature, and this pattern of anomaly has never been associated with a gestational exposure to misoprostol. The possibility of a relationship of the aberrant right subclavian artery and the pattern of blood flow verified in the carotid arteries with the eye fundus abnormalities could be causally related or simply coincidental.

[When to ask for a skin biopsy in a patient with leg ulcer? Retrospective study of 143 consecutive biopsies].

PubMed

Stansal, A; Khayat, K; Duchatelle, V; Tella, E; Gautier, V; Sfeir, D; Attal, R; Lazareth, I; Priollet, P

2018-02-01

A vascular cause is found in around 85% of leg ulcer patients, but non-vascular causes are also observed. Their diagnosis is based on a set of clinical arguments and skin biopsy with histological analysis. The aim of this study was to analyze the results of these biopsies and to find common criteria for ulcers whose skin biopsies had led to the diagnosis of a non-vascular ulcer. A retrospective study was carried out on the analysis of 143 skin biopsies of leg ulcers. The reasons for the biopsy were mainly atypical clinical signs and/or the lack of improvement in care after 6 months, as advocated by the French health authorities. The skin biopsies led to a diagnosis of non-vascular ulcer in 4.9% of cases (7/143), including skin cancer (n=5, 3.5%), cutaneous leishmaniasis (n=1, 0.7%) and Pyoderma gangrenosum (n=1, 0.7%). The univariate statistical analysis revealed that an elevated rim and abnormal excessive granulation tissue were significantly more frequently found in these ulcers. All patients with a positive skin biopsy had associated vascular involvement. This study found a 5% rate of non-vascular causes of ulcers, mainly skin cancer. Elevated rims and abnormal excessive granulation tissue were the unusual features most commonly found in these ulcers. All patients whose skin biopsy revealed a non-vascular cause had associated vascular involvement. This information confirms the need to perform a skin biopsy, even in the presence of a vascular disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Risk factors of erectile dysfunction and penile vascular changes after surgical repair of penile fracture.

PubMed

El-Assmy, A; El-Tholoth, H S; Abou-El-Ghar, M E; Mohsen, T; Ibrahiem, E H I

2012-01-01

This study was conducted to determine the preoperative and intraoperative risk factors of ED and the underlying penile vascular abnormalities among patients with penile fracture treated surgically. In all, 180 patients with penile fracture were treated surgically and followed up in one center. None of our patients had ED before the penile trauma and only two of them had risk factors for systemic vascular diseases, such as diabetes mellitus (one patient) and hypertension (one patient). After a mean follow-up of 106 months, 11 patients (6.6%) developed ED, 7 had mild ED and 4 had moderate ED. The main risk factors for subsequent ED were aging, >50 years, and bilateral corporal involvement. Among the 11 patients with ED, color Doppler ultrasonography (CDU) showed normal Doppler indices in 4 (36.4%), veno-occlusive dysfunction in 4 (36.4%) and arterial insufficiency in the remaining 3 (27.2%) patients. CDU assessments from the injured and intact sides were comparable. ED of either a psychological or vascular origin can be encountered as a long-term sequel of surgical treatment of penile fracture. Aging, >50 years, at presentation and bilateral corporal involvement is the main risk factors for subsequent development of ED.

Semaphorin 3G Provides a Repulsive Guidance Cue to Lymphatic Endothelial Cells via Neuropilin-2/PlexinD1.

PubMed

Liu, Xinyi; Uemura, Akiyoshi; Fukushima, Yoko; Yoshida, Yutaka; Hirashima, Masanori

2016-11-22

The vertebrate circulatory system is composed of closely related blood and lymphatic vessels. It has been shown that lymphatic vascular patterning is regulated by blood vessels during development, but its molecular mechanisms have not been fully elucidated. Here, we show that the artery-derived ligand semaphorin 3G (Sema3G) and the endothelial cell receptor PlexinD1 play a role in lymphatic vascular patterning. In mouse embryonic back skin, genetic inactivation of Sema3G or PlexinD1 results in abnormal artery-lymph alignment and reduced lymphatic vascular branching. Conditional ablation in mice demonstrates that PlexinD1 is primarily required in lymphatic endothelial cells (LECs). In vitro analyses show that Sema3G binds to neuropilin-2 (Nrp2), which forms a receptor complex with PlexinD1. Sema3G induces cell collapse in an Nrp2/PlexinD1-dependent manner. Our findings shed light on a molecular mechanism by which LECs are distributed away from arteries and form a branching network during lymphatic vascular development. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

[Vascular malformations in the Williams-Beuren syndrome: report of three new cases].

PubMed

Sator, Hicham; Rhouni, Fatima Ezzahra; Benjouad, Ibitihale; Rhouni, Fatima Ezzahra; Benjouad, Ibitihale; Dafiri, Rachida; Chat, Latifa

2016-01-01

The Williams-Beuren syndrome is a rare genetic disease. It combines classically specific facial dysmorphism, cardiovascular malformations and specific neuropsychological profile. We report three cases of Williams-Beuren syndrome in children with particular emphasis on vascular abnormalities observed on CT angiography and MR angiography.

Hepatic hilar and sectorial vascular and biliary anatomy in right graft adult live liver donor transplantation.

PubMed

Radtke, A; Sgourakis, G; Sotiropoulos, G C; Molmenti, E P; Nadalin, S; Fouzas, I; Schroeder, T; Saner, F H; Schenk, A; Cicinnati, V R; Malagó, M; Lang, H

2008-11-01

The aim of this study was to analyze vascular and biliary variants at the hilar and sectorial level in right graft adult living donor liver transplantation. From January 2003 to June 2007, 139 consecutive live liver donors underwent three-dimensional computed tomography (3-D CT) reconstructions and virtual 3-D liver partitioning. We evaluated the portal (PV), arterial (HA), and biliary (BD) anatomy. The hilar and sectorial biliary/vascular anatomy was predominantly normal (70%-85% and 67%-78%, respectively). BD and HA showed an equal incidence (30%) of hilar anomalies. BD and PV had a nearly identical incidence of sectorial abnormalities (64.7% and 66.2%, respectively). The most frequent "single" anomaly was seen centrally in HA (21%) and distally in BD (18%). A "double" anomaly involved BD/HA (7.2%) in the hilum, and HA/PV and BD/PV (6.5% each) sectorially. A "triple" anomaly involving all systems was found at the hilum in 1.4% of cases, and at the sectorial level in 9.4% of instances. Simultanous central and distal abnormalities were rare. In this study, 13.7% of all donor candidates showed normal hilar and sectorial anatomy involving all 3 systems. A simultaneous central and distal "triple" abnormality was not encountered. A combination of "triple" hilar anomaly with "triple" sectorial normality was observed in 2 cases (1.4%). A central "triple" normality associated with a distal "triple" abnormality occurred in 7 livers (5%). Our data showed a variety of "horizontal" (hilar or sectorial) and "vertical" (hilar and sectorial) vascular and biliary branching patterns, providing comprehensive assistance for surgical decision-making prior to right graft hepatectomy.

Murrayafoline A Induces a G0/G1-Phase Arrest in Platelet-Derived Growth Factor-Stimulated Vascular Smooth Muscle Cells

PubMed Central

Han, Joo-Hui; Kim, Yohan; Jung, Sang-Hyuk; Lee, Jung-Jin; Park, Hyun-Soo; Song, Gyu-Yong; Cuong, Nguyen Manh; Kim, Young Ho

2015-01-01

The increased potential for vascular smooth muscle cell (VSMC) growth is a key abnormality in the development of atherosclerosis and post-angioplasty restenosis. Abnormally high activity of platelet-derived growth factor (PDGF) is believed to play a central role in the etiology of these pathophysiological situations. Here, we investigated the anti-proliferative effects and possible mechanism(s) of murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa Guillamin (Rutaceae), on PDGF-BB-stimulated VSMCs. Murrayafoline A inhibited the PDGF-BB-stimulated proliferation of VSMCs in a concentration-dependent manner, as measured using a non-radioactive colorimetric WST-1 assay and direct cell counting. Furthermore, murrayafoline A suppressed the PDGF-BB-stimulated progression through G0/G1 to S phase of the cell cycle, as measured by [3H]-thymidine incorporation assay and cell cycle progression analysis. This anti-proliferative action of murrayafoline A, arresting cell cycle progression at G0/G1 phase in PDGF-BB-stimulated VSMCs, was mediated via down-regulation of the expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, CDK4, and proliferating cell nuclear antigen (PCNA), and the phosphorylation of retinoblastoma protein (pRb). These results indicate that murrayafoline A may be useful in preventing the progression of vascular complications such as restenosis after percutaneous transluminal coronary angioplasty and atherosclerosis. PMID:26330754

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

PubMed

Beck, Susanne C; Feng, Yuxi; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease

PubMed Central

Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W.

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects. PMID:28575130

Uterine Vascular Lesions

PubMed Central

Vijayakumar, Abhishek; Srinivas, Amruthashree; Chandrashekar, Babitha Moogali; Vijayakumar, Avinash

2013-01-01

Vascular lesions of the uterus are rare; most reported in the literature are arteriovenous malformations (AVMs). Uterine AVMs can be congenital or acquired. In recent years, there has been an increasing number of reports of acquired vascular lesions of the uterus following pregnancy, abortion, cesarean delivery, and curettage. It can be seen from these reports that there is confusion concerning the terminology of uterine vascular lesions. There is also a lack of diagnostic criteria and management guidelines, which has led to an increased number of unnecessary invasive procedures (eg, angiography, uterine artery embolization, hysterectomy for abnormal vaginal bleeding). This article familiarizes readers with various vascular lesions of the uterus and their management. PMID:24340126

78 FR 734 - Medical Imaging Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-04

..., LLC. The proposed indication (use) for this product is for magnetic resonance imaging in brain...) to detect and visualize areas with disruption of the blood brain barrier (specialized tissues that help protect the brain) and/or abnormal vascularity (abnormal blood circulation). FDA intends to make...

In vivo imaging of pulmonary nodule and vasculature using endoscopic co-registered optical coherence tomography and autofluorescence imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Pahlevaninezhad, Hamid; Lee, Anthony; Hohert, Geoffrey; Schwartz, Carely; Shaipanich, Tawimas; Ritchie, Alexander J.; Zhang, Wei; MacAulay, Calum E.; Lam, Stephen; Lane, Pierre M.

2016-03-01

Peripheral lung nodules found by CT-scans are difficult to localize and biopsy bronchoscopically particularly for those ≤ 2 cm in diameter. In this work, we present the results of endoscopic co-registered optical coherence tomography and autofluorescence imaging (OCT-AFI) of normal and abnormal peripheral airways from 40 patients using 0.9 mm diameter fiber optic rotary pullback catheter. Optical coherence tomography (OCT) can visualize detailed airway morphology endoscopically in the lung periphery. Autofluorescence imaging (AFI) can visualize fluorescing tissue components such as collagen and elastin, enabling the detection of airway lesions with high sensitivity. Results indicate that AFI of abnormal airways is different from that of normal airways, suggesting that AFI can provide a sensitive visual presentation for rapidly identifying possible sites of pulmonary nodules. AFI can also rapidly visualize in vivo vascular networks using fast scanning parameters resulting in vascular-sensitive imaging with less breathing/cardiac motion artifacts compared to Doppler OCT imaging. It is known that tumor vasculature is structurally and functionally different from normal vessels. Thus, AFI can be potentially used for differentiating normal and abnormal lung vasculature for studying vascular remodeling.

VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer

PubMed Central

Gerstner, Elizabeth R.; Duda, Dan G.; di Tomaso, Emmanuelle; Ryg, Peter A.; Loeffler, Jay S.; Sorensen, A. Gregory; Ivy, Percy; Jain, Rakesh K.; Batchelor, Tracy T.

2016-01-01

Most brain tumors oversecrete vascular endothelial growth factor (VEGF), which leads to an abnormally permeable tumor vasculature. This hyperpermeability allows fluid to leak from the intravascular space into the brain parenchyma, which causes vasogenic cerebral edema and increased interstitial fluid pressure. Increased interstitial fluid pressure has an important role in treatment resistance by contributing to tumor hypoxia and preventing adequate tumor penetration of chemotherapy agents. In addition, edema and the corticosteroids needed to control cerebral edema cause significant morbidity and mortality. Agents that block the VEGF pathway are able to decrease vascular permeability and, thus, cerebral edema, by restoring the abnormal tumor vasculature to a more normal state. Decreasing cerebral edema minimizes the adverse effects of corticosteroids and could improve clinical outcomes. Anti-VEGF agents might also be useful in other cancer-related conditions that increase vascular permeability, such as malignant pleural effusions or ascites. PMID:19333229

Sodium sensitive hypertension: renal and adrenal non-modulation in its pathogenesis

NASA Technical Reports Server (NTRS)

Hollenberg, N. K.; Williams, G. H.

1988-01-01

The thrust of this essay will be to organize a growing body of evidence which indicates that an abnormality of the kidney, and the adrenal, involving disordered regulation through the renin-angiotensin system, is responsible for the pathogenesis in about 45% of patients--a discrete subgroup that may be most common cause of hypertension. That fundamental abnormality leads to disordered renal sodium handling and sodium-sensitive hypertension, abnormalities in the renal vascular response to changes in sodium intake and to angiotensin II, blunted decrements of renin release in response to saline or angiotensin II, and an accentuated renal vasodilator response to angiotensin converting enzyme (ACE) inhibition. ACE inhibition not only increases renal blood flow substantially more in these patients than it does in normal subjects, ACE inhibition also restores to normal the renal vascular and adrenal response to angiotensin II, renin release in response to angiotensin II, renal sodium handling--and ultimately blood pressure. Finally, and perhaps most intriguing, similar abnormalities have been found in 50% of the normotensive offspring of patients with essential hypertension and evidence is accruing to indicate that the abnormality is inherited as a Mendelian dominant.

Cardiometabolic features of polycystic ovary syndrome.

PubMed

Hoffman, Leslie K; Ehrmann, David A

2008-04-01

Polycystic ovary syndrome (PCOS) is a complex disorder comprising both hormonal and metabolic abnormalities that include impaired glucose tolerance, type 2 diabetes, vascular disease, dyslipidemia, and obstructive sleep apnea. Insulin resistance is a central pathogenetic factor in PCOS that seems to result from a post-receptor-binding defect in insulin action. Insulin resistance and the consequent development of hyperinsulinemia contribute to the constellation of cardiometabolic abnormalities noted above. Although there is a paucity of data in regard to cardiovascular event rates and mortality in PCOS, an increased prevalence of cardiovascular risk factors has been well documented. Attention to the metabolic risks associated with PCOS, starting as early as adolescence, is essential to the medical care of these patients.

Flt1/VEGFR1 heterozygosity causes transient embryonic edema.

PubMed

Otowa, Yasunori; Moriwaki, Kazumasa; Sano, Keigo; Shirakabe, Masanori; Yonemura, Shigenobu; Shibuya, Masabumi; Rossant, Janet; Suda, Toshio; Kakeji, Yoshihiro; Hirashima, Masanori

2016-06-02

Vascular endothelial growth factor-A is a major player in vascular development and a potent vascular permeability factor under physiological and pathological conditions by binding to a decoy receptor Flt1 and its primary receptor Flk1. In this study, we show that Flt1 heterozygous (Flt1(+/-)) mouse embryos grow up to adult without life-threatening abnormalities but exhibit a transient embryonic edema around the nuchal and back regions, which is reminiscent of increased nuchal translucency in human fetuses. Vascular permeability is enhanced and an intricate infolding of the plasma membrane and huge vesicle-like structures are seen in Flt1(+/-) capillary endothelial cells. Flk1 tyrosine phosphorylation is elevated in Flt1(+/-) embryos, but Flk1 heterozygosity does not suppress embryonic edema caused by Flt1 heterozygosity. When Flt1 mutants are crossed with Aspp1(-/-) mice which exhibit a transient embryonic edema with delayed formation and dysfunction of lymphatic vessels, only 5.7% of Flt1(+/-); Aspp1(-/-) mice survive, compared to expected ratio (25%). Our results demonstrate that Flt1 heterozygosity causes a transient embryonic edema and can be a risk factor for embryonic lethality in combination with other mutations causing non-lethal vascular phenotype.

The Use of Quantitative SPECT/CT Imaging to Assess Residual Limb Health

DTIC Science & Technology

2017-10-01

loss in 2020.4 BACKGROUND The integrity of the vasculature, nerves, and soft tissue within the extremities is of high importance, as an impairment or...formation, and vascular abnormalities .6 Therefore, effective diagnosis can be critical in directing the medical treatment of patients. Standard noninva...and identify damage to their nor- mal fasicular pattern, nerve swelling or thickening, loss of nerve bundle integrity , and development of neuromas

ARTERIAL HYPERTENSION AND IRRADIATION DAMAGE TO THE NERVOUS SYSTEM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asscher, A.W.; Anson, S.G.

1962-12-29

On the basis of previous studies it appeared that irradiation damage to the nervous system might be more severe and more easily produced in hypertensive than in normotensive subjects. This hypothesis was investigated by studying the frequency of neurological complications and vascular lesions in the spinal cord after x irradiation of the cord in hypertensive and normotensive rats. Two weeks before irradiation of the spinal cord, a clip was applied to the right renal artery of the animals to produce hypertension. Single doses of 1500, 2000, or 3000 r were administered to the spinal cord in the cervical and uppermore » thoracic region of hypertensive rats (systolic blood pressure higher than 145 mm Hg) and normotensive rats. After 1500 r to spinal cord, no abnormalities were noted in the normotensive controls during the period of observation. Some hypertensive animaIs showed transient abnormalities of gait, and during the following week died suddenly. Those remaining died unexpectedly 35-259 days after irradiation without apparent preceding neurological manifestations, although acute vascular lesions were found in the irradiated regions of the spinal cord. The normotensive controls of the 2000-r group showed no abnormalities of gait or of tail sensation, but the hypertensive rats died 67-243 days after irradiation, and ntaxic episodes preceding these unexpected deaths in one animal. Ristologically, the irradiated segments of the cords showed multiple focal acute vascular necrosis. The smaller arteries in irradiated segments of the cords showed hyaline thickening; some of the smaller vessels were widely dilated and filled with blood, and their walls were necrotic. The white matter of the irradiated parts of these cords showed numerous holes (status spongiosus) in the lateral and dorsal columns. The anterior-horn cells in the irradiated zones were swollen, their nuclei pyknotic and cytoplasm devoid of Nissl granules. No abnormalities, besides thickening of the meninges in the irradiated areas, were found in the cords of the normotensive controls. After 3000 r the normotensive animals of this group showed no abnormalities of gait and Survived normally; no vascular lesions were found in their spinal cords. The hypentensive animals died suddenly 43-70 days after irradiation of the cord, and in all, death was preceded by ataxic episodes. Postmortem, numerous foci of acute vascular necrosis were found in the irradiated cord. These experiments suggest that moderate arterial hypertension seriously modifies the effect of x irradiation of the spinal cord. The transience of the ataxia in irradiated hypertensive rats suggests a possible origin in reversible vasoconstriction. When such episodes were followed by sudden death, arterial necrosis was invariably present in the irradiated region of the cord. Moreover, in hypertensive animals in which paraplegia developed, there was widespread necrosis of nerve tissue as well as organized vascular necrosis. A search of hospital records revealed three cases in which high blood pressure was recorded along with necrosis of the brain or spinal cord following therapeutic irradiation. In two of these, large doses of irradiation had been administered, and the necrosis might have been due to irradiation alone. In the third case, however, necrosis of the spinal cord occurred artd one factor which may have determined this individual sensitivity was high blood pressure. (BBB)« less

High phosphate feeding promotes mineral and bone abnormalities in mice with chronic kidney disease.

PubMed

Lau, Wei Ling; Linnes, Michael; Chu, Emily Y; Foster, Brian L; Bartley, Bryan A; Somerman, Martha J; Giachelli, Cecilia M

2013-01-01

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic syndrome characterized by imbalances in mineral homeostasis, renal osteodystrophy (ROD) and ectopic calcification. The mechanisms underlying this syndrome in individuals with chronic kidney disease (CKD) are not yet clear. We examined the effect of normal phosphate (NP) or high phosphate (HP) feeding in the setting of CKD on bone pathology, serum biochemistry and vascular calcification in calcification-prone dilute brown non-agouti (DBA/2) mice. In both NP and HP-fed CKD mice, elevated serum parathyroid hormone and alkaline phosphatase (ALP) levels were observed, but serum phosphorus levels were equivalent compared with sham controls. CKD mice on NP diet showed trabecular alterations in the long bone consistent with high-turnover ROD, including increased trabecular number with abundant osteoblasts and osteoclasts. Despite trabecular bone and serum biochemical changes, CKD/NP mice did not develop vascular calcification. In contrast, CKD/HP mice developed arterial medial calcification (AMC), more severe trabecular bone alterations and cortical bone abnormalities that included decreased cortical thickness and density, and increased cortical porosity. Cortical bone porosity and trabecular number strongly correlated with the degree of aortic calcification. HP feeding was required to induce the full spectrum of CKD-MBD symptoms in CKD mice.

Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in l-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT1R Expression

PubMed Central

Maneesai, Putcharawipa; Prasarttong, Patoomporn; Bunbupha, Sarawoot; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Tangsucharit, Panot; Prachaney, Parichat; Pakdeechote, Poungrat

2016-01-01

This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in Nω-Nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS. PMID:26938552

Computed Tomography Angiography in Microsurgery: Indications, Clinical Utility, and Pitfalls

PubMed Central

Lee, Gordon K.; Fox, Paige M.; Riboh, Jonathan; Hsu, Charles; Saber, Sepideh; Rubin, Geoffrey D.; Chang, James

2013-01-01

Objective: Computed tomographic angiography (CTA) can be used to obtain 3-dimensional vascular images and soft-tissue definition. The goal of this study was to evaluate the reliability, usefulness, and pitfalls of CTA in preoperative planning of microvascular reconstructive surgery. Methods: A retrospective review of patients who obtained preoperative CTA in preparation for planned microvascular reconstruction was performed over a 5-year period (2001–2005). The influence of CTA on the original operative plan was assessed for each patient, and CTA results were correlated to the operative findings. Results: Computed tomographic angiography was performed on 94 patients in preparation for microvascular reconstruction. In 48 patients (51%), vascular abnormalities were noted on CTA. Intraoperative findings correlated with CTA results in 97% of cases. In 42 patients (45%), abnormal CTA findings influenced the original operative plan, such as the choice of vessels, side of harvest, or nature of the reconstruction (local flap instead of free tissue transfer). Technical difficulties in performing CTA were encountered in 5 patients (5%) in whom interference from external fixation devices was the main cause. Conclusions: This large study of CTA obtained for preoperative planning of reconstructive microsurgery at both donor and recipient sites study demonstrates that CTA is safe and highly accurate. Computed tomographic angiography can alter the surgeon's reconstructive plan when abnormalities are noted preoperatively and consequently improve results by decreasing vascular complication rates. The use of CTA should be considered for cases of microsurgical reconstruction where the vascular anatomy may be questionable. PMID:24023972

Pseudo-low Frequency Hearing Loss and Its Improvement After Treatment May Be Objective Signs of Significant Vascular Pathology in Patients With Pulsatile Tinnitus.

PubMed

Jeon, Hyoung Won; Kim, So Young; Choi, Byung Se; Bae, Yun Jung; Koo, Ja-Won; Song, Jae-Jin

2016-10-01

In patients with pulsatile tinnitus (PT), physical examination such as auscultation with head position change or digital compression over the ipsilateral jugular vein provides physicians with important information. However, objective diagnosis of PT is sometimes limited because 1) audible bruit is absent on auscultation in some patients, 2) abnormal vascular structures found in radiologic evaluation is not always pathognomonic because they can be found in asymptomatic subjects as well, and 3) although an objective diagnostic tool using transcanal sound recording has recently been introduced, special equipment is needed. In this regard, recent studies that have reported ipsilateral low-frequency hearing loss (LFHL) on pure-tone audiometry (PTA) in some patients with PT, and its recovery after successful management, prompted us to conduct a retrospective observational study on the characteristics of the audiometric profile, the association between the audiometric profile and radiologic findings, and pre- and posttreatment changes in low-frequency hearing thresholds in PT patients. We tested two hypotheses: PT patients with marked vascular pathologies located close to the cochlea may show ipsilateral pseudo-LFHL (PLFHL) because of the masking effects of the PT itself, and their PLFHL may disappear if their vascular pathology is successfully managed by surgical or endovascular intervention. Retrospective case review. Tertiary referral center. A total of 85 PT subjects who underwent both audiologic and radiologic examinations. All patients' pre- and posttreatment PTA thresholds and radiologic findings were analyzed. By comparing the LFHL (an ipsilateral hearing threshold greater than 10 dB HL at both 250 and 500 Hz or greater than 20 dB HL at either 250 or 500 Hz compared with the contralateral side) group and a non-LFHL group with regard to the incidence of vascular structural abnormalities, we evaluated the incidence of abnormal vascular structures in the head and neck between the LFHL and non-LFHL groups. In addition, by comparing pre- and posttreatment PTA thresholds of seven PT patients with ipsilateral LFHL, we further evaluated the changes in low-frequency hearing thresholds and their role as an objective sign for diagnosis and outcome evaluation. Of 85 patients, 22 (25.9%) presented with ipsilateral LFHL. Compared with patients without this condition, patients with ipsilateral LFHL showed a significantly higher rate of abnormal vascular structure. In addition, most of the radiologic abnormalities found in the LFHL group were highly suspicious causative lesions that are responsible for the perception of PT according to the previous literature. In eight PT patients with ipsilateral LFHL who underwent both pre- and posttreatment audiograms, the average posttreatment pure-tone threshold at 250 Hz showed significant improvement compared with the pretreatment threshold. PT patients presenting with ipsilateral LFHL have higher possibility of having a discrete vascular pathology near the cochlea on radiologic evaluation. As ipsilateral LFHL improves in most patients after treatment, LFHL in patients with PT may be PLFHL because of the masking effects of the pulsatile sound, and the changes in the low-frequency thresholds may be applicable for objective diagnosis and evaluation of the effects of the treatment.

Expression of Genes Involved in Drosophila Wing Morphogenesis and Vein Patterning Are Altered by Spaceflight

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, Patricia A.; Hosamani, Ravikumar; Bhattacharya, Sharmila

2015-01-01

Imaginal wing discs of Drosophila melanogaster (fruit fly) defined during embryogenesis ultimately result in mature wings of stereotyped (specific) venation patterning. Major regulators of wing disc development are the epidermal growth factor receptor (EGF), Notch, Hedgehog (Hh), Wingless (Wg), and Dpp signaling pathways. Highly stereotyped vascular patterning is also characteristic of tissues in other organisms flown in space such as the mouse retina and leaves of Arabidopsis thaliana. Genetic and other adaptations of vascular patterning to space environmental factors have not yet been systematically quantified, despite widespread recognition of their critical importance for terrestrial and microgravity applications. Here we report changes in gene expression with space flight related to Drosophila wing morphogenesis and vein patterning. In addition, genetically modified phenotypes of increasingly abnormal ectopic wing venation in the Drosophila wing1 were analyzed by NASA's VESsel GENeration Analysis (VESGEN) software2. Our goal is to further develop insightful vascular mappings associated with bioinformatic dimensions of genetic or other molecular phenotypes for correlation with genetic and other molecular profiling relevant to NASA's GeneLab and other Space Biology exploration initiatives.

Measurement of leukocyte rheology in vascular disease: clinical rationale and methodology. International Society of Clinical Hemorheology.

PubMed

Wautier, J L; Schmid-Schönbein, G W; Nash, G B

1999-01-01

The measurement of leukocyte rheology in vascular disease is a recent development with a wide range of new opportunities. The International Society of Clinical Hemorheology has asked an expert panel to propose guidelines for the investigation of leukocyte rheology in clinical situations. This article first discusses the mechanical, adhesive and related functional properties of leukocytes (especially neutrophils) which influence their circulation, and establishes the rationale for clinically-related measurements of parameters which describe them. It is concluded that quantitation of leukocyte adhesion molecules, and of their endothelial receptors may assist understanding of leukocyte behaviour in vascular disease, along with measurements of flow resistance of leukocytes, free radical production, degranulation and gene expression. For instance, vascular cell adhesion molecule (VCAM-1) is abnormally present on endothelial cells in atherosclerosis, diabetes mellitus and inflammatory conditions. Soluble forms of intercellular adhesion molecule (ICAM-1) or VCAM can be found elevated in the blood of patients with rheumatoid arthritis or infections disease. In the second part of the article, possible technical approaches are presented and possible avenues for leukocyte rheological investigations are discussed.

The BK(Ca) channels deficiency as a possible reason for radiation-induced vascular hypercontractility.

PubMed

Kyrychenko, Sergii; Tishkin, Sergey; Dosenko, Victor; Ivanova, Irina; Novokhatska, Tatiana; Soloviev, Anatoly

2012-01-01

It is likely that large-conductance Ca²⁺-activated K⁺ (BK(Ca)) channels channelopathy tightly involved in vascular malfunctions and arterial hypertension development. In the present study, we compared the results of siRNAs-induced α-BK(Ca) gene silencing and vascular abnormalities produced by whole-body ionized irradiation in rats. The experimental design comprised RT-PCR and patch clamp technique, thoracic aorta smooth muscle (SM) contractile recordings and arterial blood pressure (BP) measurements on the 30th day after whole body irradiation (6Gy) and following siRNAs KCNMA1 gene silencing in vivo. The expression profile of BK(Ca) mRNA transcripts in SM was significantly decreased in siRNAs-treated rats in a manner similar to irradiated SM. In contrast, the mRNA levels of K(v) and K(ATP) were significantly increased while L-type calcium channels mRNA transcripts demonstrated tendency to increment. The SMCs obtained from irradiated animals and after KCNMA1 gene silencing showed a significant decrease in total K⁺ current density amplitude. Paxilline (500 nM)-sensitive components of outward current were significantly decreased in both irradiated and gene silencing SMCs. KCNMA1 gene silencing increased SM sensitivity to norepinephrine while Ach-induced relaxation had decreased. The silencing of KCNMA1 had no significant effect on BP while radiation produced sustained arterial hypertension. Therefore, radiation alters the form and function of the BK(Ca) channel and this type of channelopathy may contribute to related vascular abnormalities. Nevertheless, it is unlikely that BK(Ca) can operate as a crucial factor for radiation-induced arterial hypertension. Copyright © 2012 Elsevier Inc. All rights reserved.

Abnormalities in the Regulators of Angiogenesis in Patients with Scleroderma

PubMed Central

HUMMERS, LAURA K.; HALL, AMY; WIGLEY, FREDRICK M.; SIMONS, MICHAEL

2014-01-01

Objective To determine plasma levels of regulators of angiogenesis in patients with scleroderma and to correlate those levels with manifestations of scleroderma-related vascular disease. Methods Plasma levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), matrix metalloproteinase-9 (MMP-9), endostatin, pro-MMP-1, hepatocyte growth factor (HGF), placental growth factor (PlGF), and FGF-4 were examined by ELISA in a cross-sectional study of 113 patients with scleroderma and 27 healthy controls. Simple and multivariate regression models were used to look for associations between factor levels and clinical disease characteristics. Results There were marked differences in the levels of pro-angiogenic growth factors between patients with scleroderma and controls, with significant elevations of VEGF, PDGF, FGF-2, and PlGF among patients with scleroderma (p < 0.0001). Levels of MMP were also higher in scleroderma patients compared to controls (MMP-9 and pro-MMP-1) (p < 0.0001). Levels of the pro-angiogenic and anti-fibrotic factor, HGF, were noted to be lower in patients with scleroderma, but had a positive correlation with right ventricular systolic pressure (RVSP) as measured by echocardiogram (p < 0.0001) and the Raynaud Severity Score (p = 0.05). Endostatin (an anti-angiogenic factor) was notably higher in patients with scleroderma (p < 0.0001) and also correlated positively with RVSP (p = 0.023). Conclusion These results demonstrate striking abnormalities in the circulating regulators of angiogenesis in patients with scleroderma. The levels of some factors correlate with measures of vascular disease among patients with scleroderma. Dysregulated angiogenesis may play a role in the development of scleroderma vascular disease. PMID:19228661

NO/redox disequilibrium in the failing heart and cardiovascular system

PubMed Central

Hare, Joshua M.; Stamler, Jonathan S.

2005-01-01

There is growing evidence that the altered production and/or spatiotemporal distribution of reactive oxygen and nitrogen species creates oxidative and/or nitrosative stresses in the failing heart and vascular tree, which contribute to the abnormal cardiac and vascular phenotypes that characterize the failing cardiovascular system. These derangements at the integrated system level can be interpreted at the cellular and molecular levels in terms of adverse effects on signaling elements in the heart, vasculature, and blood that subserve cardiac and vascular homeostasis. PMID:15765132

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia.

PubMed

Yan, Lulu; Lee, Sangmi; Lazzaro, Douglas R; Aranda, Jacob; Grant, Maria B; Chaqour, Brahim

2015-09-18

The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness. The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization. Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization. Whereas constitutive miR-155-deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation. The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation. Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult. miR-155 binds to the 3'-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses. Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function. During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis. Under ischemic conditions, dysregulated miR-155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses. Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia*

PubMed Central

Yan, Lulu; Lee, Sangmi; Lazzaro, Douglas R.; Aranda, Jacob; Grant, Maria B.; Chaqour, Brahim

2015-01-01

The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness. The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization. Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization. Whereas constitutive miR-155-deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation. The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation. Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult. miR-155 binds to the 3′-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses. Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function. During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis. Under ischemic conditions, dysregulated miR-155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses. Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair. PMID:26242736

Line-Scanning Particle Image Velocimetry: An Optical Approach for Quantifying a Wide Range of Blood Flow Speeds in Live Animals

PubMed Central

Kim, Tyson N.; Goodwill, Patrick W.; Chen, Yeni; Conolly, Steven M.; Schaffer, Chris B.; Liepmann, Dorian; Wang, Rong A.

2012-01-01

Background The ability to measure blood velocities is critical for studying vascular development, physiology, and pathology. A key challenge is to quantify a wide range of blood velocities in vessels deep within living specimens with concurrent diffraction-limited resolution imaging of vascular cells. Two-photon laser scanning microscopy (TPLSM) has shown tremendous promise in analyzing blood velocities hundreds of micrometers deep in animals with cellular resolution. However, current analysis of TPLSM-based data is limited to the lower range of blood velocities and is not adequate to study faster velocities in many normal or disease conditions. Methodology/Principal Findings We developed line-scanning particle image velocimetry (LS-PIV), which used TPLSM data to quantify peak blood velocities up to 84 mm/s in live mice harboring brain arteriovenous malformation, a disease characterized by high flow. With this method, we were able to accurately detect the elevated blood velocities and exaggerated pulsatility along the abnormal vascular network in these animals. LS-PIV robustly analyzed noisy data from vessels as deep as 850 µm below the brain surface. In addition to analyzing in vivo data, we validated the accuracy of LS-PIV up to 800 mm/s using simulations with known velocity and noise parameters. Conclusions/Significance To our knowledge, these blood velocity measurements are the fastest recorded with TPLSM. Partnered with transgenic mice carrying cell-specific fluorescent reporters, LS-PIV will also enable the direct in vivo correlation of cellular, biochemical, and hemodynamic parameters in high flow vascular development and diseases such as atherogenesis, arteriogenesis, and vascular anomalies. PMID:22761686

Msx genes define a population of mural cell precursors required for head blood vessel maturation.

PubMed

Lopes, Miguel; Goupille, Olivier; Saint Cloment, Cécile; Lallemand, Yvan; Cumano, Ana; Robert, Benoît

2011-07-01

Vessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) in arteries and veins and pericytes in capillaries and veinules. We previously showed that, in the mouse embryo, Msx1(lacZ) and Msx2(lacZ) are expressed in mural cells and in a few endothelial cells. To unravel the role of Msx genes in vascular development, we have inactivated the two Msx genes specifically in mural cells by combining the Msx1(lacZ), Msx2(lox) and Sm22α-Cre alleles. Optical projection tomography demonstrated abnormal branching of the cephalic vessels in E11.5 mutant embryos. The carotid and vertebral arteries showed an increase in caliber that was related to reduced vascular smooth muscle coverage. Taking advantage of a newly constructed Msx1(CreERT2) allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs.

Characteristics of NO cycle coupling with urea cycle in non-hyperammonemic carriers of ornithine transcarbamylase deficiency.

PubMed

Nagasaka, Hironori; Yorifuji, Tohru; Egawa, Hiroto; Inui, Ayano; Fujisawa, Tomoo; Komatsu, Haruki; Tsukahara, Hirokazu; Uemoto, Shinji; Inomata, Yukihiro

2013-07-01

Urea cycle deficient patients with prominent hyperammonemic often exhibit abnormal production of nitric oxide (NO), which reduces vascular tone, along with amino acid abnormalities. However, information related to the metabolic changes in heterozygotes of ornithine transcarbamylase deficiency (OTCD) lacking overt hyperammonemia is quite limited. We examined vascular mediators and amino acids in non-hyperammonemic heterozygotes. Twenty-four heterozygous OTCD adult females without hyperammonemic bouts, defined as non-hyperammonemic carriers, were enrolled. We measured blood amino acids constituting urea cycle and nitric oxide (NO) cycle. Blood concentrations of nitrate/nitrite (NOx) as stable NO-metabolites, asymmetric dimethylarginine (ADMA) inhibiting NO synthesis, and endothelin-1 (ET-1) raising vascular tone were also determined. NOx concentrations were significantly lower in non-hyperammonemic carriers (p < 0.01). However, ADMA and ET-1 levels in this group were comparable to those in the age-matched control group. Arginine and citrulline levels were also significantly lower in non-hyperammonemic carriers than in controls (p < 0.01). Of the 24 non-hyperammonemic carriers, 10 often developed headaches. Their daily NOx and arginine levels were significantly lower than those in headache-free carriers (p < 0.05). In three carriers receiving oral l-arginine, blood NOx concentrations were significantly higher. In two of those three, the occurrence of headaches was decreased. These results suggest that NO cycle coupling with the urea cycle is altered substantially even in non-hyperammonemic OTCD carriers, predisposing them to headaches. Copyright © 2013 Elsevier Inc. All rights reserved.

Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state

NASA Astrophysics Data System (ADS)

Morito, Daisuke; Nishikawa, Kouki; Hoseki, Jun; Kitamura, Akira; Kotani, Yuri; Kiso, Kazumi; Kinjo, Masataka; Fujiyoshi, Yoshinori; Nagata, Kazuhiro

2014-03-01

Moyamoya disease is an idiopathic human cerebrovascular disorder that is characterized by progressive stenosis and abnormal collateral vessels. We recently identified mysterin/RNF213 as its first susceptibility gene, which encodes a 591-kDa protein containing enzymatically active P-loop ATPase and ubiquitin ligase domains and is involved in proper vascular development in zebrafish. Here we demonstrate that mysterin further contains two tandem AAA+ ATPase modules and forms huge ring-shaped oligomeric complex. AAA+ ATPases are known to generally mediate various biophysical and mechanical processes with the characteristic ring-shaped structure. Fluorescence correlation spectroscopy and biochemical evaluation suggested that mysterin dynamically changes its oligomeric forms through ATP/ADP binding and hydrolysis cycles. Thus, the moyamoya disease-associated gene product is a unique protein that functions as ubiquitin ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell.

Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state

PubMed Central

Morito, Daisuke; Nishikawa, Kouki; Hoseki, Jun; Kitamura, Akira; Kotani, Yuri; Kiso, Kazumi; Kinjo, Masataka; Fujiyoshi, Yoshinori; Nagata, Kazuhiro

2014-01-01

Moyamoya disease is an idiopathic human cerebrovascular disorder that is characterized by progressive stenosis and abnormal collateral vessels. We recently identified mysterin/RNF213 as its first susceptibility gene, which encodes a 591-kDa protein containing enzymatically active P-loop ATPase and ubiquitin ligase domains and is involved in proper vascular development in zebrafish. Here we demonstrate that mysterin further contains two tandem AAA+ ATPase modules and forms huge ring-shaped oligomeric complex. AAA+ ATPases are known to generally mediate various biophysical and mechanical processes with the characteristic ring-shaped structure. Fluorescence correlation spectroscopy and biochemical evaluation suggested that mysterin dynamically changes its oligomeric forms through ATP/ADP binding and hydrolysis cycles. Thus, the moyamoya disease-associated gene product is a unique protein that functions as ubiquitin ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell. PMID:24658080

Optical coherence tomography angiography retinal vascular network assessment in multiple sclerosis.

PubMed

Lanzillo, Roberta; Cennamo, Gilda; Criscuolo, Chiara; Carotenuto, Antonio; Velotti, Nunzio; Sparnelli, Federica; Cianflone, Alessandra; Moccia, Marcello; Brescia Morra, Vincenzo

2017-09-01

Optical coherence tomography (OCT) angiography is a new method to assess the density of the vascular networks. Vascular abnormalities are considered involved in multiple sclerosis (MS) pathology. To assess the presence of vascular abnormalities in MS and to evaluate their correlation to disease features. A total of 50 MS patients with and without history of optic neuritis (ON) and 46 healthy subjects were included. All underwent spectral domain (SD)-OCT and OCT angiography. Clinical history, Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Score (MSSS) and disease duration were collected. Angio-OCT showed a vessel density reduction in eyes of MS patients when compared to controls. A statistically significant reduction in all SD-OCT and OCT angiography parameters was noticed both in eyes with and without ON when compared with control eyes. We found an inverse correlation between SD-OCT parameters and MSSS ( p = 0.003) and between vessel density parameters and EDSS ( p = 0.007). We report a vessel density reduction in retina of MS patients. We highlight the clinical correlation between vessel density and EDSS, suggesting that angio-OCT could be a good marker of disease and of disability in MS.

Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009

PubMed Central

2010-01-01

Objective To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children. Study design Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009. Results 21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications. Conclusion Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions. PMID:20128925

Knockdown of prothrombin in zebrafish.

PubMed

Day, Kenneth; Krishnegowda, Naveen; Jagadeeswaran, Pudur

2004-01-01

Thrombin is a serine protease generated from its zymogen, prothrombin, and plays a central role in the coagulation cascade. It is also important for mammalian development. The zebrafish has now been established as an excellent genetic model for studies on mammalian hemostasis and development. In this report, we used prothrombin-specific antisense morpholinos to knock down the levels of prothrombin to characterize the effects of prothrombin deficiency in the zebrafish embryo. Prothrombin morpholino-injected zebrafish embryos yielded an early phenotype exhibiting severe abnormalities that later showed occasional bleeding. In a second late phenotype, the embryos had no observable morphological abnormalities in early stages, but showed occasional bleeding at later stages. These phenotypes resembled characteristics shown by prothrombin knockout mice. Laser-induced vascular injury on some of the normal appearing phenotypic larvae showed a prolonged time to occlusion, and recombinant zebrafish prothrombin injected into these larvae restored a normal time to occlusion thus showing the specificity of the morpholino effect. The system developed here should be useful for investigation of the role of thrombin in vertebrate development.

Protecting against vascular disease in brain

PubMed Central

2011-01-01

Endothelial cells exert an enormous influence on blood vessels throughout the circulation, but their impact is particularly pronounced in the brain. New concepts have emerged recently regarding the role of this cell type and mechanisms that contribute to endothelial dysfunction and vascular disease. Activation of the renin-angiotensin system plays a prominent role in producing these abnormalities. Both oxidative stress and local inflammation are key mechanisms that underlie vascular disease of diverse etiology. Endogenous mechanisms of vascular protection are also present, including antioxidants, anti-inflammatory molecules, and peroxisome proliferator-activated receptor-γ. Despite their clear importance, studies of mechanisms that underlie cerebrovascular disease continue to lag behind studies of vascular biology in general. Identification of endogenous molecules and pathways that protect the vasculature may result in targeted approaches to prevent or slow the progression of vascular disease that causes stroke and contributes to the vascular component of dementia and Alzheimer's disease. PMID:21335467

The Role of Transient Receptor Potential Channel 6 Channels in the Pulmonary Vasculature

PubMed Central

Malczyk, Monika; Erb, Alexandra; Veith, Christine; Ghofrani, Hossein Ardeschir; Schermuly, Ralph T.; Gudermann, Thomas; Dietrich, Alexander; Weissmann, Norbert; Sydykov, Akylbek

2017-01-01

Canonical or classical transient receptor potential channel 6 (TRPC6) is a Ca2+-permeable non-selective cation channel that is widely expressed in the heart, lung, and vascular tissues. The use of TRPC6-deficient (“knockout”) mice has provided important insights into the role of TRPC6 in normal physiology and disease states of the pulmonary vasculature. Evidence indicates that TRPC6 is a key regulator of acute hypoxic pulmonary vasoconstriction. Moreover, several studies implicated TRPC6 in the pathogenesis of pulmonary hypertension. Furthermore, a unique genetic variation in the TRPC6 gene promoter has been identified, which might link the inflammatory response to the upregulation of TRPC6 expression and ultimate development of pulmonary vascular abnormalities in idiopathic pulmonary arterial hypertension. Additionally, TRPC6 is critically involved in the regulation of pulmonary vascular permeability and lung edema formation during endotoxin or ischemia/reperfusion-induced acute lung injury. In this review, we will summarize latest findings on the role of TRPC6 in the pulmonary vasculature. PMID:28670316

Mechanisms of Normal and Abnormal Endometrial Bleeding

PubMed Central

Lockwood, Charles J.

2011-01-01

Expression of tissue factor (TF), the primary initiator of coagulation, is enhanced in decidualized human endometrial stromal cells (HESC) during the progesterone-dominated luteal phase. Progesterone also augments a second HESC hemostatic factor, plasminogen activator inhibitor-1 (PAI-1). In contrast, progestins inhibit HESC matrix metalloproteinase (MMP)-1, 3 and 9 expression to stabilize endometrial stromal and vascular extracellular matrix. Through these mechanisms decidualized endometrium is rendered both hemostatic and resistant to excess trophoblast invasion in the mid-luteal phase and throughout gestation to prevent hemorrhage and accreta. In non-fertile cycles, progesterone withdrawal results in decreased HESC TF and PAI-expression and increased MMP activity and inflammatory cytokine production promoting the controlled hemorrhage of menstruation and related tissue sloughing. In contrast to these well ordered biochemical processes, unpredictable endometrial bleeding associated with anovulation reflects absence of progestational effects on TF, PAI-1 and MMP activity as well as unrestrained angiogenesis rendering the endometrium non-hemostatic, proteolytic and highly vascular. Abnormal bleeding associated with long-term progestin-only contraceptives results not from impaired hemostasis but from unrestrained angiogenesis leading to large fragile endometrial vessels. This abnormal angiogenesis reflects progestational inhibition of endometrial blood flow promoting local hypoxia and generation of reactive oxygen species that increase production of angiogenic factors such as vascular endothelial growth factor (VEGF) in HESCs and Angiopoietin-2 (Ang-2) in endometrial endothelial cells while decreasing HESC expression of angiostatic, Ang-1. The resulting vessel fragility promotes bleeding. Aberrant angiogenesis also underlies abnormal bleeding associated with myomas and endometrial polyps however there are gaps in our understanding of this pathology. PMID:21499503

Human Herpesvirus-8-Transformed Endothelial Cells Have Functionally Activated Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor

PubMed Central

Masood, Rizwan; Cesarman, Ethel; Smith, D. Lynne; Gill, Parkash S.; Flore, Ornella

2002-01-01

Kaposi’s sarcoma is a vascular tumor commonly associated with human immunodeficiency virus (HIV)-1 and human herpesvirus (HHV-8) also known as Kaposi’s sarcoma-associated herpesvirus. The principal features of this tumor are abnormal proliferation of vascular structures lined with spindle-shaped endothelial cells. HHV-8 may transform a subpopulation of endothelial cells in vitro via viral and cellular gene expression. We hypothesized that among the cellular genes, vascular endothelial growth factors (VEGFs) and their cognate receptors may be involved in viral-mediated transformation. We have shown that HHV-8-transformed endothelial cells (EC-HHV-8) express higher levels of VEGF, VEGF-C, VEGF-D, and PlGF in addition to VEGF receptors-1, -2, and -3. Furthermore, antibodies to VEGF receptor-2 inhibited cell proliferation and viability. Similarly, inhibition of VEGF gene expression with antisense oligonucleotides inhibited EC-HHV-8 cell proliferation/viability. The growth and viability of primary endothelial cells and a fibroblast cell line however were unaffected by either the VEGF receptor-2 antibody or the VEGF antisense oligodeoxynucleotides. VEGF and VEGF receptors are thus induced in EC-HHV-8 and participate in the transformation. Inhibitors of VEGF may thus modulate the disease process during development and progression. PMID:11786394

Metabolic Vascular Syndrome: New Insights into a Multidimensional Network of Risk Factors and Diseases.

PubMed

Scholz, Gerhard H; Hanefeld, Markolf

2016-10-01

Since 1981, we have used the term metabolic syndrome to describe an association of a dysregulation in lipid metabolism (high triglycerides, low high-density lipoprotein cholesterol, disturbed glucose homeostasis (enhanced fasting and/or prandial glucose), gout, and hypertension), with android obesity being based on a common soil (overnutrition, reduced physical activity, sociocultural factors, and genetic predisposition). We hypothesized that main traits of the syndrome occur early and are tightly connected with hyperinsulinemia/insulin resistance, procoagulation, and cardiovascular diseases. To establish a close link between the traits of the metabolic vascular syndrome, we focused our literature search on recent original work and comprehensive reviews dealing with the topics metabolic syndrome, visceral obesity, fatty liver, fat tissue inflammation, insulin resistance, atherogenic dyslipidemia, arterial hypertension, and type 2 diabetes mellitus. Recent research supports the concept that the metabolic vascular syndrome is a multidimensional and interactive network of risk factors and diseases based on individual genetic susceptibility and epigenetic changes where metabolic dysregulation/metabolic inflexibility in different organs and vascular dysfunction are early interconnected. The metabolic vascular syndrome is not only a risk factor constellation but rather a life-long abnormality of a closely connected interactive cluster of developing diseases which escalate each other and should continuously attract the attention of every clinician.

A case report of spinal dural arteriovenous fistula: origins, determinants, and consequences of abnormal vascular malformations.

PubMed

Zakhary, Sherry M; Hoehmann, Christopher L; Cuoco, Joshua A; Hitscherich, Kyle; Alam, Hamid; Torres, German

2017-06-01

A spinal dural arteriovenous fistula is an abnormally layered connection between radicular arteries and venous plexus of the spinal cord. This vascular condition is relatively rare with an incidence of 5-10 cases per million in the general population. Diagnosis of spinal dural arteriovenous fistula is differentiated by contrast-enhanced magnetic resonance angiography or structural magnetic resonance imaging, but a definitive diagnosis requires spinal angiography methods. Here, we report a case of a 67-year-old female with a spinal dural arteriovenous fistula, provide a pertinent clinical history to the case nosology, and discuss the biology of adhesive proteins, chemotactic molecules, and transcription factors that modify the behavior of the vasculature to possibly cause sensorimotor deficits.

Imaging features of non-traumatic vascular liver emergencies.

PubMed

Onur, Mehmet Ruhi; Karaosmanoglu, Ali Devrim; Akca, Onur; Ocal, Osman; Akpinar, Erhan; Karcaaltincaba, Musturay

2017-05-01

Acute non-traumatic liver disorders can originate from abnormalities of the hepatic artery, portal vein and hepatic veins. Ultrasonography and computed tomography can be used in non-traumatic acute vascular liver disorders according to patient status, indication and appropriateness of imaging modality. Awareness of the imaging findings, in the appropriate clinical context, is crucial for prompt and correct diagnosis, as delay may cause severe consequences with significant morbidity and mortality. This review article will discuss imaging algorithms, and multimodality imaging findings for suspected acute vascular disorders of the liver.

Vascular involvement in systemic sclerosis (scleroderma)

PubMed Central

Pattanaik, Debendra; Brown, Monica; Postlethwaite, Arnold E

2011-01-01

Systemic sclerosis (SSc) is an acquired multiorgan connective tissue disease with variable mortality and morbidity dictated by clinical subset type. The etiology of the basic disease and pathogenesis of the systemic autoimmunity, fibrosis, and fibroproliferative vasculopathy are unknown and debated. In this review, the spectrum of vascular abnormalities and the options currently available to treat the vascular manifestations of SSc are discussed. Also discussed is how the hallmark pathologies (ie, how autoimmunity, vasculopathy, and fibrosis of the disease) might be effected and interconnected with modulatory input from lysophospholipids, sphingosine 1-phosphate, and lysophosphatidic acid. PMID:22096374

Characterization of tumor microvascular structure and permeability: comparison between magnetic resonance imaging and intravital confocal imaging

NASA Astrophysics Data System (ADS)

Reitan, Nina Kristine; Thuen, Marte; Goa, Pa˚L. Erik; de Lange Davies, Catharina

2010-05-01

Solid tumors are characterized by abnormal blood vessel organization, structure, and function. These abnormalities give rise to enhanced vascular permeability and may predict therapeutic responses. The permeability and architecture of the microvasculature in human osteosarcoma tumors growing in dorsal window chambers in athymic mice were measured by confocal laser scanning microscopy (CLSM) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Dextran (40 kDa) and Gadomer were used as molecular tracers for CLSM and DCE-MRI, respectively. A significant correlation was found between permeability indicators. The extravasation rate Ki as measured by CLSM correlated positively with DCE-MRI parameters, such as the volume transfer constant Ktrans and the initial slope of the contrast agent concentration-time curve. This demonstrates that these two techniques give complementary information. Extravasation was further related to microvascular structure and was found to correlate with the fractal dimension and vascular density. The structural parameter values that were obtained from CLSM images were higher for abnormal tumor vasculature than for normal vessels.

Scleroderma en coup de sabre with recurrent episodes of brain hemorrhage.

PubMed

Takahashi, Takehiro; Asano, Yoshihide; Oka, Tomonori; Miyagaki, Tomomitsu; Tamaki, Zenshiro; Nonaka, Senshu; Sato, Shinichi

2016-02-01

We report a 39-year-old man referred to our facility with linear sclerotic lesions along the several Blaschko's lines of the scalp. A year before the referral, he had had an episode of brain hemorrhage, although there was no evidence of vascular malformation or any other risk factors of brain hemorrhage for his young age. On the diagnosis of scleroderma en coup de sabre, prednisolone intake was initiated, and the skin lesions were well controlled. However, in the course of our follow up, he had another episode of brain hemorrhage, again without any evidence of cerebral vascular abnormalities. Organic intracranial abnormalities in this disease are well-documented, but there have been few reports on comorbid recurrent brain hemorrhages. We herein discuss the possible relationship of the skin lesions with the brain hemorrhages in our case, taking notice of the implication of developmental abnormalities behind these apparently independent phenomena inside and outside the cranium. © 2015 Japanese Dermatological Association.

Inner retinal vasculopathy in Zika virus disease.

PubMed

Singh, Mandeep S; Marquezan, Maria Carolina; Omiadze, Revaz; Reddy, Ashvini K; Belfort, Rubens; May, William N

2018-06-01

Zika virus infection is associated with vision-threatening ocular complications including uveitis and outer retinopathy. The aim of this report is to describe a case of an adult patient with serologically confirmed Zika infection who presented with retinal vascular abnormalities that coincided with systemic post-viral neurological manifestations of the disease. A 34-year-old white female presented with symptoms of peripheral neuropathy following serologically confirmed Zika virus infection that was acquired in Puerto Rico four months prior to presentation. Ocular evaluation revealed perifoveal microaneurysms which were not associated with visual symptoms. These data potentially expand the phenotypic spectrum of Zika virus retinopathy. In addition to outer retinal abnormalities which are well-described in infants and adults, inner retinal vascular abnormalities may also occur and may be temporally associated with post-viral neurological sequelae of Zika virus infection. Clinicians should be aware of potential retinal involvement in affected patients who present with neurological symptoms after recovery from acute Zika virus infection.

Perfusion lung imaging in the adult respiratory distress syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pistolesi, M.; Miniati, M.; Di Ricco, G.

1986-07-01

In 29 perfusion lung scans (PLS) of 19 patients with ARDS, 20 of which were obtained within six days from the onset of respiratory symptoms, perfusion abnormalities were the rule. These included focal, nonsegmental defects, mostly peripheral and dorsal, and perfusion redistribution away from the dependent lung zones. PLS were scored for the presence and intensity of perfusion abnormalities and the scores of perfusion redistribution were validated against numerical indices of blood flow distribution per unit lung volume. PLS scores were correlated with arterial blood gas values, hemodynamic parameters, and chest radiographic scores of ARDS. Arterial oxygen tension correlated withmore » the scores of both perfusion defects and redistribution. Perfusion defects correlated better with the radiographic score of ARDS, and perfusion redistribution with PAP and vascular resistance. ARDS patients exhibit peculiar patterns of PLS abnormalities not observed in other disorders. Thus, PLS may help considerably in the detection and evaluation of pulmonary vascular injury in ARDS.« less

Digital image processing of vascular angiograms

NASA Technical Reports Server (NTRS)

Selzer, R. H.; Blankenhorn, D. H.; Beckenbach, E. S.; Crawford, D. W.; Brooks, S. H.

1975-01-01

A computer image processing technique was developed to estimate the degree of atherosclerosis in the human femoral artery. With an angiographic film of the vessel as input, the computer was programmed to estimate vessel abnormality through a series of measurements, some derived primarily from the vessel edge information and others from optical density variations within the lumen shadow. These measurements were combined into an atherosclerosis index, which was found to correlate well with both visual and chemical estimates of atherosclerotic disease.

Characterization of the Tumor Microenvironment and Tumor–Stroma Interaction by Non-invasive Preclinical Imaging

PubMed Central

Ramamonjisoa, Nirilanto; Ackerstaff, Ellen

2017-01-01

Tumors are often characterized by hypoxia, vascular abnormalities, low extracellular pH, increased interstitial fluid pressure, altered choline-phospholipid metabolism, and aerobic glycolysis (Warburg effect). The impact of these tumor characteristics has been investigated extensively in the context of tumor development, progression, and treatment response, resulting in a number of non-invasive imaging biomarkers. More recent evidence suggests that cancer cells undergo metabolic reprograming, beyond aerobic glycolysis, in the course of tumor development and progression. The resulting altered metabolic content in tumors has the ability to affect cell signaling and block cellular differentiation. Additional emerging evidence reveals that the interaction between tumor and stroma cells can alter tumor metabolism (leading to metabolic reprograming) as well as tumor growth and vascular features. This review will summarize previous and current preclinical, non-invasive, multimodal imaging efforts to characterize the tumor microenvironment, including its stromal components and understand tumor–stroma interaction in cancer development, progression, and treatment response. PMID:28197395

Congenital portosystemic vascular malformations.

PubMed

Guérin, Florent; Blanc, Thomas; Gauthier, Frédéric; Abella, Stephanie Franchi; Branchereau, Sophie

2012-08-01

Congenital portosystemic shunts are developmental abnormalities of the portal venous system resulting in the diversion of portal blood away from the liver to the systemic venous system. Such malformations are believed to come from an insult occurring between the fourth and eighth week of gestation during the development of hepatic and systemic venous systems, and could explain their frequent association with cardiac and other vascular anomalies. They are currently categorized into end-to-side shunts (type I) or side-to-side shunts (type II). This article aims to review the common symptoms and complications encountered in congenital portosystemic shunts, the surgical and endovascular treatment, and the role of liver transplantation in this disease. We will also focus on the current controversies and the areas where there is potential for future studies. Copyright © 2012. Published by Elsevier Inc.

Complex genetics of familial exudative vitreoretinopathy and related pediatric retinal detachments

PubMed Central

Kondo, Hiroyuki

2015-01-01

Familial exudative vitreoretinopathy (FEVR) is a hereditary vitreoretinal disorder that can cause various types of retinal detachments. The abnormalities in eyes with FEVR are caused by poor vascularization in the peripheral retina. The genetics of FEVR is highly heterogeneous, and mutations in the genes for Wnt signaling and a transcription factor have been reported to be responsible for FEVR. These factors have been shown to be the regulators of the pathophysiological pathways of retinal vascular development. Studies conducted to identify the causative genes of FEVR have uncovered a diverse and complex relationship between FEVR and other diseases; for example, Norrie disease, a Mendelian-inherited disease; retinopathy of prematurity, a multifactorial genetic disease; and Coats disease, a nongenetic disease, associated with pediatric retinal detachments. PMID:29018668

Regulation of programmed cell death or apoptosis in atherosclerosis.

PubMed

Geng, Y J

1997-01-01

Intimal thickening caused by accumulation of cells, lipids, and connective tissue characterizes atherosclerosis, an arterial disease that leads to cardiac and cerebral infarction. Apoptosis, or genetically programmed cell death, is important for the development and morphogenesis of organs and tissues. As in other tissues, cells of cardiovascular tissues can undergo apoptosis. Increased apoptosis has been found in both human and animal atherosclerotic lesions, mediating tissue turnover and lesion development. In addition to vascular cells, many activated immune cells, mainly macrophages and T cells, are present in atherosclerotic lesions, where these cells produce biologically active substances such as the proinflammatory cytokines tumor necrosis factor, interleukin-1 (IL-1), and interferon-gamma. Simultaneous exposure to these cytokines may trigger apoptosis of vascular smooth muscle cells. The products of death-regulating genes including Fas/Fas ligand, members of IL-1 beta cysteinyl protease (caspase) family, the tumor suppressive gene p53, and the protooncogene c-myc have been found in vascular cells and may participate in the regulation of vascular apoptosis during the development of atherosclerosis. Abnormal occurrence of apoptosis may take place in atherosclerotic lesions, including attenuation or acceleration of the apoptotic death process. The former may cause an increase in the cellularity of the lesions, and the latter can reduce cellular components important for maintaining the integrity and stability of the plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of patients with atherosclerosis and its major complications, heart attack and stroke.

Altered Redox Balance in the Development of Chronic Hypoxia-induced Pulmonary Hypertension.

PubMed

Jernigan, Nikki L; Resta, Thomas C; Gonzalez Bosc, Laura V

2017-01-01

Normally, the pulmonary circulation is maintained in a low-pressure, low-resistance state with little resting tone. Pulmonary arteries are thin-walled and rely heavily on pulmonary arterial distension and recruitment for reducing pulmonary vascular resistance when cardiac output is elevated. Under pathophysiological conditions, however, active vasoconstriction and vascular remodeling lead to enhanced pulmonary vascular resistance and subsequent pulmonary hypertension (PH). Chronic hypoxia is a critical pathological factor associated with the development of PH resulting from airway obstruction (COPD, sleep apnea), diffusion impairment (interstitial lung disease), developmental lung abnormalities, or high altitude exposure (World Health Organization [WHO]; Group III). The rise in pulmonary vascular resistance increases right heart afterload causing right ventricular hypertrophy that can ultimately lead to right heart failure in patients with chronic lung disease. PH is typically characterized by diminished paracrine release of vasodilators, antimitogenic factors, and antithrombotic factors (e.g., nitric oxide and protacyclin) and enhanced production of vasoconstrictors and mitogenic factors (e.g., reactive oxygen species and endothelin-1) from the endothelium and lung parenchyma. In addition, phenotypic changes to pulmonary arterial smooth muscle cells (PASMC), including alterations in Ca 2+ homeostasis, Ca 2+ sensitivity, and activation of transcription factors are thought to play prominent roles in the development of both vasoconstrictor and arterial remodeling components of hypoxia-associated PH. These changes in PASMC function are briefly reviewed in Sect. 1 and the influence of altered reactive oxygen species homeostasis on PASMC function discussed in Sects. 2-4.

Presence of cardiovascular structural changes in essential hypertensive patients with coronary microvascular disease and effects of long-term treatment.

PubMed

Virdis, A; Ghiadoni, L; Lucarini, A; Di Legge, V; Taddei, S; Salvetti, A

1996-04-01

In asymptomatic essential hypertensive patients with angiographically normal coronary arteries and without left ventricular hypertrophy, dipyridamole-induced ischemic-like ST segment depression may be a marker of coronary microvascular disease. In this study we evaluated, first, whether this cardiac abnormality is linked to structural or functional vascular abnormalities, and second, the effect of antihypertensive treatment by 12-month administration of the angiotensin converting enzyme (ACE) inhibitor captopril (50 mg twice a day orally). In essential hypertensives with dipypridamole echocardiography stress test (DET) (DET+, n = 8) and without (DET-, n = 8) ST segment depression greater than 0.1 mV during intravenous dipyridamole infusion (0.84 mg/kg over 10 min), we studied the forearm blood flow (FBF, venous plethysmography, mL/100) modifications induced by intrabrachial acetylcholine (Ach) (0.15, 0.45, 1.5, 4.5, 15 micrograms/100 mL/min x 5 min each), an endothelium-dependent vasodilator, and by sodium nitroprusside (SNP) (1, 2, 4 micrograms/100 mL/min x 5 min each), a smooth muscle cell relaxant compound. Minimal forearm vascular resistances (MFVR), an index of arteriolar structural changes, were also calculated. Both Ach and SNP caused greater vasodilation in DET- as compared to DET+ while MFVRs were lower in DET- compared to DET+. After treatment, both DET+ and DET- patients showed a significant and similar reduction in blood pressure and left ventricular mass index, while vasodilation to acetylcholine and sodium nitroprusside was increased only in the DET+ group. In addition, forearm minimal vascular resistances were significantly reduced only in DET+ patients, who showed disappearance of dipyridamole-induced ischemic-like ST segment depression. In conclusion, these data confirm that essential hypertensive patients with microvascular coronary disease are characterized by the presence of structural changes in the forearm vascular bed. Our results also indicate that both cardiac and forearm vascular abnormalities can be reversed by antihypertensive treatment with an ACE inhibitor.

Prominent Intrapulmonary Bronchopulmonary Anastomoses and Abnormal Lung Development in Infants and Children with Down Syndrome.

PubMed

Bush, Douglas; Abman, Steven H; Galambos, Csaba

2017-01-01

To determine the frequency of histologic features of impaired lung vascular and alveolar development and to identify the presence of intrapulmonary bronchopulmonary anastomoses (IBA) in infants and children who died with Down syndrome. A retrospective review of autopsy reports and lung histology from 13 children with Down syndrome (ages: 0-8 years) was performed. Histologic features of abnormal lung development were identified and semiquantified, including the presence of IBA. Three-dimensional reconstructions of IBA were also performed. Comparisons were made with 4 age-matched patients without Down syndrome with congenital heart defects who underwent autopsies during this time period. Of the 13 subjects with Down syndrome, 69% died from cardiac events, 77% had a congenital heart defect, and 46% had a clinical diagnosis of pulmonary hypertension. Lung histology from all subjects with Down syndrome demonstrated alveolar simplification, and 92% had signs of persistence of a double capillary network in the distal lung. The lungs from the subjects with Down syndrome frequently had features of pulmonary arterial hypertensive remodeling (85%), and prominent bronchial vessels and IBA were observed in all subjects with Down syndrome. These features were more frequent in subjects with Down syndrome compared with control subjects. Children with Down syndrome who died of cardiopulmonary diseases often have histologic evidence of impaired lung alveolar and vascular development, including the presence of prominent IBA and pulmonary hypertension. We speculate that children with Down syndrome are at risk for reduced lung surface area and recruitment of IBA, which may worsen gas exchange in subjects with Down syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

[Association between neuropathy and peripheral vascular insufficiency in patients with diabetes mellitus type 2].

PubMed

Millán-Guerrero, Rebeca O; Vásquez, Clemente; Isaís-Millán, Sara; Trujillo-Hernández, Benjamín; Caballero-Hoyos, Ramiro

2011-01-01

Diabetes mellitus (DM) can present complications of neuropathy and peripheral arterial disease with high risk for developing foot ulcers and consequent amputations. To identify the association between peripheral vascular disease, and neuropathy in type 2 Diabetes mellitus patients from the Hospital General de Zona No. 1 IMSS in Colima, Mexico. Cross-sectional study of 80 patients with diabetes mellitus evaluated by means of the Edinburgh Claudication Questionnaire, Michigan Neuropathy Screening Instrument, ankle-arm index, Motor Nerve Conduction Velocity and H-reflex. 51 women and 29 men were studied. Mean age was 53.9 +/- 9.6 years, mean diabetes mellitus progression was 8 +/- 6.6 years and mean glucose level was 283 +/- 110 mg/mL. Neuropathy presented in 65 patients (81.2%). Ankle/arm index revealed 19% of patients presented with moderate peripheral vascular insufficiency. Motor Nerve Conduction Velocity was abnormal in 40% of patients and H-reflex was absent in 70%. Grade 2 motor-sensitive polyneuropathy was found in 70-80% of patients and moderate peripheral vascular insufficiency in 19%. It can thus be inferred that the complication of diabetic neuropathy appears before that of peripheral vessel damage.

Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth

PubMed Central

Meyer, Nicole; Woidacki, Katja; Knöfler, Martin; Meinhardt, Gudrun; Nowak, Désirée; Velicky, Philipp; Pollheimer, Jürgen; Zenclussen, Ana C.

2017-01-01

Intrauterine growth restriction (IUGR) is caused by insufficient remodeling of spiral arteries (SAs). The mechanism underlying the relevance of natural killer cells (NKs) and mast cells (MCs) for SA remodeling and its effects on pregnancy outcome are not well understood. We show that NK depletion arrested SA remodeling without affecting pregnancy. MC depletion resulted in abnormally remodeled SAs and IUGR. Combined absence of NKs and MCs substantially affected SA remodeling and impaired fetal growth. We found that α-chymase mast cell protease (Mcpt) 5 mediates apoptosis of uterine smooth muscle cells, a key feature of SA remodeling. Additionally, we report a previously unknown source for Mcpt5: uterine (u) NKs. Mice with selective deletion of Mcpt5+ cells had un-remodeled SAs and growth-restricted progeny. The human α-chymase CMA1, phylogenetic homolog of Mcpt5, stimulated the ex vivo migration of human trophoblasts, a pre-requisite for SA remodeling. Our results show that chymases secreted by uMCs and uNKs are pivotal to the vascular changes required to support pregnancy. Understanding the mechanisms underlying pregnancy-induced vascular changes is essential for developing therapeutic options against pregnancy complications associated with poor vascular remodeling. PMID:28327604

PubMed

Gueguen, Marie; Vallin, Benjamin; Glorian, Martine; Blaise, Régis; Limon, Isabelle

2016-01-01

In response to various types of vascular stress, the smooth muscle cells of the vessel wall (VSMCs) change phenotype and acquire the capacity to react to abnormal signals. This phenomenon favors the involvement of these cells in the development of major vascular diseases, such as atherosclerosis, and some complications of angioplasty, such as restenosis. The cyclic adenosine monophosphate (cAMP) pathway plays a key role in the integration of stimuli from the immediate environment and in the development of cellular responses. The temporal and spatial subcellular compartmentalization of cAMP ensures that the signals transmitted are specific. This compartmentalization is dependent on the diversity of (1) proteins directly or indirectly regulating the synthesis, degradation or release of cAMP; (2) intracellular effectors of cAMP; (3) isoforms of all these proteins with unique biochemical properties and unique patterns of regulation and (4) the scaffolding proteins on which the macromolecular complexes are built. This review illustrates the ways in which changes in the profile of adenylyl cyclases (ACs) may play critical roles in signal integration, the response of muscle cells and pathological vascular remodeling. It also illustrates the relevance of the renewed consideration of ACs as potentially interesting treatment targets. © Société de Biologie, 2016.

Dynamic release and clearance of circulating microparticles during cardiac stress.

PubMed

Augustine, Daniel; Ayers, Lisa V; Lima, Eduardo; Newton, Laura; Lewandowski, Adam J; Davis, Esther F; Ferry, Berne; Leeson, Paul

2014-01-03

Microparticles are cell-derived membrane vesicles, relevant to a range of biological responses and known to be elevated in cardiovascular disease. To investigate microparticle release during cardiac stress and how this response differs in those with vascular disease. We measured a comprehensive panel of circulating cell-derived microparticles by a standardized flow cytometric protocol in 119 patients referred for stress echocardiography. Procoagulant, platelet, erythrocyte, and endothelial but not leukocyte, granulocyte, or monocyte-derived microparticles were elevated immediately after a standardized dobutamine stress echocardiogram and decreased after 1 hour. Twenty-five patients developed stress-induced wall motion abnormalities suggestive of myocardial ischemia. They had similar baseline microparticle levels to those who did not develop ischemia, but, interestingly, their microparticle levels did not change during stress. Furthermore, no stress-induced increase was observed in those without inducible ischemia but with a history of vascular disease. Fourteen patients subsequently underwent coronary angiography. A microparticle rise during stress echocardiography had occurred only in those with normal coronary arteries. Procoagulant, platelet, erythrocyte, and endothelial microparticles are released during cardiac stress and then clear from the circulation during the next hour. This stress-induced rise seems to be a normal physiological response that is diminished in those with vascular disease.

Deposition of collagen type I onto skeletal endothelium reveals a new role for blood vessels in regulating bone morphology

PubMed Central

Ben Shoham, Adi; Rot, Chagai; Stern, Tomer; Krief, Sharon; Akiva, Anat; Dadosh, Tali; Sabany, Helena; Lu, Yinhui; Kadler, Karl E.

2016-01-01

Recently, blood vessels have been implicated in the morphogenesis of various organs. The vasculature is also known to be essential for endochondral bone development, yet the underlying mechanism has remained elusive. We show that a unique composition of blood vessels facilitates the role of the endothelium in bone mineralization and morphogenesis. Immunostaining and electron microscopy showed that the endothelium in developing bones lacks basement membrane, which normally isolates the blood vessel from its surroundings. Further analysis revealed the presence of collagen type I on the endothelial wall of these vessels. Because collagen type I is the main component of the osteoid, we hypothesized that the bone vasculature guides the formation of the collagenous template and consequently of the mature bone. Indeed, some of the bone vessels were found to undergo mineralization. Moreover, the vascular pattern at each embryonic stage prefigured the mineral distribution pattern observed one day later. Finally, perturbation of vascular patterning by overexpressing Vegf in osteoblasts resulted in abnormal bone morphology, supporting a role for blood vessels in bone morphogenesis. These data reveal the unique composition of the endothelium in developing bones and indicate that vascular patterning plays a role in determining bone shape by forming a template for deposition of bone matrix. PMID:27621060

Genetic Inactivation of the Adenosine A2A Receptor Attenuates Pathologic but Not Developmental Angiogenesis in the Mouse Retina

PubMed Central

Liu, Xiao-Ling; Zhou, Rong; Pan, Qi-Qi; Jia, Xiao-Lin; Gao, Wei-Na; Wu, Jun; Lin, Jing; Chen, Jiang-Fan

2010-01-01

Purpose. The adenosine A2A receptor (A2AR) modulates normal vascularization and pathologic angiogenesis in many tissues and may contribute to the pathogenesis of retinopathy of prematurity (ROP) characterized by abnormal retinal vascularization in surviving premature infants. Here, the authors studied the effects of the genetic inactivation of A2AR on normal retinal vascularization and the development of pathologic angiogenesis in oxygen-induced retinopathy (OIR), an animal model of ROP. Methods. After exposure to 75% oxygen for 5 days (postnatal day [P] 7–P12) and subsequently to room air for the next 9 days (P13–P21), we evaluated retinal vascular morphology by ADPase staining in retinal whole mounts, retinal neovascularization response by histochemistry in serial retinal sections, and retinal VEGF gene expression by real-time PCR analysis in A2AR knockout (KO) mice and their wild-type (WT) littermates. Results. At P17, A2AR KO mice displayed attenuated OIR compared with WT littermates, as evidenced by reduced vaso-obliteration and areas of nonperfusion in the center of the retina, reduced pathologic angiogenesis as evident by decreased non-ganglion cells and neovascular nuclei, and inhibited hypoxia-induced retinal VEGF gene expression. Notably, the attenuation of pathologic angiogenesis by A2AR inactivation was selective for OIR because it did not affect normal retinal vascularization during postnatal development. Conclusions. These findings provide the first evidence that A2AR is critical for the development of OIR and suggest a novel therapeutic approach of A2AR inactivation for ROP by selectively targeting pathologic but not developmental angiogenesis in the retina. PMID:20610844

Segmented swept source optical coherence tomography angiography assessment of the perifoveal vasculature in patients with X-linked juvenile retinoschisis: a serial case report.

PubMed

Stringa, Francesco; Tsamis, Emmanouli; Papayannis, Alessandro; Chwiejczak, Katarzyna; Jalil, Assad; Biswas, Susmito; Ahmad, Hassan; Stanga, Paulo Eduardo

2017-01-01

To describe perifoveal microvascular changes occurring in X-linked juvenile retinoschisis (XLRS) using swept source optical coherence tomography angiography (SS OCTA). This is a serial case report of three patients. Retrospective data of patients affected by XLRS were collected. Structural optical coherence tomography (OCT) and color fundus photography (CFPh) were carried out with Topcon ® OCT 2000 3D OCT as part of the standard care. Two patients were imaged on Topcon Atlantis ® SS OCTA and one on Topcon Triton ® SS OCTA. SS OCTA images were acquired using the 3 × 3 mm fovea-centered cubes scanning protocol. Analysis of both perifoveal superficial vascular plexus (pSVP) and perifoveal deep vascular plexus (pDVP) was performed by two observers after automated segmentation. Four eyes of three males (mean age 14 ± 3.8 years) were analyzed. All eyes showed foveoschisis on CFPh images. OCT B-scans of three eyes showed schistic cysts in the ganglion cell layer, inner nuclear layer (INL) and outer nuclear layer (ONL); in one eye, cysts were depicted in INL and ONL only. In two eyes, SS OCTA showed abnormal foveal avascular zone (FAZ) shape in the pSVP, and in the other two, FAZ shape was abnormal in both plexuses. In all eyes, retinal vascular abnormalities (ie, microvascular protrusions) were present in pDVP. SS OCTA can depict perifoveal microvascular changes in young patients affected by XLRS. In this study, the structural and vascular changes seem to be more evident in the pDVP and may represent a useful biomarker of prognosis.

The ocular pathology of Norrie disease in a fetus of 11 weeks' gestational age.

PubMed

Parsons, M A; Curtis, D; Blank, C E; Hughes, H N; McCartney, A C

1992-01-01

The ocular pathology of Norrie disease was studied for the first time in a fetus of 11 weeks' gestation, following prenatal diagnosis using genetic markers for Norrie disease and elective abortion. The eyes were histologically normal, with no evidence of primary neuroectodermal maldevelopment of the retina, previously postulated to be the cause of the ocular changes. We believe that the retinal and other manifestations of Norrie disease are the result of a primary abnormality of vascular proliferation, probably in relation to persistent hyperplastic primary vitreous after approximately 14 weeks' gestation. We postulate that the ocular and otological effects of Norrie disease may be due to a genetically mediated abnormality of secretion of, or sensitivity to, angiogenic growth factors at endodermal-neuroectodermal interfaces during fetal and postnatal development.

Redox-dependent impairment of vascular function in sickle cell disease.

PubMed

Aslan, Mutay; Freeman, Bruce A

2007-12-01

The vascular pathophysiology of sickle cell disease (SCD) is influenced by many factors, including adhesiveness of red and white blood cells to endothelium, increased coagulation, and homeostatic perturbation. The vascular endothelium is central to disease pathogenesis because it displays adhesion molecules for blood cells, balances procoagulant and anticoagulant properties of the vessel wall, and regulates vascular homeostasis by synthesizing vasoconstricting and vasodilating substances. The occurrence of intermittent vascular occlusion in SCD leads to reperfusion injury associated with granulocyte accumulation and enhanced production of reactive oxygen species. The participation of nitric oxide (NO) in oxidative reactions causes a reduction in NO bioavailability and contributes to vascular dysfunction in SCD. Therapeutic strategies designed to counteract endothelial, inflammatory, and oxidative abnormalities may reduce the frequency of hospitalization and blood transfusion, the incidence of pain, and the occurrence of acute chest syndrome and pulmonary hypertension in patients with SCD.

Presumed bilateral branch retinal vein occlusions secondary to antiepileptic agents

PubMed Central

Hussain, Rumana N; Banerjee, Somnath

2011-01-01

A 61-year-old man presented to the ophthalmology department having developed bilateral branch retinal vein occlusions. Baseline blood tests revealed no abnormality; however, subsequent investigations showed a raised plasma homocysteine (HC) level. The patient has been treated for refractory epilepsy for a number of years. Although antiepileptic medications have been shown to reduce folate levels and result in a raised HC level, this has not previously been shown to be to a level causing a retinal vascular event. PMID:21654889

Incidence of Central Vein Stenosis and Occlusion Following Upper Extremity PICC and Port Placement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gonsalves, Carin F., E-mail: Carin.Gonsalves@mail.tju.edu; Eschelman, David J.; Sullivan, Kevin L.

2003-04-15

The purpose of this study was to determine the incidence of central vein stenosis and occlusion following upper extremity placement of peripherally inserted central venous catheters(PICCs) and venous ports. One hundred fifty-four patients who underwent venography of the ipsilateral central veins prior to initial and subsequent venous access device insertion were retrospectively identified. All follow-up venograms were interpreted at the time of catheter placement by one interventional radiologist over a 5-year period and compared to the findings on initial venography. For patients with central vein abnormalities, hospital and home infusion service records and radiology reports were reviewed to determine cathetermore » dwelltime and potential alternative etiologies of central vein stenosis or occlusion. The effect of catheter caliber and dwell time on development of central vein abnormalities was evaluated. Venography performed prior to initial catheter placement showed that 150 patients had normal central veins. Three patients had central vein stenosis, and one had central vein occlusion. Subsequent venograms (n = 154)at the time of additional venous access device placement demonstrated 8 patients with occlusions and 10 with stenoses. Three of the 18 patients with abnormal follow-up venograms were found to have potential alternative causes of central vein abnormalities. Excluding these 3 patients and the 4 patients with abnormal initial venograms, a 7% incidence of central vein stenosis or occlusion was found in patients with prior indwelling catheters and normal initial venograms. Catheter caliber showed no effect on the subsequent development of central vein abnormalities. Patients who developed new or worsened central vein stenosis or occlusion had significantly (p =0.03) longer catheter dwell times than patients without central vein abnormalities. New central vein stenosis or occlusion occurred in 7% of patients following upper arm placement of venous access devices.Patients with longer catheter dwell time were more likely to develop central vein abnormalities. In order to preserve vascular access for dialysis fistulae and grafts and adhere to Dialysis Outcomes Quality Initiative guidelines, alternative venous access sites should be considered for patients with chronic renal insufficiency and end-stage renal disease.« less

Frequency and characteristics of dual pathology in patients with lesional epilepsy.

PubMed

Cendes, F; Cook, M J; Watson, C; Andermann, F; Fish, D R; Shorvon, S D; Bergin, P; Free, S; Dubeau, F; Arnold, D L

1995-11-01

We studied 167 patients who had identifiable lesions and temporal or extratemporal partial epilepsy. Pathology included neuronal migration disorders (NMDs) (48), low-grade tumors (52), vascular malformations (34), porencephalic cysts (16), and gliotic lesions as a result of cerebral insults early in life (17). MRI volumetric studies using thin (1.5- or 3-mm) coronal images were performed in all patients and in 44 age-matched normal controls. An atrophic hippocampal formation (HF), indicating dual pathology, was present in 25 patients (15%). Abnormal HF volumes were present in those with lesions involving temporal (17%) but also extratemporal (14%) areas. Age at onset and duration of epilepsy did not influence the presence of HF atrophy. However, febrile seizures in early childhood were more frequently, although not exclusively, found in patients with hippocampal atrophy. The frequency of hippocampal atrophy in our patients with low-grade tumors (2%) and vascular lesions (9%) was low. Dual pathology was far more common in patients with NMDs (25%), porencephalic cysts (31%), and reactive gliosis (23.5%). Some structural lesions, such as NMDs, are more likely to be associated with hippocampal atrophy, independent of the distance of the lesion from the HF. In other types of lesions, such as vascular malformations, dual pathology was found when the lesion was close to the HF. A common pathogenic mechanism during pre- or perinatal development may explain the occurrence of concomitant mesial temporal sclerosis and other structural lesions because of either (1) associated developmental abnormalities or (2) predisposition to prolonged febrile convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

Histopathological features of Proteus syndrome.

PubMed

Hoey, S E H; Eastwood, D; Monsell, F; Kangesu, L; Harper, J I; Sebire, N J

2008-05-01

Proteus syndrome is a rare, sporadic overgrowth disorder for which the underlying genetic defect remains unknown. Although the clinical course is well-described there is no systematic histopathological description of the lesional pathology. To describe the histopathological features encountered in a series of patients with Proteus syndrome from a single centre. Patients with Proteus syndrome who had undergone therapeutic surgical resection or biopsy were identified from a database and the histopathological findings were reviewed, with particular regard to descriptive features of the underlying tissue abnormality. There were 18 surgical specimens from nine patients, median age 4 years (range 1-9), classified into four main categories: soft-tissue swellings (lipomatous lesions), vascular anomalies (vascular malformation and haemangioma), macrodactyly (hamartomatous overgrowth) and others (sebaceous naevus and nonspecific features). In all cases, the clinical features of overgrowth were due to increased amounts of disorganized tissue, indicating a hamartomatous-type defect in which normal tissue constituents were present, but with an abnormal distribution and architecture. Vascular malformations represented a prominent category of lesions, accounting for 50% of the specimens, predominantly comprising lymphatic and lymphovascular malformations. No malignancy or cytological atypia was identified in any case. The histopathological features of lesions resected from children with Proteus syndrome predominantly include hamartomatous mixed connective tissue lesions, benign neoplasms such as lipomata, and lymphatic-rich vascular malformations.

Potential involvement of the extracranial venous system in central nervous system disorders and aging

PubMed Central

2013-01-01

Background The role of the extracranial venous system in the pathology of central nervous system (CNS) disorders and aging is largely unknown. It is acknowledged that the development of the venous system is subject to many variations and that these variations do not necessarily represent pathological findings. The idea has been changing with regards to the extracranial venous system. Discussion A range of extracranial venous abnormalities have recently been reported, which could be classified as structural/morphological, hemodynamic/functional and those determined only by the composite criteria and use of multimodal imaging. The presence of these abnormalities usually disrupts normal blood flow and is associated with the development of prominent collateral circulation. The etiology of these abnormalities may be related to embryologic developmental arrest, aging or other comorbidities. Several CNS disorders have been linked to the presence and severity of jugular venous reflux. Another composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI) was recently introduced. CCSVI is characterized by abnormalities of the main extracranial cerebrospinal venous outflow routes that may interfere with normal venous outflow. Summary Additional research is needed to better define the role of the extracranial venous system in relation to CNS disorders and aging. The use of endovascular treatment for the correction of these extracranial venous abnormalities should be discouraged, until potential benefit is demonstrated in properly-designed, blinded, randomized and controlled clinical trials. Please see related editorial: http://www.biomedcentral.com/1741-7015/11/259. PMID:24344742

Subtle gray matter changes in temporo-parietal cortex associated with cardiovascular risk factors.

PubMed

de Toledo Ferraz Alves, Tânia Corrêa; Scazufca, Márcia; Squarzoni, Paula; de Souza Duran, Fábio Luiz; Tamashiro-Duran, Jaqueline Hatsuko; Vallada, Homero P; Andrei, Anna; Wajngarten, Mauricio; Menezes, Paulo R; Busatto, Geraldo F

2011-01-01

Vascular risk factors may play an important role in the pathophysiology of Alzheimer's disease (AD). While there is consistent evidence of gray matter (GM) abnormalities in earlier stages of AD, the presence of more subtle GM changes associated with vascular risk factors in the absence of clinically significant vascular events has been scarcely investigated. This study aimed to examine GM changes in elderly subjects with cardiovascular risk factors. We predicted that the presence of cardiovascular risk would be associated with GM abnormalities involving the temporal-parietal cortices and limbic structures. We recruited 248 dementia-free subjects, age range 66-75 years, from the population-based "São Paulo Ageing and Health Study", classified in accordance to their Framingham Coronary Heart Disease Risk (FCHDR) score to undergo an MRI scan. We performed an overall analysis of covariance, controlled to total GM and APOE4 status, to investigate the presence of regional GM abnormalities in association with FCHDR subgroups (high-risk, medium-risk, and low-risk), and followed by post hoc t-test. We also applied a co-relational design in order to investigate the presence of linear progression of the GM vulnerability in association with cardiovascular risk factor. Voxel-based morphometry showed that the presence of cardiovascular risk factors were associated with regional GM loss involving the temporal cortices bilaterally. Those results retained statistical significance after including APOE4 as a covariate of interest. We also observed that there was a negative correlation between FCHDR scores and rGM distribution in the parietal cortex. Subclinical cerebrovascular abnormalities involving GM loss may provide an important link between cardiovascular risk factors and AD.

The JCR:LA-cp rat: a novel rodent model of cystic medial necrosis.

PubMed

Pung, Yuh Fen; Chilian, William M; Bennett, Martin R; Figg, Nichola; Kamarulzaman, Mohd Hamzah

2017-03-01

Although there are multiple rodent models of the metabolic syndrome, very few develop vascular complications. In contrast, the JCR:LA-cp rat develops both metabolic syndrome and early atherosclerosis in predisposed areas. However, the pathology of the normal vessel wall has not been described. We examined JCR:LA control (+/+) or cp/cp rats fed normal chow diet for 6 or 18 mo. JCR:LA-cp rats developed multiple features of advanced cystic medial necrosis including "cysts," increased collagen formation and proteoglycan deposition around cysts, apoptosis of vascular smooth muscle cells, and spotty medial calcification. These appearances began within 6 mo and were extensive by 18 mo. JCR:LA-cp rats had reduced medial cellularity, increased medial thickness, and vessel hypoxia that was most marked in the adventitia. In conclusion, the normal chow-fed JCR:LA-cp rat represents a novel rodent model of cystic medial necrosis, associated with multiple metabolic abnormalities, vascular smooth muscle cell apoptosis, and vessel hypoxia. NEW & NOTEWORTHY Triggers for cystic medial necrosis (CMN) have been difficult to study due to lack of animal models to recapitulate the pathologies seen in humans. Our study is the first description of CMN in the rat. Thus the JCR:LA-cp rat represents a useful model to investigate the underlying molecular changes leading to the development of CMN. Copyright © 2017 the American Physiological Society.

Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen.

PubMed

Raffel, Glen D; Chu, Gerald C; Jesneck, Jonathan L; Cullen, Dana E; Bronson, Roderick T; Bernard, Olivier A; Gilliland, D Gary

2009-01-01

The infant leukemia-associated gene Ott1 (Rbm15) has broad regulatory effects within murine hematopoiesis. However, germ line Ott1 deletion results in fetal demise prior to embryonic day 10.5, indicating additional developmental requirements for Ott1. The spen gene family, to which Ott1 belongs, has a transcriptional activation/repression domain and RNA recognition motifs and has a significant role in the development of the head and thorax in Drosophila melanogaster. Early Ott1-deficient embryos show growth retardation and incomplete closure of the notochord. Further analysis demonstrated placental defects in the spongiotrophoblast and syncytiotrophoblast layers, resulting in an arrest of vascular branching morphogenesis. The rescue of the placental defect using a conditional allele with a trophoblast-sparing cre transgene allowed embryos to form a normal placenta and survive gestation. This outcome showed that the process of vascular branching morphogenesis in Ott1-deficient animals was regulated by the trophoblast compartment rather than the fetal vasculature. Mice surviving to term manifested hyposplenia and abnormal cardiac development. Analysis of global gene expression of Ott1-deficient embryonic hearts showed an enrichment of hypoxia-related genes and a significant alteration of several candidate genes critical for cardiac development. Thus, Ott1-dependent pathways, in addition to being implicated in leukemogenesis, may also be important for the pathogenesis of placental insufficiency and cardiac malformations.

The pathology and pathophysiology of vascular dementia.

PubMed

Kalaria, Raj N

2017-12-19

Vascular dementia (VaD) is widely recognised as the second most common type of dementia. Consensus and accurate diagnosis of clinically suspected VaD relies on wide-ranging clinical, neuropsychological and neuroimaging measures in life but more importantly pathological confirmation. Factors defining subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes as well as time after the initial vascular event. Atherosclerotic and cardioembolic diseases combined appear the most common subtypes of vascular brain injury. In recent years, cerebral small vessel disease (SVD) has gained prominence worldwide as an important substrate of cognitive impairment. SVD is characterised by arteriolosclerosis, lacunar infarcts and cortical and subcortical microinfarcts and diffuse white matter changes, which involve myelin loss and axonal abnormalities. Global brain atrophy and focal degeneration of the cerebrum including medial temporal lobe atrophy are also features of VaD similar to Alzheimer's disease. Hereditary arteriopathies have provided insights into the mechanisms of dementia particularly how arteriolosclerosis, a major contributor of SVD promotes cognitive impairment. Recently developed and validated neuropathology guidelines indicated that the best predictors of vascular cognitive impairment were small or lacunar infarcts, microinfarcts, perivascular space dilation, myelin loss, arteriolosclerosis and leptomeningeal cerebral amyloid angiopathy. While these substrates do not suggest high specificity, VaD is likely defined by key neuronal and dendro-synaptic changes resulting in executive dysfunction and related cognitive deficits. Greater understanding of the molecular pathology is needed to clearly define microvascular disease and vascular substrates of dementia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neurovascular abnormalities in brain disorders: highlights with angiogenesis and magnetic resonance imaging studies.

PubMed

Chen, Chiao-Chi V; Chen, Yu-Chen; Hsiao, Han-Yun; Chang, Chen; Chern, Yijuang

2013-07-05

The coupling between neuronal activity and vascular responses is controlled by the neurovascular unit (NVU), which comprises multiple cell types. Many different types of dysfunction in these cells may impair the proper control of vascular responses by the NVU. Magnetic resonance imaging, which is the most powerful tool available to investigate neurovascular structures or functions, will be discussed in the present article in relation to its applications and discoveries. Because aberrant angiogenesis and vascular remodeling have been increasingly reported as being implicated in brain pathogenesis, this review article will refer to this hallmark event when suitable.

A prospective study for the detection of vascular injury in adult and pediatric patients with cervicothoracic seat belt signs.

PubMed

Rozycki, Grace S; Tremblay, Lorraine; Feliciano, David V; Tchorz, Kathryn; Hattaway, Aaron; Fountain, Jack; Pettitt, Barbara J

2002-04-01

A delayed diagnosis of injury to cervicothoracic vessels from blunt trauma may cause significant adverse sequelae. The association of a cervicothoracic seat belt sign with such an injury is unknown. Algorithms were prospectively studied for the detection of occult vascular injury in patients with cervicothoracic seat belt signs. Patients with neck seat belt signs underwent arteriography or computed tomographic angiography (CTA). Those with thoracic seat belt signs underwent aortography/arteriography if a ruptured thoracic aorta or injury to a great vessel was suspected or a neurovascular abnormality was present. During a 17-month period, 797 patients were admitted to the trauma service secondary to motor vehicle crashes. One hundred thirty-one (16.4%) had cervical or thoracic seat belt signs. Four (3%) of the patients had carotid artery injuries, the presence of which was strongly associated with a Glasgow Coma Scale score < 14, an Injury Severity Score > 16 (p < 0.0001), and the presence of a clavicle and/or first rib fracture (p < 0.0037). Of the remaining patients, 17 had thoracic trauma. There were no vascular injuries in the children and only one had thoracic trauma. The algorithms are safe and accurate for the detection of cervicothoracic vascular injury in adult and pediatric patients with seat belt signs. The cervicothoracic seat belt mark and an abnormal physical examination are an effective combination in screening for cervicothoracic vascular injury.

Heart in TLC

MedlinePlus

... Although rare, some patients have coarctation of the aorta, renal artery stenosis, or thoracic or abdominal aneurysms. ... and thoracic vascular abnormalities, including coarctation of the aorta. An abdominal ultrasound is the initial modality of ...

Testicular cellular toxicity of cadmium : transmission electron microscopy examination.

PubMed

Haffor, A S; Abou-Tarboush, F M

2004-07-01

It is clear that environmental heavy metals influence life systems and reproductive system. In the present study histological investigation revealed that cadmium was testicular toxicant in mice. Here we compared the fine-structure of spermatogenesis in two groups of mice (SWR), experimental and control. The experimental group underwent cadmium ingestion at 1 mg/kg daily for 4 weeks. The control group underwent ingestion of distilled water with equal dosages, using the same type of injectors, for 4-weeks. After cadmium exposure period both control and experimental groups were killed and samples of the testes were processed for microscopic examination. Ultra sections were examined and photographed by Transmission Electron Microscope (JEOL- 100SX) at 80KV. Ultrastructure examination revealed, vascular endothelial, interstitial, and sertoli cells damages. Early impairments of germinal cellular differentiation resulted in deformations in all parts of late spermatid. There were dislocation of accrosomal granules, nuclear damage associated with chromatin heterogeneity, detached spermatid from the apical process of sertoli cell, disarrangement of the mitochondria, abnormal oriented tail piece, and abnormal microtubules complex. These ultra morphological abnormalities relate to cell injury and to the resulting physiological abnormality, necrobiosis. Based on the results of this investigation it can be concluded that cadmium ingestion at 1000 microg/kg caused testicular toxicity and abnormalities in early sperm development.

Vascular loop in the cerebellopontine angle causing pulsatile tinnitus and headache: a case report

PubMed Central

Ramly, NA; Roslenda, AR; Suraya, A; Asma, A

2014-01-01

Tinnitus is a common disorder, it can be classified as pulsatile and non-pulsatile or objective and subjective. Pulsatile tinnitus is less common than non-pulsatile and can be due to vascular tumour such as glomus or vascular abnormality. We presented an interesting case of a 30 year-old Malay lady with a two-year history of pulsatile tinnitus which was worsening in three months duration. It was associated with intermittent headache. Clinical examination and tuning fork test were unremarkable. Apart from mild hearing loss at high frequency on the left ear, the pure tone audiogram (PTA) was otherwise normal. In view of the patient’s young age with no risk factor for high frequency loss, a magnetic resonance imaging (MRI) was performed to look for any abnormality in the cerebellopontine angle. It revealed a single vessel looping around the left vestibulocochlear and facial nerves at the cisternal portion, likely a branch of the anteroinferior cerebellar artery (AICA). Literature review on the pathophysiology and treatment option in this condition is discussed. PMID:26417253

Widefield in vivo spectral and fluorescence imaging microscopy of microvessel blood supply and oxygenation

NASA Astrophysics Data System (ADS)

Lee, Jennifer; Kozikowski, Raymond; Wankhede, Mamta; Sorg, Brian S.

2011-02-01

Abnormal microvascular function and angiogenesis are key components of various diseases that can contribute to the perpetuation of the disease. Several skin diseases and ophthalmic pathologies are characterized by hypervascularity, and in cancer the microvasculature of tumors is structurally and functionally abnormal. Thus, the microvasculature can be an important target for treatment of diseases characterized by abnormal microvasculature. Motivated largely by cancer research, significant effort has been devoted to research on drugs that target the microvasculature. Several vascular targeting drugs for cancer therapy are in clinical trials and approved for clinical use, and several off-label uses of these drugs have been reported for non-cancer diseases. The ability to image and measure parameters related to microvessel function preclinically in laboratory animals can be useful for development and comparison of vascular targeting drugs. For example, blood supply time measurements give information related to microvessel morphology and can be measured with first-pass fluorescence imaging. Hemoglobin saturation measurements give an indication of microvessel oxygen transport and can be measured with spectral imaging. While each measurement individually gives some information regarding microvessel function, the measurements together may yield even more information since theoretically microvessel morphology can influence microvessel oxygenation, especially in metabolically active tissue like tumors. However, these measurements have not yet been combined. In this study, we report the combination of blood supply time imaging and hemoglobin saturation imaging of microvessel networks in tumors using widefield fluorescence and spectral imaging, respectively. The correlation between the measurements in a mouse mammary tumor is analyzed.

Glomeruloid hemangioma and POEMS syndrome.

PubMed

Hernández Aragüés, I; Pulido Pérez, A; Ciudad Blanco, C; Parra Blanco, V; Suárez Fernández, R

2017-03-01

POEMS syndrome is a paraneoplastic manifestation associated with hematopoietic disorders such as multiple myeloma and Castleman disease. POEMS is an acronym for the main clinical features of the syndrome, namely, Polyneuropathy, Organomegaly, Endocrinopathy, M protein, and Skin abnormalities. Glomeruloid hemangiomas are considered to be a specific clinical marker of POEMS syndrome. However, while they are not pathognomonic, their presence should raise suspicion of this syndrome or alert clinicians to its possible future development, as these lesions can appear years before the onset of the syndrome. We report the cases of 2 women with plasma cell dyscrasias and sudden onset of lesions with a vascular appearance and histologic findings consistent with glomeruloid hemangioma. Recognition of this vascular tumor is important for the early diagnosis of POEMS syndrome. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Acquired uterine arteriovenous malformation developing in retained products of conception: a diagnostic dilemma.

PubMed

Goyal, Surbhi; Goyal, Ankur; Mahajan, Surbhi; Sharma, Shikha; Dev, Geeta

2014-01-01

Abnormal uterine bleeding in the postabortal period requires meticulous diagnostic work-up to decide proper management. Imaging modalities including Doppler sonography and magnetic resonance imaging in concert with clinical and laboratory findings are useful to narrow the differential diagnoses but are not definitive. Presence of increased uterine vascularity and arteriovenous shunting is non-specific and can be detected in a variety of conditions including retained trophoblastic tissue, gestational trophoblastic disease, arteriovenous malformation (AVM), placental polyp and vascular neoplasm. We present here a case of a multiparous woman with unexplained postabortal bleeding posing a diagnostic challenge. Excluding the possibility of AVM before attempting dilatation and curettage in such a clinical scenario is crucial to prevent catastrophic bleeding. © 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.

Optical Microangiography Based on Optical Coherence Tomography

NASA Astrophysics Data System (ADS)

Reif, Roberto; Wang, Ruikang K.

Proper homeostasis regulation of in vivo biological systems requires microvascular blood perfusion, which is the process of delivering blood into the tissue's capillary beds. Abnormal tissue vascularization has been associated with various diseases such as cancer, diabetes, neurological disorders, wounds, and inflammation. Understanding the changes in the vascular network or microangiography will have an important role in determining the causes and developing potential treatments for these diseases. Optical coherence tomography (OCT) is a noninvasive method for imaging three-dimensional biological tissues with high resolution (~10 µm) and without requiring the use of contrast agents. In this chapter we review several techniques for using OCT to determine blood flow velocities and the vessel morphology (optical microangiography). Different techniques will be discussed with a brief explanation of their limitations. Also, methods for quantifying these images are presented, as well as the depiction of several applications.

ULTRAHIGH SPEED SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF RETINAL AND CHORIOCAPILLARIS ALTERATIONS IN DIABETIC PATIENTS WITH AND WITHOUT RETINOPATHY.

PubMed

Choi, WooJhon; Waheed, Nadia K; Moult, Eric M; Adhi, Mehreen; Lee, ByungKun; De Carlo, Talisa; Jayaraman, Vijaysekhar; Baumal, Caroline R; Duker, Jay S; Fujimoto, James G

2017-01-01

To investigate the utility of ultrahigh speed, swept source optical coherence tomography angiography in visualizing retinal microvascular and choriocapillaris (CC) changes in diabetic patients. The study was prospective and cross-sectional. A 1,050 nm wavelength, 400 kHz A-scan rate swept source optical coherence tomography prototype was used to perform volumetric optical coherence tomography angiography of the retinal and CC vasculatures in diabetic patients and normal subjects. Sixty-three eyes from 32 normal subjects, 9 eyes from 7 patients with proliferative diabetic retinopathy, 29 eyes from 16 patients with nonproliferative diabetic retinopathy, and 51 eyes from 28 diabetic patients without retinopathy were imaged. Retinal and CC microvascular abnormalities were observed in all stages of diabetic retinopathy. In nonproliferative diabetic retinopathy and proliferative diabetic retinopathy, optical coherence tomography angiography visualized a variety of vascular abnormalities, including clustered capillaries, dilated capillary segments, tortuous capillaries, regions of capillary dropout, reduced capillary density, abnormal capillary loops, and foveal avascular zone enlargement. In proliferative diabetic retinopathy, retinal neovascularization above the inner limiting membrane was visualized. Regions of CC flow impairment in patients with proliferative diabetic retinopathy and nonproliferative diabetic retinopathy were also observed. In 18 of the 51 of eyes from diabetic patients without retinopathy, retinal mircrovascular abnormalities were observed and CC flow impairment was found in 24 of the 51 diabetic eyes without retinopathy. The ability of optical coherence tomography angiography to visualize retinal and CC microvascular abnormalities suggests it may be a useful tool for understanding pathogenesis, evaluating treatment response, and earlier detection of vascular abnormalities in patients with diabetes.

Excimer laser phototherapy for the dissolution of vascular obstruction

DOEpatents

Gruen, D.M.; Young, C.E.; Pellin, M.J.

1984-01-09

Removal of abnormal human tissue with reduced thermal damage is achieved by selecting a laser having a wavelength in the order of 290 to 400 nm, orienting a laser-transmitting glass member toward the abnormal tissue and directing the laser through the glass member at power densities, pulse rates, and times sufficient to cause multiphoton absorption and bond breaking by Coulomb repulsion rather than thermal destruction. 2 figures.

Clinical and imaging features in lung torsion and description of a novel imaging sign.

PubMed

Hammer, Mark M; Madan, Rachna

2018-04-01

We set out to identify the clinical and imaging features seen in lung torsion, a rare but emergent diagnosis leading to vascular compromise of a lobe or entire lung. We retrospectively identified 10 patients with torsion who underwent chest CT. We evaluated each case for the presence of bronchial obstruction and abnormal fissure orientation. In seven patients who underwent contrast-enhanced CTs, we assessed for the presence of the antler sign, a novel sign seen on axial images demonstrating abnormal curvature of the artery and branches originating on one side. Five patients had right middle lobe (RML) torsion after right upper lobectomy, and the remaining occurred following thoracentesis, aortic surgery, or spontaneously. Chest CTs demonstrated bronchial obstruction in eight cases and presence of abnormal fissure orientation in four patients. The antler sign was present in three patients with whole-lung torsion and one patient with lobar torsion; vascular swirling was seen on 3-D images in all seven patients with contrast-enhanced CTs. Lung parenchymal imaging findings in lung torsion may be non-specific. Identification of the antler sign on contrast-enhanced chest CT, in combination with other signs such as bronchial obstruction and abnormal fissure orientation, indicates rotation of the bronchovascular pedicle. The presence of this sign should prompt further evaluation with 3-dimensional reconstructions.

O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals.

PubMed

Sawaguchi, Shogo; Varshney, Shweta; Ogawa, Mitsutaka; Sakaidani, Yuta; Yagi, Hirokazu; Takeshita, Kyosuke; Murohara, Toyoaki; Kato, Koichi; Sundaram, Subha; Stanley, Pamela; Okajima, Tetsuya

2017-04-11

The glycosyltransferase EOGT transfers O-GlcNAc to a consensus site in epidermal growth factor-like (EGF) repeats of a limited number of secreted and membrane proteins, including Notch receptors. In EOGT-deficient cells, the binding of DLL1 and DLL4, but not JAG1, canonical Notch ligands was reduced, and ligand-induced Notch signaling was impaired. Mutagenesis of O-GlcNAc sites on NOTCH1 also resulted in decreased binding of DLL4. EOGT functions were investigated in retinal angiogenesis that depends on Notch signaling. Global or endothelial cell-specific deletion of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of different Notch1 mutant alleles exacerbated the abnormalities in Eogt -/- retina, and Notch target gene expression was decreased in Eogt -/- endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development.

Fetoplacental Vascular Endothelial Dysfunction as an Early Phenomenon in the Programming of Human Adult Diseases in Subjects Born from Gestational Diabetes Mellitus or Obesity in Pregnancy

PubMed Central

Leiva, Andrea; Pardo, Fabián; Ramírez, Marco A.; Farías, Marcelo; Casanello, Paola; Sobrevia, Luis

2011-01-01

Gestational diabetes mellitus (GDM) and obesity in pregnancy (OP) are pathological conditions associated with placenta vascular dysfunction coursing with metabolic changes at the fetoplacental microvascular and macrovascular endothelium. These alterations are seen as abnormal expression and activity of the cationic amino acid transporters and endothelial nitric oxide synthase isoform, that is, the “endothelial L-arginine/nitric oxide signalling pathway.” Several studies suggest that the endogenous nucleoside adenosine along with insulin, and potentially arginases, are factors involved in GDM-, but much less information regards their role in OP-associated placental vascular alterations. There is convincing evidence that GDM and OP prone placental endothelium to an “altered metabolic state” leading to fetal programming evidenced at birth, a phenomenon associated with future development of chronic diseases. In this paper it is suggested that this pathological state could be considered as a metabolic marker that could predict occurrence of diseases in adulthood, such as cardiovascular disease, obesity, diabetes mellitus (including gestational diabetes), and metabolic syndrome. PMID:22144986

Peripheral retinopathy in offspring of carriers of Norrie disease gene mutations. Possible transplacental effect of abnormal Norrin.

PubMed

Mintz-Hittner, H A; Ferrell, R E; Sims, K B; Fernandez, K M; Gemmell, B S; Satriano, D R; Caster, J; Kretzer, F L

1996-12-01

The Norrie disease (ND) gene (Xp11.3) (McKusick 310600) consists of one untranslated exon and two exons partially translated as the Norrie disease protein (Norrin). Norrin has sequence homology and computer-predicted tertiary structure of a growth factor containing a cystine knot motif, which affects endothelial cell migration and proliferation. Norrie disease (congenital retinal detachment), X-linked primary retinal dysplasia (congenital retinal fold), and X-linked exudative vitreoretinopathy (congenital macular ectopia) are allelic disorders. Blood was drawn for genetic studies from members of two families to test for ND gene mutations. Sixteen unaffected family members were examined ophthalmologically. If any retinal abnormality were identified, fundus photography and fluorescein angiography was performed. Family A had ND (R109stp), and family B had X-linked exudative vitreoretinopathy (R121L). The retinas of 11 offspring of carrier females were examined: three of seven carrier females, three of three otherwise healthy females, and one of one otherwise healthy male had peripheral inner retinal vascular abnormalities. The retinas of five offspring of affected males were examined: none of three carrier females and none of two otherwise healthy males had this peripheral retinal finding. Peripheral inner retinal vascular abnormalities similar to regressed retinopathy of prematurity were identified in seven offspring of carriers of ND gene mutations in two families. These ophthalmologic findings, especially in four genetically healthy offspring, strongly support the hypothesis that abnormal Norrin may have an adverse transplacental (environmental) effect on normal inner retinal vasculogenesis.

Abnormal splenic artery diameter/hepatic artery diameter ratio in cirrhosis-induced portal hypertension

PubMed Central

Zeng, Dao-Bing; Dai, Chuan-Zhou; Lu, Shi-Chun; He, Ning; Wang, Wei; Li, Hong-Jun

2013-01-01

AIM: To determine an optimal cutoff value for abnormal splenic artery diameter/proper hepatic artery diameter (S/P) ratio in cirrhosis-induced portal hypertension. METHODS: Patients with cirrhosis and portal hypertension (n = 770) and healthy volunteers (n = 31) underwent volumetric computed tomography three-dimensional vascular reconstruction to measure the internal diameters of the splenic artery and proper hepatic artery to calculate the S/P ratio. The cutoff value for abnormal S/P ratio was determined using receiver operating characteristic curve analysis, and the prevalence of abnormal S/P ratio and associations between abnormal S/P ratio and major complications of portal hypertension were studied using logistic regression. RESULTS: The receiver operating characteristic analysis showed that the cutoff points for abnormal splenic artery internal diameter and S/P ratio were > 5.19 mm and > 1.40, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 74.2%, 45.2%, 97.1%, and 6.6%, respectively. The prevalence of an abnormal S/P ratio in the patients with cirrhosis and portal hypertension was 83.4%. Patients with a higher S/P ratio had a lower risk of developing ascites [odds ratio (OR) = 0.708, 95%CI: 0.508-0.986, P = 0.041] and a higher risk of developing esophageal and gastric varices (OR = 1.483, 95%CI: 1.010-2.175, P = 0.044) and forming collateral circulation (OR = 1.518, 95%CI: 1.033-2.230, P = 0.034). After splenectomy, the portal venous pressure and maximum and mean portal venous flow velocities were reduced, while the flow rate and maximum and minimum flow velocities of the hepatic artery were increased (P < 0.05). CONCLUSION: The prevalence of an abnormal S/P ratio is high in patients with cirrhosis and portal hypertension, and it can be used as an important marker of splanchnic hemodynamic disturbances. PMID:23483462

Tumor Endothelial Cells

PubMed Central

Dudley, Andrew C.

2012-01-01

The vascular endothelium is a dynamic cellular “organ” that controls passage of nutrients into tissues, maintains the flow of blood, and regulates the trafficking of leukocytes. In tumors, factors such as hypoxia and chronic growth factor stimulation result in endothelial dysfunction. For example, tumor blood vessels have irregular diameters; they are fragile, leaky, and blood flow is abnormal. There is now good evidence that these abnormalities in the tumor endothelium contribute to tumor growth and metastasis. Thus, determining the biological basis underlying these abnormalities is critical for understanding the pathophysiology of tumor progression and facilitating the design and delivery of effective antiangiogenic therapies. PMID:22393533

Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia.

PubMed

Román, Gustavo C; Kalaria, Raj N

2006-12-01

Alzheimer's disease (AD) and vascular dementia (VaD) are widely accepted as the most common forms of dementia. Cerebrovascular lesions frequently coexist with AD, creating an overlap in the clinical and pathological features of VaD and AD. This review assembles evidence for a role for cholinergic mechanisms in the pathogenesis of VaD, as has been established for AD. We first consider the anatomy and vascularization of the basal forebrain cholinergic neuronal system, emphasizing its susceptibility to the effects of arterial hypertension, sustained hypoperfusion, and ischemic cerebrovascular disease. The impact of aging and consequences of disruption of the cholinergic system in cognition and in control of cerebral blood flow are further discussed. We also summarize preclinical and clinical evidence supporting cholinergic deficits and the use of cholinesterase inhibitors in patients with VaD. We postulate that vascular pathology likely plays a common role in initiating cholinergic neuronal abnormalities in VaD and AD.

Time to foster a rational approach to preventing cardiovascular morbid events.

PubMed

Cohn, Jay N; Duprez, Daniel A

2008-07-29

Efforts to prevent atherosclerotic morbid events have focused primarily on risk factor prevention and intervention. These approaches, based on the statistical association of risk factors with events, have dominated clinical practice in the last generation. Because the cardiovascular abnormalities eventuating in morbid events are detectable in the arteries and heart before the development of symptomatic disease, recent efforts have focused on identifying the presence of these abnormalities as a more sensitive and specific guide to the need for therapy. Advances in noninvasive techniques for studying the vasculature and the left ventricle now provide the opportunity to use early disease rather than risk factors as the tool for clinical decision making. A disease scoring system has been developed using 10 tests of vascular and cardiac function and structure. More extensive data to confirm the sensitivity and specificity of this scoring system and to demonstrate its utility in tracking the response to therapy are needed to justify widespread application in clinical practice.

Avascular Retinal Findings in a Child With Achondroplasia.

PubMed

Hua, Hong-Uyen T; Tran, Kimberly D; Medina, Carlos A; Fallas, Brenda; Negron, Cathy; Berrocal, Audina M

2017-03-01

The authors present clinical and angiographic findings in a 12-year-old girl with achondroplasia who presented with bilateral retinal peripheral nonperfusion and unilateral rhegmatogenous retinal detachment, which has not been previously described in achondroplasia. This report contributes incremental knowledge regarding aberrant retinal vascular phenomena observed in pediatric disease states and implicates the possible role of mutations in the FGFR3 gene in peripheral vascular abnormalities. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:272-274.]. Copyright 2017, SLACK Incorporated.

Vascular abnormalities of the distal deep digital flexor tendon in 8 draught horses identified on histological examination.

PubMed

Crişan, Melania Ioana; Damian, Aurel; Gal, Adrian; Miclăuş, Viorel; Cernea, Cristina L; Denoix, Jean-Marie

2013-08-01

The purpose of this study was to provide a detailed description of the vascular changes in the distal part of deep digital flexor tendon (DDFT). Eight isolated forelimbs were collected from 8 horses with DDF tendinopathy diagnosed post-mortem by ultrasound and gross anatomopathological examination. The samples were fixed in 10% neutral buffered formalin, softened in 4% phenol and dehydrated with ethylic alcohol. Goldner's Trichrome staining method was used. The histopathological examination revealed vascular proliferation associated with structural disorders of blood vessels. Angiogenesis, fibroplasia and consecutive hypertrophy of the vascular wall with or without vascular occlusion were the most common findings. Other histopathological findings were: endothelial cell edema, progressive metaplasia from squamous to cubic cells, vascular wall hyalinization, endothelial cells apoptosis/necrosis and endothelial desquamation. These results demonstrated damage of the distal deep digital flexor tendon vasculature which may progressively alter the structural integrity of the tendon and contribute to degenerative lesions. Copyright © 2013 Elsevier Ltd. All rights reserved.

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

PubMed Central

Hanson, Daniel R; Gottesman, Irving I

2005-01-01

Background Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. Discussion A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. Summary A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons. PMID:15707482

From hemobiology to vascular disease: a review of the potential of gliclazide to influence the pathogenesis of diabetic vascular disease.

PubMed

Jennings, P E

1994-01-01

Patients with type II diabetes commonly die from thrombotic vascular disease. Large vessel occlusion due to thrombosis or atherosclerotic stenosis is a process accelerated by diabetes and results in premature death. Diabetic small vessel disease, with its unique microangiopathic process, underlies many of the large vessel changes as well as causing retinopathy and nephropathy. The microangiopathic changes produce a prothrombotic tendency that has been widely reported in type II diabetes. There is reduced endothelial cell production of prostacyclin and the activators of fibrinolysis, together with increased platelet reactivity. In addition, there is increased lipid peroxidation and oxidative stress due to excess free-radical activity and impaired antioxidant defenses particularly in the presence of microvascular disease. The development of many of these abnormalities is associated with poor long-term glycemic control. However, the changes are also seen in atherosclerosis in nondiabetic patients where the progression of the disease can be modified by antiplatelet agents and antioxidants. The process of vascular damage is accelerated by diabetes, often due to co-existing disease and aging, although it is not clear that improvement in long-term glycemic control by lowering blood glucose levels to near to the nondiabetic state reduces the development of small and large vessel disease. Although the biochemical mechanism underlying this observation remains uncertain, protein glycosylation and increased platelet reactivity are implicated and interrelated. Increased oxidative stress due to excess free-radical activity may be central to diabetic vascular disease as endothelial cell damage, lipoprotein oxidation, modification of both platelet reactivity and arachidonic acid cascade are all properties of free radicals and their reaction products lipid peroxides.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure.

PubMed

Chowdhury, Biswajit; Xiang, Bo; Liu, Michelle; Hemming, Richard; Dolinsky, Vernon W; Triggs-Raine, Barbara

2017-01-01

Hyaluronan (HA) is required for endothelial-to-mesenchymal transition and normal heart development in the mouse. Heart abnormalities in hyaluronidase 2 (HYAL2)-deficient ( Hyal2 - /- ) mice and humans suggested removal of HA is also important for normal heart development. We have performed longitudinal studies of heart structure and function in Hyal2 -/- mice to determine when, and how, HYAL2 deficiency leads to these abnormalities. Echocardiography revealed atrial enlargement, atrial tissue masses, and valvular thickening at 4 weeks of age, as well as diastolic dysfunction that progressed with age, in Hyal2 -/- mice. These abnormalities were associated with increased HA, vimentin-positive cells, and fibrosis in Hyal2 -/- compared with control mice. Based on the severity of heart dysfunction, acute and chronic groups of Hyal2 -/- mice that died at an average of 12 and 25 weeks respectively, were defined. Increased HA levels and mesenchymal cells, but not vascular endothelial growth factor in Hyal2 -/- embryonic hearts, suggest that HYAL2 is important to inhibit endothelial-to-mesenchymal transition. Consistent with this, in wild-type embryos, HYAL2 and HA were readily detected, and HA levels decreased with age. These data demonstrate that disruption of normal HA catabolism in Hyal2 -/- mice causes increased HA, which may promote endothelial-to-mesenchymal transition and proliferation of mesenchymal cells. Excess endothelial-to-mesenchymal transition, resulting in increased mesenchymal cells, is the likely cause of morphological heart abnormalities in both humans and mice. In mice, these abnormalities result in progressive and severe diastolic dysfunction, culminating in heart failure. © 2016 The Authors.

Abnormal vascular and neural retinal morphology in congenital lifetime isolated growth hormone deficiency.

PubMed

Pereira-Gurgel, Virginia M; Faro, Augusto C N; Salvatori, Roberto; Chagas, Thiago A; Carvalho-Junior, José F; Oliveira, Carla R P; Costa, Ursula M M; Melo, Gustavo B; Hellström, Ann; Aguiar-Oliveira, Manuel H

Experimental models demonstrate an important role of GH in retinal development. However, the interactions between GH and the neuro-vascularization of the human retina are still not clear. A model of untreated congenital isolated GH deficiency (IGHD) may clarify the actions of GH on the retina. The purpose of this work was to assess the retinal neuro-vascularization in untreated congenital IGHD (cIGHD). In a cross sectional study, we performed an endocrine and ophthalmological assessment of 25 adult cIGHD subjects, homozygous for a null mutation (c.57+1G>A) in the GHRH receptor gene and 28 matched controls. Intraocular pressure measurement, retinography (to assess the number of retinal vascular branching points and the optic disc and cup size), and optical coherence tomography (to assess the thickness of macula) were performed. cIGHD subjects presented a more significant reduction of vascular branching points in comparison to controls (91% vs. 53% [p=0.049]). The percentage of moderate reduction was higher in cIGHD than in controls (p=0.01). The percentage of individuals with increased optic disc was higher in cIGHD subjects in comparison to controls (92.9% vs. 57.1%). The same occurred for cup size (92.9% vs. 66.7%), p<0.0001 in both cases. There was no difference in macula thickness. Most cIGHD individuals present moderate reduction of vascular branching points, increase of optic disc and cup size, but have similar thickness of the macula. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Role of Nogo and the Mitochondria–Endoplasmic Reticulum Unit in Pulmonary Hypertension

PubMed Central

Sutendra, Gopinath; Dromparis, Peter; Wright, Paulette; Bonnet, Sébastien; Haromy, Alois; Hao, Zhengrong; McMurtry, M. Sean; Michalak, Marek; Vance, Jean E.; Sessa, William C.; Michelakis, Evangelos D.

2013-01-01

Pulmonary arterial hypertension (PAH) is caused by excessive proliferation of vascular cells, which occlude the lumen of pulmonary arteries (PAs) and lead to right ventricular failure. The cause of the vascular remodeling in PAH remains unknown, and the prognosis of PAH remains poor. Abnormal mitochondria in PAH PA smooth muscle cells (SMCs) suppress mitochondria-dependent apoptosis and contribute to the vascular remodeling. We hypothesized that early endoplasmic reticulum (ER) stress, which is associated with clinical triggers of PAH including hypoxia, bone morphogenetic protein receptor II mutations, and HIV/herpes simplex virus infections, explains the mitochondrial abnormalities and has a causal role in PAH. We showed in SMCs from mice that Nogo-B, a regulator of ER structure, was induced by hypoxia in SMCs of the PAs but not the systemic vasculature through activation of the ER stress–sensitive transcription factor ATF6. Nogo-B induction increased the distance between the ER and mitochondria and decreased ER-to-mitochondria phospholipid transfer and intramitochondrial calcium. In addition, we noted inhibition of calcium-sensitive mitochondrial enzymes, increased mitochondrial membrane potential, decreased mitochondrial reactive oxygen species, and decreased mitochondria-dependent apoptosis. Lack of Nogo-B in PASMCs from Nogo-A/B−/− mice prevented these hypoxia-induced changes in vitro and in vivo, resulting in complete resistance to PAH. Nogo-B in the serum and PAs of PAH patients was also increased. Therefore, triggers of PAH may induce Nogo-B, which disrupts the ER-mitochondria unit and suppresses apoptosis. This could rescue PASMCs from death during ER stress but enable the development of PAH through overproliferation. The disruption of the ER-mitochondria unit may be relevant to other diseases in which Nogo is implicated, such as cancer and neurodegeneration. PMID:21697531

Hemostasis biomarkers and incident cognitive impairment: the REGARDS study.

PubMed

Gillett, S R; McClure, L A; Callas, P W; Thacker, E L; Unverzagt, F W; Wadley, V G; Letter, A J; Cushman, M

2018-05-07

Vascular risk factors are associated with cognitive impairment, a condition with substantial public health burden. We hypothesized that hemostasis biomarkers related to vascular disease would be associated with risk of incident cognitive impairment. We performed a nested case control study including 1,082 participants with 3.5 years of follow-up in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a longitudinal cohort study of 30,239 black and white Americans ≥45 years old. Participants were free of stroke or cognitive impairment at baseline. Baseline D-dimer, fibrinogen, factor VIII, and protein C were measured in 495 cases who developed cognitive impairment during follow-up (based on abnormal scores on ≥2 of 3 cognitive tests) and 587 controls. Unadjusted ORs for incident cognitive impairment were 1.32 (95% CI 1.02, 1.70) for D-dimer >0.50 μg/mL, 1.83 (CI 1.24, 2.71) for fibrinogen >90 th percentile, 1.63 (CI 1.11, 2.38) for factor VIII >90 th percentile and 1.10 (CI 0.73, 1.65) for protein C < 10 th percentile. There were no differences in associations by race or region. Adjustment for demographic, vascular and health behavior risk factors attenuated these associations. However, having at least 2 elevated biomarkers was associated with incident cognitive impairment, with an adjusted OR 1.73 (CI 1.10, 2.69). Elevated D-dimer, fibrinogen, and factor VIII were not associated with occurrence of cognitive impairment after multivariable adjustment; however, having at least 2 abnormal biomarkers was associated, suggesting the burden of these biomarkers is relevant. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Intermittent hypoxia during recovery from neonatal hyperoxic lung injury causes long-term impairment of alveolar development: A new rat model of BPD.

PubMed

Mankouski, Anastasiya; Kantores, Crystal; Wong, Mathew J; Ivanovska, Julijana; Jain, Amish; Benner, Eric J; Mason, Stanley N; Tanswell, A Keith; Auten, Richard L; Jankov, Robert P

2017-02-01

Bronchopulmonary dysplasia (BPD) is a chronic lung injury characterized by impaired alveologenesis that may persist into adulthood. Rat models of BPD using varying degrees of hyperoxia to produce injury either cause early mortality or spontaneously recover following removal of the inciting stimulus, thus limiting clinical relevance. We sought to refine an established rat model induced by exposure to 60% O 2 from birth by following hyperoxia with intermittent hypoxia (IH). Rats exposed from birth to air or 60% O 2 until day 14 were recovered in air with or without IH (FI O 2 = 0.10 for 10 min every 6 h) until day 28 Animals exposed to 60% O 2 and recovered in air had no evidence of abnormal lung morphology on day 28 or at 10-12 wk. In contrast, 60% O 2 -exposed animals recovered in IH had persistently increased mean chord length, more dysmorphic septal crests, and fewer peripheral arteries. Recovery in IH also increased pulmonary vascular resistance, Fulton index, and arterial wall thickness. IH-mediated abnormalities in lung structure (but not pulmonary hypertension) persisted when reexamined at 10-12 wk, accompanied by increased pulmonary vascular reactivity and decreased exercise tolerance. Increased mean chord length secondary to IH was prevented by treatment with a peroxynitrite decomposition catalyst [5,10,15,20-Tetrakis(4-sulfonatophenyl)-21H,23H-porphyrin iron (III) chloride, 30 mg/kg/day, days 14-28], an effect accompanied by fewer inflammatory cells. We conclude that IH during recovery from hyperoxia-induced injury prevents recovery of alveologenesis and leads to changes in lung and pulmonary vascular function lasting into adulthood, thus more closely mimicking contemporary BPD. Copyright © 2017 the American Physiological Society.

Manifestations of Hypoxia in the Second and Third Trimester Placenta.

PubMed

Parks, W Tony

2017-10-16

The placental pathologies that develop in the context of hypoxic insults to the fetus and placenta are termed maternal vascular malperfusion (MVM). On molecular analysis, these lesions primarily show evidence of oxidative damage, suggesting that they arise in the context of hypoxia-reperfusion injury. The earliest abnormalities are likely incomplete or absent remodeling of maternal spiral arteries (decidual arteriopathy). These vascular remodeling defects then lead to subsequent damage patterns, including accelerated villous maturation, distal villous hypoplasia, increased syncytial knots, villous infarction, retroplacental hemorrhage, and placental hypoplasia. MVM may occur in a surprisingly wide array of clinical disorders, but the relation between these clinical disorders and placental MVM is complex. It seems likely that these clinical disorders represent final common pathways for multiple etiologies, only some of which result in MVM. Birth Defects Research 109:1345-1357, 2017.© 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Acute and Perioperative Care of the Burn-Injured Patient

PubMed Central

Bittner, Edward A.; Shank, Erik; Woodson, Lee; Martyn, J.A. Jeevendra

2016-01-01

Care of burn-injured patients requires knowledge of the pathophysiologic changes affecting virtually all organs from the onset of injury until wounds are healed. Massive airway and/or lung edema can occur rapidly and unpredictably after burn and/or inhalation injury. Hemodynamics in the early phase of severe burn injury are characterized by a reduction in cardiac output, increased systemic and pulmonary vascular resistance. Approximately 2–5 days after major burn injury, a hyperdynamic and hypermetabolic state develops. Electrical burns result in morbidity much higher than expected based on burn size alone. Formulae for fluid resuscitation should serve only as guideline; fluids should be titrated to physiologic end points. Burn injury is associated basal and procedural pain requiring higher than normal opioid and sedative doses. Operating room concerns for the burn-injured patient include airway abnormalities, impaired lung function, vascular access, deceptively large and rapid blood loss, hypothermia and altered pharmacology. PMID:25485468

Alternative Medicine in Diabetes - Role of Angiogenesis, Oxidative Stress, and Chronic Inflammation

PubMed Central

El-Refaei, Mohamed F.; Abduljawad, Suha H.; Alghamdi, Ahmed H.

2014-01-01

Diabetes is a chronic metabolic disorder that is characterized by hyperglycemia due to lack of or resistance to insulin. Patients with diabetes are frequently afflicted with ischemic vascular disease and impaired wound healing. Type 2 diabetes is known to accelerate atherosclerotic processes, endothelial cell dysfunction, glycosylation of extracellular matrix proteins, and vascular denervation. Herbal medicines and naturally occurring substances may positively affect diabetes management, and could thus be utilized as cost-effective means of supporting treatment in developing countries. Natural treatments have been used in these countries for a long time to treat diabetes. The present review analyses the features of aberrant angiogenesis, abnormalities in growth factors, oxidative stress, and metabolic derangements relevant to diabetes, and how herbal substances and their active chemical constituents may counteract these events. Evidence for possible biochemical effectiveness and limitations of herbal medicines are given, as well as details regarding the role of cytokines and nitric oxide. PMID:26177484

Vascular endothelial growth factor and its relationship to the prognosis and treatment of breast, ovarian, and cervical cancer.

PubMed

Delli Carpini, Jennifer; Carpini, Jennifer Delli; Karam, Amer K; Montgomery, Leslie

2010-03-01

Tumor neovascularization is a complex process that plays a crucial role in the development of many different types of cancer. Vascular endothelial growth factor (VEGF) is a potent mitogen that is involved with mitogenesis, angiogenesis, endothelial survival, and the induction of hematopoiesis. By increasing vascular permeability in endothelial cells, it helps tumors recruit wound-healing proteins fibrin and fibrinogen from the plasma, suggesting that tumor formation is a process of abnormal wound healing dependent on the ability to generate a blood supply. The human female reproductive tract is highly dependent on VEGF for normal functions such as endometrial proliferation and development of the corpus luteum. The unique influence of female sex steroid hormones on the expression and activity of VEGF deems angiogenesis an important facet of the development of breast and ovarian cancer. Additionally, the up-regulation of VEGF by the E6 oncoprotein of the human papillomavirus suggests that VEGF plays an important role in the development of cervical cancer. Clinical trials have investigated the humanized monoclonal antibody bevacizumab as potential treatment for all three forms of cancer; the data show that in breast cancer, the use of bevacizumab may lengthen the disease-free survival for women with advanced breast cancer, but does not appear to change their overall survival. It may have a role as salvage chemotherapy for ovarian and cervical cancer, though further research is needed to establish it as a definitive form of treatment.

The morphological classification of normal and abnormal red blood cell using Self Organizing Map

NASA Astrophysics Data System (ADS)

Rahmat, R. F.; Wulandari, F. S.; Faza, S.; Muchtar, M. A.; Siregar, I.

2018-02-01

Blood is an essential component of living creatures in the vascular space. For possible disease identification, it can be tested through a blood test, one of which can be seen from the form of red blood cells. The normal and abnormal morphology of the red blood cells of a patient is very helpful to doctors in detecting a disease. With the advancement of digital image processing technology can be used to identify normal and abnormal blood cells of a patient. This research used self-organizing map method to classify the normal and abnormal form of red blood cells in the digital image. The use of self-organizing map neural network method can be implemented to classify the normal and abnormal form of red blood cells in the input image with 93,78% accuracy testing.

Antagonism of CD11b with neutrophil inhibitory factor (NIF) inhibits vascular lesions in diabetic retinopathy.

PubMed

Veenstra, Alexander A; Tang, Jie; Kern, Timothy S

2013-01-01

Leukocytes and proteins that govern leukocyte adhesion to endothelial cells play a causal role in retinal abnormalities characteristic of the early stages of diabetic retinopathy, including diabetes-induced degeneration of retinal capillaries. Leukocyte integrin αmβ2 (CD11b/CD18, MAC1), a protein mediating adhesion, has been shown to mediate damage to endothelial cells by activated leukocytes in vitro. We hypothesized that Neutrophil Inhibitory Factor (NIF), a selective antagonist of integrin αmβ2, would inhibit the diabetes-induced degeneration of retinal capillaries by inhibiting the excessive interaction between leukocytes and retinal endothelial cells in diabetes. Wild type animals and transgenic animals expressing NIF were made diabetic with streptozotocin and assessed for diabetes-induced retinal vascular abnormalities and leukocyte activation. To assess if the leukocyte blocking therapy compromised the immune system, animals were challenged with bacteria. Retinal superoxide production, leukostasis and leukocyte superoxide production were increased in wild type mice diabetic for 10 weeks, as was the ability of leukocytes isolated from diabetic animals to kill retinal endothelial cells in vitro. Retinal capillary degeneration was significantly increased in wild type mice diabetic 40 weeks. In contrast, mice expressing NIF did not develop any of these abnormalities, with the exception that non-diabetic and diabetic mice expressing NIF generated greater amounts of superoxide than did similar mice not expressing NIF. Importantly, NIF did not significantly impair the ability of mice to clear an opportunistic bacterial challenge, suggesting that NIF did not compromise immune surveillance. We conclude that antagonism of CD11b (integrin αmβ2) by NIF is sufficient to inhibit early stages of diabetic retinopathy, while not compromising the basic immune response.

Antagonism of CD11b with Neutrophil Inhibitory Factor (NIF) Inhibits Vascular Lesions in Diabetic Retinopathy

PubMed Central

Veenstra, Alexander A.; Tang, Jie; Kern, Timothy S.

2013-01-01

Leukocytes and proteins that govern leukocyte adhesion to endothelial cells play a causal role in retinal abnormalities characteristic of the early stages of diabetic retinopathy, including diabetes-induced degeneration of retinal capillaries. Leukocyte integrin αmβ2 (CD11b/CD18, MAC1), a protein mediating adhesion, has been shown to mediate damage to endothelial cells by activated leukocytes in vitro. We hypothesized that Neutrophil Inhibitory Factor (NIF), a selective antagonist of integrin αmβ2, would inhibit the diabetes-induced degeneration of retinal capillaries by inhibiting the excessive interaction between leukocytes and retinal endothelial cells in diabetes. Wild type animals and transgenic animals expressing NIF were made diabetic with streptozotocin and assessed for diabetes-induced retinal vascular abnormalities and leukocyte activation. To assess if the leukocyte blocking therapy compromised the immune system, animals were challenged with bacteria. Retinal superoxide production, leukostasis and leukocyte superoxide production were increased in wild type mice diabetic for 10 weeks, as was the ability of leukocytes isolated from diabetic animals to kill retinal endothelial cells in vitro. Retinal capillary degeneration was significantly increased in wild type mice diabetic 40 weeks. In contrast, mice expressing NIF did not develop any of these abnormalities, with the exception that non-diabetic and diabetic mice expressing NIF generated greater amounts of superoxide than did similar mice not expressing NIF. Importantly, NIF did not significantly impair the ability of mice to clear an opportunistic bacterial challenge, suggesting that NIF did not compromise immune surveillance. We conclude that antagonism of CD11b (integrin αmβ2) by NIF is sufficient to inhibit early stages of diabetic retinopathy, while not compromising the basic immune response. PMID:24205223

Focal neurological deficits

MedlinePlus

... include: Abnormal blood vessels (vascular malformation) Brain tumor Cerebral palsy Degenerative nerve illness (such as multiple sclerosis) Disorders of a single nerve or nerve group (for example, carpal tunnel syndrome ) Infection of the brain (such as meningitis or encephalitis) Injury Stroke Home ...

[Pathophysiology of sickle cell disease].

PubMed

Elion, J; Laurance, S; Lapouméroulie, C

2010-12-01

It has been 100 years since Herrick published the first medical case report of sickle cell disease. In 1949, Pauling discovered hemoglobin S (HbS). As early as the 1960-70s, emerged a coherent detailed molecular-level description of pathophysiology of sickle disease. It involved polymerization of deoxyhemoglobin S with formation of long fibers inside red blood cells (RBC) causing a distorted sickle shape and shortened lifespan. These changes constitute the basic disease process and account for hemolytic anemia and for obstructive events underlying vasoocclusive crises (VOC). However, they do not explain the mechanisms that trigger VOC. The purpose of this review is to present recent data on dehydration of sickle cell RBC, abnormalities in RBC adhesion to the vascular endothelium, the role of inflammatory events and of activation of all cells in the vessel, and abnormalities of vascular tone and carbon monoxide metabolism. These data provide new insight into the pathophysiology of the first molecular disease.

Optic disc dysplasia in poland syndrome.

PubMed

Maxfield, Steven D; Strominger, Mitchell B

2014-06-01

To report optic disc dysplasia in a case of Poland syndrome. Non-interventional case report. A 2-year-old boy with Poland syndrome was referred for ophthalmic evaluation after abnormal optic discs were found on exam. Physical exam at birth revealed right-sided aplasia of the pectoralis major muscle, symbrachydactyly, hypoplastic scapula, and an abnormal third rib. On dilated examination the optic nerve heads were dysplastic. The findings included multiple cilioretinal vessels, situs inversus, inferotemporal excavation, and surrounding pigmentary disturbances. Only one case of optic disc anomaly has been reported in Poland syndrome and was described as morning glory syndrome. The optic discs in our patient do not fit well with other optic disc excavation syndromes but are most reminiscent of those in papillorenal syndrome. As both Poland syndrome and papillorenal syndrome share vascular dysfunction as a possible etiology, this case adds to the literature of vascular dysgenesis in Poland syndrome.

The renin-angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations.

PubMed

Vargas, Félix; Rodríguez-Gómez, Isabel; Vargas-Tendero, Pablo; Jimenez, Eugenio; Montiel, Mercedes

2012-04-01

Thyroid disorders are among the most common endocrine diseases and affect virtually all physiological systems, with an especially marked impact on cardiovascular and renal systems. This review summarizes the effects of thyroid hormones on the renin-angiotensin system (RAS) and the participation of the RAS in the cardiovascular and renal manifestations of thyroid disorders. Thyroid hormones are important regulators of cardiac and renal mass, vascular function, renal sodium handling, and consequently blood pressure (BP). The RAS acts globally to control cardiovascular and renal functions, while RAS components act systemically and locally in individual organs. Various authors have implicated the systemic and local RAS in the mediation of functional and structural changes in cardiovascular and renal tissues due to abnormal thyroid hormone levels. This review analyzes the influence of thyroid hormones on RAS components and discusses the role of the RAS in BP, cardiac mass, vascular function, and renal abnormalities in thyroid disorders.

Three-dimensional ultrasonography and power Doppler for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding.

PubMed

El-Sharkawy, Mohamed; El-Mazny, Akmal; Ramadan, Wafaa; Hatem, Dina; Abdel-Hafiz, Aly; Hammam, Mohamed; Nada, Adel

2016-03-16

Ultrasonography has been extensively used in women suspected of having a gynecological malignancy. The aim of this study is to evaluate the efficacy of 3D ultrasonography and power Doppler for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding. This cross-sectional study included 78 premenopausal women with abnormal uterine bleeding scheduled for hysteroscopy and endometrial curettage. The endometrial thickness (ET), uterine artery pulsatility index (PI) and resistance index (RI), and endometrial volume (EV) and 3D power Doppler vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured and compared with hysteroscopic and histopathologic findings. The ET (P <0.001), EV (P <0.001), and endometrial VI (P <0.001) and VFI (P = 0.043) were significantly increased in patients with atypical endometrial hyperplasia and endometrial carcinoma (n = 10) than those with benign endometrium (n = 68); whereas, the uterine artery PI and RI and endometrial FI were not significantly different between the two groups. The best marker for discrimination between benign and malignant endometrium was the VI with an area under the ROC curve of 0.88 at a cutoff value of 0.81%. 3D ultrasonography and power Doppler, especially endometrial VI, may be useful for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding.

The anatomy of nuchal translucency at 10-14 weeks gestation in fetuses with trisomy 21: An incredible medical mystery.

PubMed

Nafziger, Elizabeth; Vilensky, Joel A

2014-04-01

Nuchal translucency (NT) is a hypo-echoic region of subcutaneous fluid accumulation in the posterior neck at the level of the cervical spine between the skin and soft tissues found at 10-14 weeks gestation. This ultrasound finding is important because increased NT measurements place the fetus at increased risk for chromosomal and structural abnormalities. It is a fascinating phenomenon that displays the intersection of anatomy, development, and imaging. In addition, with the ever increasing use of ultrasound in anatomy, NT is a readily demonstrable example of how important ultrasound has become to the practice of medicine. Articles on NT were obtained from OVID database and reviewed for their contribution to an understanding of the anatomical basis of NT. Whereas it is well established that the ultrasound finding of increased NT is a sensitive marker for Trisomy 21 at 10-14 weeks gestation, why this phenomena occurs has yet to be explained. The basis of nuchal edema is most likely multifactorial, a combination of delayed or disturbed lymphangiogenesis, cardiac and vascular abnormalities, and abnormal extracellular matrix components. Further research on the development of the fetal head and neck related to lymphatic development and fluid regulation during 8-14 weeks gestation will enable a greater understanding of how and why increased NT occurs compared to what is currently known. This could lead to early intervention to manage some of the repercussions of Trisomy 21 and other abnormalities related to NT. Copyright © 2014 Wiley Periodicals, Inc.

The role of perivascular adipose tissue in vascular smooth muscle cell growth

PubMed Central

Miao, Chao-Yu; Li, Zhi-Yong

2012-01-01

Adipose tissue is the largest endocrine organ, producing various adipokines and many other substances. Almost all blood vessels are surrounded by perivascular adipose tissue (PVAT), which has not received research attention until recently. This review will discuss the paracrine actions of PVAT on the growth of underlying vascular smooth muscle cells (VSMCs). PVAT can release growth factors and inhibitors. Visfatin is the first identified growth factor derived from PVAT. Decreased adiponectin and increased tumour necrosis factor-α in PVAT play a pathological role for neointimal hyperplasia after endovascular injury. PVAT-derived angiotensin II, angiotensin 1–7, reactive oxygen species, complement component 3, NO and H2S have a paracrine action on VSMC contraction, endothelial or fibroblast function; however, their paracrine actions on VSMC growth remain to be directly verified. Factors such as monocyte chemoattractant protein-1, interleukin-6, interleukin-8, leptin, resistin, plasminogen activator inhibitor type-1, adrenomedullin, free fatty acids, glucocorticoids and sex hormones can be released from adipose tissue and can regulate VSMC growth. Most of them have been verified for their secretion by PVAT; however, their paracrine functions are unknown. Obesity, vascular injury, aging and infection may affect PVAT, causing adipocyte abnormality and inflammatory cell infiltration, inducing imbalance of PVAT-derived growth factors and inhibitors, leading to VSMC growth and finally resulting in development of proliferative vascular disease, including atherosclerosis, restenosis and hypertension. In the future, using cell-specific gene interventions and local treatments may provide definitive evidence for identification of key factor(s) involved in PVAT dysfunction-induced vascular disease and thus may help to develop new therapies. LINKED ARTICLES This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3 PMID:21470202

Sildenafil Citrate Increases Fetal Weight in a Mouse Model of Fetal Growth Restriction with a Normal Vascular Phenotype

PubMed Central

Dilworth, Mark Robert; Andersson, Irene; Renshall, Lewis James; Cowley, Elizabeth; Baker, Philip; Greenwood, Susan; Sibley, Colin Peter; Wareing, Mark

2013-01-01

Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5th centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5th centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. 14C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR. PMID:24204949

Hemorheological abnormalities in human arterial hypertension

NASA Astrophysics Data System (ADS)

Lo Presti, Rosalia; Hopps, Eugenia; Caimi, Gregorio

2014-05-01

Blood rheology is impaired in hypertensive patients. The alteration involves blood and plasma viscosity, and the erythrocyte behaviour is often abnormal. The hemorheological pattern appears to be related to some pathophysiological mechanisms of hypertension and to organ damage, in particular left ventricular hypertrophy and myocardial ischemia. Abnormalities have been observed in erythrocyte membrane fluidity, explored by fluorescence spectroscopy and electron spin resonance. This may be relevant for red cell flow in microvessels and oxygen delivery to tissues. Although blood viscosity is not a direct target of antihypertensive therapy, the rheological properties of blood play a role in the pathophysiology of arterial hypertension and its vascular complications.

Using impedance cardiography to detect subclinical cardiovascular disease in women with multiple risk factors: a pilot study.

PubMed

Demarzo, Arthur P

2009-01-01

Early detection of cardiovascular disease (CVD) could initiate appropriate treatment and prevent progression. This study used impedance cardiography (ICG) waveform analysis with postural change to detect functional CVD in women older than 40 years with no history of CVD and >or=2 of the following risk factors: cigarette smoking, poor diet, physical inactivity, central adiposity, family history of premature CVD, hypertension, and dyslipidemia. A study group of 32 women underwent ICG in standing and supine positions. An age-matched control group had 20 women with an active lifestyle, no risk factors, and no history of CVD. All women in the control group had normal ICG data. All women in the study group had some abnormal ICG data, with 28 (87.5%) having multiple ICG abnormalities. ICG data indicated that 13 (40.6%) had ventricular dysfunction, 14 (43.8%) had high vascular resistive load, and 30 (93.8%) had elevated vascular pulsatile load. The data suggest that subclinical CVD, detectable by ICG, is prevalent in women older than 40 years with multiple risk factors. Abnormal ICG results could expedite the initiation of customized treatment as part of a preventive approach to CVD. (c) 2009 Wiley Periodicals, Inc.

The role of completion imaging following carotid artery endarterectomy.

PubMed

Ricco, Jean-Baptiste; Schneider, Fabrice; Illuminati, Giulio; Samson, Russell H

2013-05-01

A variety of completion imaging methods can be used during carotid endarterectomy to recognize technical errors or intrinsic abnormalities such as mural thrombus or platelet aggregation, but none of these methods has achieved wide acceptance, and their ability to improve the outcome of the operation remains a matter of controversy. It is unclear if completion imaging is routinely necessary and which abnormalities require re-exploration. Proponents of routine completion imaging argue that identification of these abnormalities will allow their immediate correction and avoid a perioperative stroke. However, much of the evidence in favor of this argument is incidental, and many experienced vascular surgeons who perform carotid endarterectomy do not use any completion imaging technique and report equally good outcomes using a careful surgical protocol. Furthermore, certain postoperative strokes, including intracerebral hemorrhage and hyperperfusion syndrome, are unrelated to the surgical technique and cannot be prevented by completion imaging. This controversial subject is now open to discussion, and our debaters have been given the task to clarify the evidence to justify their preferred option for completion imaging during carotid endarterectomy. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

PubMed Central

Fukumura, Dai; Kloepper, Jonas; Amoozgar, Zohreh; Duda, Dan G.; Jain, Rakesh K.

2018-01-01

Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research. PMID:29508855

Immunological modes of pregnancy loss: inflammation, immune effectors, and stress.

PubMed

Kwak-Kim, Joanne; Bao, Shihua; Lee, Sung Ki; Kim, Joon Woo; Gilman-Sachs, Alice

2014-08-01

Inflammatory immune response plays a key role in reproductive failures such as multiple implantation failures (MIF), early pregnancy loss, and recurrent pregnancy losses (RPL). Cellular immune responses particularly mediated by natural killer (NK), and T cells are often dysregulated in these conditions. Excessive or inappropriate recruitment of peripheral blood NK cells to the uterus may lead to cytotoxic environment in utero, in which proliferation and differentiation of trophoblast is hampered. In addition, inadequate angiogenesis by uterine NK cells often leads to abnormal vascular development and blood flow patterns, which, in turn, leads to increased oxidative stress or ischemic changes in the invading trophoblast. T-cell abnormalities with increased Th1 and Th17 immunity, and decreased Th2 and T regulatory immune responses may play important roles in RPL and MIF. A possible role of stress in inflammatory immune response is also reviewed. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Identification of a rare BMP pathway mutation in a non-syndromic human brain arteriovenous malformation via exome sequencing.

PubMed

Walcott, Brian P; Winkler, Ethan A; Zhou, Sirui; Birk, Harjus; Guo, Diana; Koch, Matthew J; Stapleton, Christopher J; Spiegelman, Dan; Dionne-Laporte, Alexandre; Dion, Patrick A; Kahle, Kristopher T; Rouleau, Guy A; Lawton, Michael T

2018-01-01

Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that can result in hemorrhagic stroke. A genetic basis for AVMs is suspected, and we investigated potential mutations in a 14-year-old girl who developed a recurrent brain AVM. Whole-exome sequencing (WES) of AVM lesion tissue and blood was performed accompanied by in silico modeling, protein expression observation in lesion tissue and zebrafish modeling. A stop-gain mutation (c.C739T:p.R247X) in the gene SMAD family member 9 ( SMAD9 ) was discovered. In the human brain tissue, immunofluorescent staining demonstrated a vascular predominance of SMAD9 at the protein level. Vascular SMAD9 was markedly reduced in AVM peri-nidal blood vessels, which was accompanied by a decrease in phosphorylated SMAD4, a downstream effector protein of the bone morphogenic protein signaling pathway. Zebrafish modeling ( Tg kdrl:eGFP ) of the morpholino splice site and translation-blocking knockdown of SMAD9 resulted in abnormal cerebral artery-to-vein connections with morphologic similarities to human AVMs. Orthogonal trajectories of evidence established a relationship between the candidate mutation discovered in SMAD9 via WES and the clinical phenotype. Replication in similar rare cases of recurrent AVM, or even more broadly sporadic AVM, may be informative in building a more comprehensive understanding of AVM pathogenesis.

Infrared thermal imaging for detection of peripheral vascular disorders

PubMed Central

Bagavathiappan, S.; Saravanan, T.; Philip, John; Jayakumar, T.; Raj, Baldev; Karunanithi, R.; Panicker, T. M. R.; Korath, M. Paul; Jagadeesan, K.

2009-01-01

Body temperature is a very useful parameter for diagnosing diseases. There is a definite correlation between body temperature and diseases. We have used Infrared Thermography to study noninvasive diagnosis of peripheral vascular diseases. Temperature gradients are observed in the affected regions of patients with vascular disorders, which indicate abnormal blood flow in the affected region. Thermal imaging results are well correlated with the clinical findings. Certain areas on the affected limbs show increased temperature profiles, probably due to inflammation and underlying venous flow changes. In general the temperature contrast in the affected regions is about 0.7 to 1° C above the normal regions, due to sluggish blood circulation. The results suggest that the thermal imaging technique is an effective technique for detecting small temperature changes in the human body due to vascular disorders. PMID:20126565

Congenital abnormalities of the inferior vena cava presenting clinically in adolescent males.

PubMed

Halparin, Jessica; Monagle, Paul; Newall, Fiona

2015-04-01

Congenital anatomic abnormality of the inferior vena cava (IVC) is an important risk factor for the development of spontaneous proximal lower extremity deep vein thrombosis (DVT) in young adults. The incidence of DVT associated with congenital IVC anomalies in paediatric populations has not been described, and the implications of IVC anomalies for treatment and outcomes of DVT are unknown. This study reports a series of five adolescent males with spontaneous lower extremity DVTs and underlying congenital IVC abnormalities. Cases were identified by searching the institutional database of patients treated with anticoagulation for venous thromboembolism at a tertiary children's hospital. The demographics, clinical presentations, imaging findings, treatment courses, and outcomes are described. All cases occurred in males, and accounted for approximately twenty percent of adolescent males presenting with DVT. IVC abnormality is likely an under-recognized risk factor for DVT in this age group, and detailed vascular imaging should be pursued in adolescents with spontaneous proximal lower extremity DVT when initial ultrasonography does not delineate the proximal clot extent. Management requires individual risk-benefit assessment in the context of providing developmentally appropriate care. Further research is required to establish long-term outcomes and determine optimal treatment strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.

NASAs VESGEN: Systems Analysis of Vascular Phenotypes from Stress and Other Signaling Pathways Using GeneLab.

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, Patricia A.; Weitzel, Alexander; Vyas, Ruchi J.; Murray, Matthew C.; Wyatt, Sarah E.

2016-01-01

One fundamental requirement shared by humans with all higher terrestrial life forms, including insect wings, higher land plants and other vertebrates, is a complex, fractally branching vascular system. NASA's VESsel GENeration Analysis (VESGEN) software maps and quantifies vascular trees, networks, and tree-network composites according to weighted physiological rules such as vessel connectivity, tapering and bifurcational branching. According to fluid dynamics, successful vascular transport requires a complex distributed system of highly regulated laminar flow. Microvascular branching rules within vertebrates, dicot leaves and the other organisms therefore display many similarities. One unifying perspective is that vascular patterning offers a useful readout that necessarily integrates complex molecular signaling pathways. VESGEN has elucidated changes in vascular pattern resulting from inflammatory, stress response, developmental and other signaling within numerous tissues and major model organisms studied for Space Biology. For a new VESGEN systems approach, we analyzed differential gene expression in leaves of Arabidopsis thaliana reported by GeneLab (GLDS-7) for spaceflight. Vascular-related changes in leaf gene expression were identified that can potentially be phenocopied by mutants in ground-based experiments. To link transcriptional, protein and other molecular change with phenotype, alterations in the Euclidean and dynamic dimensions (x,y,t) of vascular patterns for Arabidopsis leaves and other model species are being co-localized with signaling patterns of single molecular expression analyzed as information dimensions (i,j,k,...). Previously, Drosophila microarray data returned from space suggested significant changes in genes related to wing venation development that include EGF, Notch, Hedghog, Wingless and Dpp signaling. Phenotypes of increasingly abnormal ectopic wing venation in the (non-spaceflight) Drosophila wing generated by overexpression of a Notch antagonist were analyzed by VESGEN. Other VESGEN research applications include the mouse retina, GI and coronary vessels, avian placental analogs and translational studies in the astronaut retina related to health challenges for long-duration missions.

Commentary: Using Impedance Cardiography to Detect Asymptomatic Cardiovascular Disease in Prehypertensive Adults with Risk Factors.

PubMed

DeMarzo, Arthur P

2018-06-01

New guidelines on hypertension eliminated the classification of prehypertension and divided those blood pressure (BP) levels into elevated BP and stage 1 hypertension. For elevated BP, this study showed that cardiovascular (CV) abnormalities were prevalent in adults over 40 years of age with at least 2 CV risk factors. Detecting abnormalities of the CV system moves a patient from being at high risk to having earlystage cardiovascular disease (CVD) and supports a decision to treat. By redefining stage 1 and lowering the target BP, the new guidelines have set an ambitious goal for early intervention to prevent progression of CVD. Proper drug selection and titration are critical. Hypertensive patients have diverse CV abnormalities that can be quantified by impedance cardiography. By stratifying patients with ventricular, vascular, and hemodynamic abnormalities, treatment can be customized based on the abnormal underlying mechanisms to rapidly control BP and prevent progression of CVD.

[Congenital abnormalities of the aorta in children and adolescents].

PubMed

Eichhorn, J G; Ley, S

2007-11-01

Aortic abnormalities are common cardiovascular malformations accounting for 15-20% of all congenital heart disease. Ultrafast CT and MR imaging are noninvasive, accurate and robust techniques that can be used in the diagnosis of aortic malformations. While their sensitivity in detecting vascular abnormalities seems to be as good as that of conventional catheter angiocardiography, at over 90%, they are superior in the diagnosis of potentially life-threatening complications, such as tracheal, bronchial, or esophageal compression. It has been shown that more than 80% of small children with aortic abnormalities benefit directly from the use of noninvasive imaging: either cardiac catheterization is no longer necessary or radiation doses and periods of general anesthesia for interventional catheterization procedures can be much reduced. The most important congenital abnormalities of the aorta in children and adolescents are presented with reference to examples, and the value of CT and MR angiography is documented.

[Melorheostosis associated with arteriovenous malformation of the ear].

PubMed

Ingen-Housz-Oro, S; Chigot, V; Hamel-Teillac, D; Brunelle, F; De Prost, Y

2001-09-01

Melorheostosis is a rare bone dystrophy that may be associated with various vascular malformations. We report a case of arteriovenous fistulae of the ear associated with melorheostosis limited to the same side of the body. A 13 year-old boy presented a congenital port-wine nevus of the right side of the head complicated by an arteriovenous fistulae and angiomatous nodules of the ear. He was treated by laser, surgery of the nodules, arterial embolisations and sclerotherapy. In 1999, he had a benign trauma of the right hand. The X-ray showed hyperostosis resembling wax flowing down a candle reaching the carpus and some of the metacarpals and the phalanges of the right hand, typical of melorheostosis. The complete radiographic check-up showed the same characteristic appearance on the right side of the skull and the long bones of the right upper limb. Except a deformation of the right fingers, there were no others symptoms. Melorheostosis is a rare, sporadic and benign bone dysplasia that may be localized to a single limb or disseminated. The diagnosis is usually made in late childhood. Pain, stiffness, deformation of a limb are the main clinical manifestations. The skin may be erythematous and sclerotic. The radiographic appearance is characteristic with hyperostosis on one side of the bone resembling wax flowing down a candle. A vascular abnormality is present in 17 p. 100 of cases (hemangiomas, aneurysms, renal artery stenosis.). In these cases, melorheostosis is usually limited to the same side of the vascular lesion. We report the first case of arteriovenous fistulae of the ear associated with melorheostosis, on the same side of the body. The physiopathology of melorheostosis is still unknown but the association with a homolateral vascular abnormality suggests a localized defect in embryogenesis of the vascular and skeletal systems.

Retinal Vascular Changes and Prospective Risk of Disabling Dementia: the Circulatory Risk in Communities Study (CIRCS)

PubMed Central

Jinnouchi, Hiroshige; Kitamura, Akihiko; Yamagishi, Kazumasa; Kiyama, Masahiko; Imano, Hironori; Okada, Takeo; Cui, Renzhe; Umesawa, Mitsumasa; Muraki, Isao; Hayama-Terada, Mina; Kawasaki, Ryo; Sankai, Tomoko; Ohira, Tetsuya

2017-01-01

Aim: To investigate the association of retinal vascular changes with a risk of dementia in longitudinal population-based study. Methods: We performed a nested case-control study of 3,718 persons, aged 40–89 years, enrolled between 1983 and 2004. Retinal vascular changes were observed in 351 cases with disabling dementia (average period before the onset, 11.2 years) and in 702 controls matched for sex, age, and baseline year. Incidence of disabling dementia was defined as individuals who received cares for disabilities including dementia-related symptoms and/or behavioral disturbance. Conditional logistic regression analysis was used to calculate odds ratio (OR) and multivariable adjusted OR (Models 1 and 2) for incidence of disabling dementia according to each retinal vascular change. Regarding confounding variables, Model 1 included overweight status, hypertension, hyperglycemia, dyslipidemia, and smoking status, whereas Model 2 also included incidence of stroke prior to disabling dementia for further analysis. Results: The proportion of cases (controls) with retinal vascular changes was 23.1 (15.7)% for generalized arteriolar narrowing, 7.7 (7.5)% for focal arteriolar narrowing, 15.7 (11.8)% for arteriovenous nicking, 10.5 (9.3)% for increased arteriolar wall reflex, and 11.4 (9.8)% for any other retinopathy. Generalized arteriolar narrowing was associated with an increased risk of disabling dementia: crude OR, 1.66 (95% confidence interval, 1.19–2.31); Model 1: OR, 1.58 (1.12–2.23); Model 2: OR, 1.48 (1.04–2.10). The number of retinal abnormalities was associated in a dose–response manner with the risk. Conclusion: Generalized arteriolar narrowing and total number of retinal abnormalities may be useful markers for identifying persons at higher risks of disabling dementia. PMID:27904027

Nailfold capillaroscopy abnormalities correlate with cutaneous and visceral involvement in systemic sclerosis patients.

PubMed

Sato, Lucy T; Kayser, Cristiane; Andrade, Luís E C

2009-01-01

The aim of this study was to correlate quantitative and semiquantitative nailfold capillaroscopy (NFC) parameters with the extent of cutaneous and visceral involvement in systemic sclerosis (SSc) patients. The presence of clinical and serological alterations was evaluated retrospectively and correlated with NFC findings (number of capillary loops/mm, vascular deletion score and number of enlarged and giant capillary loops). For evaluation of disease extension five manifestations were analyzed: finger pad lesions, skin involvement, esophageal involvement, interstitial lung disease, and pulmonary hypertension. There were 105 NFC examinations in 92 patients, 13 of whom were evaluated at two different time points. Patients with diffuse cutaneous SSc had a higher vascular deletion score than patients with limited cutaneous SSc, sine scleroderma SSc, and overlap syndrome (1.67+/-0.91 vs 0.99+/-0.82; p=0.0005). Modified Rodnan's skin score correlated positively with capillary deletion, evaluated by the vascular deletion score and the number of capillary loops/mm (p<0.001 and p=0.012; respectively). Patients with three or more involved tracts presented lower number of capillary loops/mm (8.00+/-1.69 vs 9.23+/-1.31 capillary loops/mm; p=0.025) and a higher vascular deletion score (1.41+/-0.95 vs 0.73+/-0.76; p=0.027) when compared to patients with less than three affected tracts. Vascular deletion score was significantly higher in patients with anti-Scl-70 antibodies that in patients without anti-Scl-70 antibodies (p=0.02). NFC abnormalities correlated positively with the diffuse form of SSc, the degree of cutaneous involvement, the number of affected tracts, and the presence of anti-Scl-70 antibodies.

Resolution of brainstem edema after treatment of a dural tentorial arteriovenous fistula.

PubMed

Alvarez, Hortensia; Sasaki-Adams, Deanna; Castillo, Mauricio

2015-10-01

We report a patient with a petrosal arterio-venous dural fistula draining into the ponto-mesencephalic and medullary venous systems presenting with edema of the brain stem and complete reversal of magnetic resonance imaging (MRI) abnormalities after combined endovascular and surgical treatments. The venous anatomy of the posterior fossa and the significance of the venous involvement as the cause of clinical symptoms and imaging abnormalities in cerebro-medullary vascular lesions are discussed. © The Author(s) 2015.

[A Project to Reduce the Occlusion Rate in Hemodialysis Arteriovenous Access].

PubMed

Huang, Jia-Ling; Jang, Jeng-Fong; Lee, Kun-Feng; Shie, Yu-Ting; Jin, Mei-Hua

2015-06-01

Vascular occlusions in patients frequently necessitate that duty nurses work overtime to manage related vascular problems. For patients, vascular occlusions require invasive treatments that are painful, take time to heal, and increase anxiety. Furthermore, vascular occlusions seriously influence the effectiveness of hemodialysis. This project worked to reduce the rates of occlusion from 18.6% to < 15% for hemodialysis arteriovenous grafts (AVGs) and from 5.2% to < 2.6% for arteriovenous fistulas (AVFs). This project was conducted between September 1st, 2012 and July 31th, 2013. Our approach used a retrospective study, literature review, meeting discussions, and data compilation. The four main problems identified as associated with occlusion were: (1) low blood pressure during hemodialysis; (2) successive fistula puncture sites were located too close to one another; (3) abnormal blood flow; and (4) poor moisture control. Our solutions included: 1) adjusting and creating forms; 2) adjusting related nursing procedures; and 3) organizing a related lecture for our department. The occlusion rates of AVG and AVF decreased from 18.6% to 7.4% and 5.2% to 0.9%, respectively. We significantly reduced AVG and AVF occlusion rates by using simple methods such as using a tourniquet ruler, designing big-print, illustrated patient instruction sheets on preventing low blood pressure, creating a simplified fistula puncture site series chart, creating a moisture control card, and scheduling follow-up visits for patients with abnormal blood flow at the OPD. This project provides a reference for other hemodialysis departments.

Acetylcholine protects mesenteric arteries against hypoxia/reoxygenation injury via inhibiting calcium-sensing receptor.

PubMed

Zhao, Ming; He, Xi; Yang, Yong-Hua; Yu, Xiao-Jiang; Bi, Xue-Yuan; Yang, Yang; Xu, Man; Lu, Xing-Zhu; Sun, Qiang; Zang, Wei-Jin

2015-04-01

The Ca(2+)-sensing receptor (CaSR) plays an important role in regulating vascular tone. In the present study, we investigated the positive effects of the vagal neurotransmitter acetylcholine by suppressing CaSR activation in mesenteric arteries exposed to hypoxia/reoxygenation (H/R). The artery rings were exposed to a modified 'ischemia mimetic' solution and an anaerobic environment to simulate an H/R model. Our results showed that acetylcholine (10(-6) mol/L) significantly reduced the contractions induced by KCl and phenylephrine and enhanced the endothelium-dependent relaxation induced by acetylcholine. Additionally, acetylcholine reduced CaSR mRNA expression and activity when the rings were subjected to 4 h of hypoxia and 12 h of reoxygenation. Notably, the CaSR antagonist NPS2143 significantly reduced the contractions but did not improve the endothelium-dependent relaxation. When a contractile response was achieved with extracellular Ca(2+), both acetylcholine and NPS2143 reversed the H/R-induced abnormal vascular vasoconstriction, and acetylcholine reversed the calcimimetic R568-induced abnormal vascular vasoconstriction in the artery rings. In conclusion, this study suggests that acetylcholine ameliorates the dysfunctional vasoconstriction of the arteries after H/R, most likely by decreasing CaSR expression and activity, thereby inhibiting the increase in intracellular calcium concentration. Our findings may be indicative of a novel mechanism underlying ACh-induced vascular protection. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Hemorrhoids: From basic pathophysiology to clinical management

PubMed Central

Lohsiriwat, Varut

2012-01-01

This review discusses the pathophysiology, epidemiology, risk factors, classification, clinical evaluation, and current non-operative and operative treatment of hemorrhoids. Hemorrhoids are defined as the symptomatic enlargement and distal displacement of the normal anal cushions. The most common symptom of hemorrhoids is rectal bleeding associated with bowel movement. The abnormal dilatation and distortion of the vascular channel, together with destructive changes in the supporting connective tissue within the anal cushion, is a paramount finding of hemorrhoids. It appears that the dysregulation of the vascular tone and vascular hyperplasia might play an important role in hemorrhoidal development, and could be a potential target for medical treatment. In most instances, hemorrhoids are treated conservatively, using many methods such as lifestyle modification, fiber supplement, suppository-delivered anti-inflammatory drugs, and administration of venotonic drugs. Non-operative approaches include sclerotherapy and, preferably, rubber band ligation. An operation is indicated when non-operative approaches have failed or complications have occurred. Several surgical approaches for treating hemorrhoids have been introduced including hemorrhoidectomy and stapled hemorrhoidopexy, but postoperative pain is invariable. Some of the surgical treatments potentially cause appreciable morbidity such as anal stricture and incontinence. The applications and outcomes of each treatment are thoroughly discussed. PMID:22563187

Hemorrhoids: from basic pathophysiology to clinical management.

PubMed

Lohsiriwat, Varut

2012-05-07

This review discusses the pathophysiology, epidemiology, risk factors, classification, clinical evaluation, and current non-operative and operative treatment of hemorrhoids. Hemorrhoids are defined as the symptomatic enlargement and distal displacement of the normal anal cushions. The most common symptom of hemorrhoids is rectal bleeding associated with bowel movement. The abnormal dilatation and distortion of the vascular channel, together with destructive changes in the supporting connective tissue within the anal cushion, is a paramount finding of hemorrhoids. It appears that the dysregulation of the vascular tone and vascular hyperplasia might play an important role in hemorrhoidal development, and could be a potential target for medical treatment. In most instances, hemorrhoids are treated conservatively, using many methods such as lifestyle modification, fiber supplement, suppository-delivered anti-inflammatory drugs, and administration of venotonic drugs. Non-operative approaches include sclerotherapy and, preferably, rubber band ligation. An operation is indicated when non-operative approaches have failed or complications have occurred. Several surgical approaches for treating hemorrhoids have been introduced including hemorrhoidectomy and stapled hemorrhoidopexy, but postoperative pain is invariable. Some of the surgical treatments potentially cause appreciable morbidity such as anal stricture and incontinence. The applications and outcomes of each treatment are thoroughly discussed.

A microengineered model of RBC transfusion-induced pulmonary vascular injury.

PubMed

Seo, Jeongyun; Conegliano, David; Farrell, Megan; Cho, Minseon; Ding, Xueting; Seykora, Thomas; Qing, Danielle; Mangalmurti, Nilam S; Huh, Dongeun

2017-06-13

Red blood cell (RBC) transfusion poses significant risks to critically ill patients by increasing their susceptibility to acute respiratory distress syndrome. While the underlying mechanisms of this life-threatening syndrome remain elusive, studies suggest that RBC-induced microvascular injury in the distal lung plays a central role in the development of lung injury following blood transfusion. Here we present a novel microengineering strategy to model and investigate this key disease process. Specifically, we created a microdevice for culturing primary human lung endothelial cells under physiological flow conditions to recapitulate the morphology and hemodynamic environment of the pulmonary microvascular endothelium in vivo. Perfusion of the microengineered vessel with human RBCs resulted in abnormal cytoskeletal rearrangement and release of intracellular molecules associated with regulated necrotic cell death, replicating the characteristics of acute endothelial injury in transfused lungs in vivo. Our data also revealed the significant effect of hemodynamic shear stress on RBC-induced microvascular injury. Furthermore, we integrated the microfluidic endothelium with a computer-controlled mechanical stretching system to show that breathing-induced physiological deformation of the pulmonary microvasculature may exacerbate vascular injury during RBC transfusion. Our biomimetic microsystem provides an enabling platform to mechanistically study transfusion-associated pulmonary vascular complications in susceptible patient populations.

Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of Hereditary Hemorrhagic Telangiectasia.

PubMed

Crist, Angela M; Lee, Amanda R; Patel, Nehal R; Westhoff, Dawn E; Meadows, Stryder M

2018-05-01

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that leads to abnormal connections between arteries and veins termed arteriovenous malformations (AVM). Mutations in TGFβ pathway members ALK1, ENG and SMAD4 lead to HHT. However, a Smad4 mouse model of HHT does not currently exist. We aimed to create and characterize a Smad4 endothelial cell (EC)-specific, inducible knockout mouse (Smad4 f/f ;Cdh5-Cre ERT2 ) that could be used to study AVM development in HHT. We found that postnatal ablation of Smad4 caused various vascular defects, including the formation of distinct AVMs in the neonate retina. Our analyses demonstrated that increased EC proliferation and size, altered mural cell coverage and distorted artery-vein gene expression are associated with Smad4 deficiency in the vasculature. Furthermore, we show that depletion of Smad4 leads to decreased Vegfr2 expression, and concurrent loss of endothelial Smad4 and Vegfr2 in vivo leads to AVM enlargement. Our work provides a new model in which to study HHT-associated phenotypes and links the TGFβ and VEGF signaling pathways in AVM pathogenesis.

Successful Treatment with Microvascular Decompression Surgery of a Patient with Hemiparesis Caused by Vertebral Artery Compression of the Medulla Oblongata: Case Report and Review of the Literature.

PubMed

Ren, Jibin; Sun, Hongtao; Diao, Yunfeng; Niu, Xuegang; Wang, Hang; Wei, Zhengjun; Yuan, Fei

2017-12-01

There are few reports on hemiparesis caused by vascular medullary compression, which can occur because of dolichoectasia of the vertebrobasilar arterial system. In this article, we report a case of vertebral artery compression of the medulla oblongata in a 67-year-old woman. The patient was hypertensive, and she developed hemiparesis and intermittent spasms over 5 years. These spasms had worsened during the last year. Cranial nerve magnetic resonance imaging showed compression of the medulla oblongata by the left vertebral artery. A motor evoked potential (MEP) examination showed abnormal conduction of MEPs of bilateral toe abductors. The patient underwent microvascular decompression surgery under general anesthesia through a retrosigmoid keyhole approach. This operation led to relief of vascular compression and symptomatic improvement. Our case suggests that detailed history, imaging studies, and electrophysiologic studies help lead to a correct and early diagnosis of hemiparesis caused by vascular compression of the rostral ventrolateral medulla. Microvascular decompression surgery improves patient symptoms, and intraoperative electrophysiologic monitoring helps to avoid injury to important adjacent nerves. Copyright © 2017 Elsevier Inc. All rights reserved.

Vascular hand-arm vibration syndrome--magnetic resonance angiography.

PubMed

Poole, C J M; Cleveland, T J

2016-01-01

The diagnosis of vascular hand-arm vibration syndrome (HAVS) requires consistent symptoms, photographic evidence of digital blanching and sufficient exposure to hand-transmitted vibration (HTV; A(8) > 2.5 m/s2). There is no reliable quantitative investigation for distinguishing HAVS from other causes of Raynaud's phenomenon and from normal individuals. Hypothenar and thenar hammer syndromes produce similar symptoms to HAVS but are difficult to diagnose clinically and may be confused with HAVS. Magnetic resonance angiography (MRA) is a safe and minimally invasive method of visualizing blood vessels. Three cases of vascular HAVS are described in which MRA revealed occlusions of the ulnar, radial and superficial palmar arteries. It is proposed that HTV was the cause of these occlusions, rather than blows to the hand unrelated to vibration, the assumed mechanism for the hammer syndromes. All three cases were advised not to expose their hands to HTV despite one of them being at Stockholm vascular stage 2 (early). MRA should be the investigation of choice for stage 2 vascular HAVS or vascular HAVS with unusual features or for a suspected hammer syndrome. The technique is however technically challenging and best done in specialist centres in collaboration with an occupational physician familiar with the examination of HAVS cases. Staging for HAVS should be developed to include anatomical arterial abnormalities as well as symptoms and signs of blanching. Workers with only one artery supplying a hand, or with only one palmar arch, may be at increased risk of progression and therefore should not be exposed to HTV irrespective of their Stockholm stage. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis.

PubMed

Ehret, Fanny; Vogler, Steffen; Pojar, Sherin; Elliott, David A; Bradke, Frank; Steiner, Barbara; Kempermann, Gerd

2015-03-01

Could impaired adult hippocampal neurogenesis be a relevant mechanism underlying CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)? Memory symptoms in CADASIL, the most common hereditary form of vascular dementia, are usually thought to be primarily due to vascular degeneration and white matter lacunes. Since adult hippocampal neurogenesis, a process essential for the integration of new spatial memory occurs in a highly vascularized niche, we considered dysregulation of adult neurogenesis as a potential mechanism for the manifestation of dementia in CADASIL. Analysis in aged mice overexpressing Notch3 with a CADASIL mutation, revealed vascular deficits in arteries of the hippocampal fissure but not in the niche of the dentate gyrus. At 12 months of age, cell proliferation and survival of newborn neurons were reduced not only in CADASIL mice but also in transgenic controls overexpressing wild type Notch3. At 6 months, hippocampal neurogenesis was altered in CADASIL mice independent of overt vascular abnormalities in the fissure. Further, we identified Notch3 expression in hippocampal precursor cells and maturing neurons in vivo as well as in cultured hippocampal precursor cells. Overexpression and knockdown experiments showed that Notch3 signaling negatively regulated precursor cell proliferation. Notch3 overexpression also led to deficits in KCl-induced precursor cell activation. This suggests a cell-autonomous effect of Notch3 signaling in the regulation of precursor proliferation and activation and a loss-of-function effect in CADASIL. Consequently, besides vascular damage, aberrant precursor cell proliferation and differentiation due to Notch3 dysfunction might be an additional independent mechanism for the development of hippocampal dysfunction in CADASIL. Copyright © 2014. Published by Elsevier Inc.

Deletion of chromosome 9p21 noncoding cardiovascular risk interval in mice alters Smad2 signaling and promotes vascular aneurysm.

PubMed

Loinard, Céline; Basatemur, Gemma; Masters, Leanne; Baker, Lauren; Harrison, James; Figg, Nichola; Vilar, José; Sage, Andrew P; Mallat, Ziad

2014-12-01

Vascular aneurysm is an abnormal local dilatation of an artery that can lead to vessel rupture and sudden death. The only treatment involves surgical or endovascular repair or exclusion. There is currently no approved medical therapy for this condition. Recent data established a strong association between genetic variants in the 9p21 chromosomal region in humans and the presence of cardiovascular diseases, including aneurysms. However, the mechanisms linking this 9p21 DNA variant to cardiovascular risk are still unknown. Here, we show that deletion of the orthologous 70-kb noncoding interval on mouse chromosome 4 (chr4(Δ70kb/Δ70kb) mice) is associated with reduced aortic expression of cyclin-dependent kinase inhibitor genes p19Arf and p15Inkb. Vascular smooth muscle cells from chr4(Δ70kb/Δ70kb) mice show reduced transforming growth factor-β-dependent canonical Smad2 signaling but increased cyclin-dependent kinase-dependent Smad2 phosphorylation at linker sites, a phenotype previously associated with tumor growth and consistent with the mechanistic link between reduced canonical transforming growth factor-β signaling and susceptibility to vascular diseases. We also show that targeted deletion of the 9p21 risk interval promotes susceptibility to aneurysm development and rupture when mice are subjected to a validated model of aneurysm formation. The vascular disease of chr4(Δ70kb/Δ70kb) mice is prevented by treatment with a cyclin-dependent kinase inhibitor. The results establish a direct mechanistic link between 9p21 noncoding risk interval and susceptibility to aneurysm and may have important implications for the understanding and treatment of vascular diseases. © 2014 American Heart Association, Inc.

Rodent Studies of Cardiovascular Deconditioning

NASA Technical Reports Server (NTRS)

Shoukas, Artin A.

1999-01-01

Changes in blood pressure can occur for two reasons: 1) A decrease in cardiac output resulting from the altered contractility of the heart or through changes in venous filling pressure via the Frank Starling mechanism or; 2) A change in systemic vascular resistance. The observed changes in cardiac output and blood pressure after long term space flight cannot be entirely explained through changes in contractility or heart rate alone. Therefore, alterations in filling pressure mediated through changes in systemic venous capacitance and arterial resistance function may be important determinants of cardiac output and blood pressure after long term space flight. Our laboratory and previous studies have shown the importance of veno-constriction mediated by the carotid sinus baroreceptor reflex system on overall circulatory homeostasis and in the regulation of cardiac output. Our proposed experiments test the overall hypothesis that alterations in venous capacitance function and arterial resistance by the carotid sinus baroreceptor reflex system are an important determinant of the cardiac output and blood pressure response seen in astronauts after returning to earth from long term exposure to microgravity. This hypothesis is important to our overall understanding of circulatory adjustments made during long term space flight. It also provides a framework for investigating counter measures to reduce the incidence of orthostatic hypotension caused by an attenuation of cardiac output. We continue to use hind limb unweighted (HLU) rat model to simulate the patho physiological effects as they relate to cardiovascular deconditioning in microgravity. We have used this model to address the hypothesis that microgravity induced cardiovascular deconditioning results in impaired vascular responses and that these impaired vascular responses result from abnormal alpha-1 AR signaling. The impaired vascular reactivity results in attenuated blood pressure and cardiac output responses to an orthostatic challenge. We have used in vitro vascular reactivity assays to explore abnormalities in vascular responses in vessels from HLU animals and, cardiac output (CO), blood pressure (BP) and heart rate (HR) measurements to characterize changes in hemodynamics following HLU.

Dual-fibular reconstruction of a massive tibial defect after Ewing's sarcoma resection in a pediatric patient with a vascular variation.

PubMed

Saridis, Alkis G; Megas, Panagiotis D; Georgiou, Christos S; Diamantakis, Georgios M; Tyllianakis, Minos E

2011-01-01

In the management of malignancies of the extremities, limb salvage procedures have recently taken on greater significance. For those patients under intense adjuvant chemotherapy and with massive bone loss, free vascularized fibular grafting is currently advocated as a reliable reconstructive option, maybe because of the controversial results of bone transport in similar situations. However, when there is a vascular abnormality of either the recipient or donor extremity, microsurgical procedures are not feasible, further limiting potential reconstructive alternatives. We present the case of a 13-year-old female patient with Ewing's sarcoma of the right tibia. Preoperative angiography showed that vascularity of the affected side depended totally on a single peroneal artery. The patient was treated initially with multiagent chemotherapy, followed by an excision of 23 cm. The defect was bridged by a gradual medial transportation of the ipsilateral fibula with the Ilizarov technique and strengthened by nonvascularized transfer of the contralateral fibula. Total external fixation time was 162 days. After the removal of the Ilizarov frame a walking cast was applied for another month. At 5 years postoperatively there was no recurrence of the malignancy. The patient had full weight-bearing ability on the affected limb, with preservation of the ankle and knee joints motion and without any limb length discrepancy or axial deformity. The functional outcome that was visible was graded excellent. Transverse distraction osteogenesis of the ipsilateral fibula performed well under chemotherapy, showing unproblematic callus formation. Supplemented with nonvascularized transfer of the contralateral fibula, provided a reconstructive option with biological affinity, sufficient biomechanical strength and durability, and with a decreased complication rate. This case report presents a viable option, especially in cases in which vascular abnormalities of either the donor or the recipient limb, combined with multiagent chemotherapy, restrict potential reconstructive alternatives. It also highlights why vascularized bone graft should not be regarded as a panacea for all situations in which a fibular graft is required. Level IV, case report.

Cardiovascular disease in childhood: the role of obesity.

PubMed

Herouvi, Despina; Karanasios, Evangelos; Karayianni, Christina; Karavanaki, Kyriaki

2013-06-01

In recent years, childhood obesity is becoming an epidemic health problem. It is now evident from many studies that childhood obesity is correlated with adult excess weight status and the development of risk factors for cardiovascular diseases in adulthood, including hypertension, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome. The exposure to obesity and to the above risk factors during childhood subsequently lead to atherosclerotic development, such as altered vascular structure and function, although the mechanisms are still unclear. Several non-invasive, and thus easy-to-obtain measures of arterial structure and function, have been shown to be clinically useful in providing information about vasculature early in the course of atherosclerosis, including measurement of endothelial function, carotid intima media thickness, and arterial stiffness. The early detection of cardiovascular abnormalities is essential because the control of the atherogenic process is more effective during its early stages. The present review focuses on the cardiovascular consequences of obesity, on the mechanisms and the methods of measurement of endothelial dysfunction in obese children and adolescents, and on the ways of intervention for the improvement of vascular health.

Computational Modeling of 3D Tumor Growth and Angiogenesis for Chemotherapy Evaluation

PubMed Central

Tang, Lei; van de Ven, Anne L.; Guo, Dongmin; Andasari, Vivi; Cristini, Vittorio; Li, King C.; Zhou, Xiaobo

2014-01-01

Solid tumors develop abnormally at spatial and temporal scales, giving rise to biophysical barriers that impact anti-tumor chemotherapy. This may increase the expenditure and time for conventional drug pharmacokinetic and pharmacodynamic studies. In order to facilitate drug discovery, we propose a mathematical model that couples three-dimensional tumor growth and angiogenesis to simulate tumor progression for chemotherapy evaluation. This application-oriented model incorporates complex dynamical processes including cell- and vascular-mediated interstitial pressure, mass transport, angiogenesis, cell proliferation, and vessel maturation to model tumor progression through multiple stages including tumor initiation, avascular growth, and transition from avascular to vascular growth. Compared to pure mechanistic models, the proposed empirical methods are not only easy to conduct but can provide realistic predictions and calculations. A series of computational simulations were conducted to demonstrate the advantages of the proposed comprehensive model. The computational simulation results suggest that solid tumor geometry is related to the interstitial pressure, such that tumors with high interstitial pressure are more likely to develop dendritic structures than those with low interstitial pressure. PMID:24404145

Scaffold Composition Determines the Angiogenic Outcome of Cell-Based Vascular Endothelial Growth Factor Expression by Modulating Its Microenvironmental Distribution.

PubMed

Gaudiello, Emanuele; Melly, Ludovic; Cerino, Giulia; Boccardo, Stefano; Jalili-Firoozinezhad, Sasan; Xu, Lifen; Eckstein, Friedrich; Martin, Ivan; Kaufmann, Beat A; Banfi, Andrea; Marsano, Anna

2017-12-01

Delivery of genetically modified cells overexpressing Vascular Endothelial Growth Factor (VEGF) is a promising approach to induce therapeutic angiogenesis in ischemic tissues. The effect of the protein is strictly modulated by its interaction with the components of the extracellular matrix. Its therapeutic potential depends on a sustained but controlled release at the microenvironmental level in order to avoid the formation of abnormal blood vessels. In this study, it is hypothesized that the composition of the scaffold plays a key role in modulating the binding, hence the therapeutic effect, of the VEGF released by 3D-cell constructs. It is found that collagen sponges, which poorly bind VEGF, prevent the formation of localized hot spots of excessive concentration, therefore, precluding the development of aberrant angiogenesis despite uncontrolled expression by a genetically engineered population of adipose tissue-derived stromal cells. On the contrary, after seeding on VEGF-binding egg-white scaffolds, the same cell population caused aberrantly enlarged vascular structures after 14 d. Collagen-based engineered tissues also induced a safe and efficient angiogenesis in both the patch itself and the underlying myocardium in rat models. These findings open new perspectives on the control and the delivery of proangiogenic stimuli, and are fundamental for the vascularization of engineered tissues/organs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Therapeutic indications for percutaneous laser in patients with vascular malformations and tumors].

PubMed

Labau, D; Cadic, P; Ouroussoff, G; Ligeron, C; Laroche, J-P; Guillot, B; Dereure, O; Quéré, I; Galanaud, J-P

2014-12-01

Lasers are increasingly used to treat vascular abnormalities. Indeed, this technique is non-invasive and allows a specific treatment. The aim of this review is to present some biophysical principles of the lasers, to describe the different sorts of lasers available for treatment in vascular medicine indications. Three principal lasers exist in vascular medicine: the pulsed-dye laser, for the treatment of superficial pink lesions, the NdYAG-KTP laser for purple and bigger lesions, and the NdYAG long pulse laser for even deeper and bigger vascular lesions. In vascular malformations, port wine stains can also be treated by pulsed-dye laser, KTP or NdYAG when they are old and thick. Telangiectasias are good indications for the three sorts of lasers, depending on their depth, color and size. Microcystic lymphatic malformations can be improved by laser treatment. Arterio-venous malformations constitute a contraindication of laser treatment. In vascular tumors, involuted infantile hemangiomas constitute an excellent indication of pulsed-dye laser treatment. Controlled studies are necessary to evaluate and to compare the efficacy of each laser, in order to determine their optimal indications and optimal parameters for each machine. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Evaluation of vascular variations at cerebellopontine angle by 3D T2WI magnetic-resonance imaging in patients with vertigo.

PubMed

Beyazal Celiker, Fatma; Dursun, Engin; Celiker, Metin; Durakoglugil, Tugba; Beyazal, Mehmet; Inecikli, Mehmet Fatih; Ozgur, Abdulkadir; Terzi, Suat

2017-01-01

Vascular loops of the anterior-inferior cerebellar artery (AICA) at the cerebellopontine angle (CPA) are considered related to auditory-vestibular symptoms. Clinical association of these anatomical aberrations, which can be grouped together as vascular compression syndromes, is controversial. Magnetic resonance imaging (MRI) is widely used to visualize this anatomical region, given its high sensitivity and specificity. To elucidate the clinical relationship of vertigo symptoms with vascular loop compression syndrome by evaluating the neurovascular contacts of the vestibulocochlear nerve (VCN) and AICA at the CPA and internal auditory canal via high-resolution MRI. The study included 417 patients (178 with vertigo and 239 without vertigo) undergoing MRI for various clinical causes. MRI scans were assessed to study the presence of vascular abnormalities at the CPA. According to our findings, type 1 vascular variation was observed most frequently in both sides. MRI findings were similar for the patients with and without vertigo. Identifying the prevalence of the vascular loops of the AICA primarily depends on diagnostic technique, and our results identified a slightly higher prevalence than those of previous studies, which might be partly related to the high-sensitivity of 3-dimensional T2-weighted MRI.

Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice.

PubMed

Ohlmann, Andreas; Scholz, Michael; Goldwich, Andreas; Chauhan, Bharesh K; Hudl, Kristiane; Ohlmann, Anne V; Zrenner, Eberhart; Berger, Wolfgang; Cvekl, Ales; Seeliger, Mathias W; Tamm, Ernst R

2005-02-16

Norrie disease is an X-linked retinal dysplasia that presents with congenital blindness, sensorineural deafness, and mental retardation. Norrin, the protein product of the Norrie disease gene (NDP), is a secreted protein of unknown biochemical function. Norrie disease (Ndp(y/-)) mutant mice that are deficient in norrin develop blindness, show a distinct failure in retinal angiogenesis, and completely lack the deep capillary layers of the retina. We show here that the transgenic expression of ectopic norrin under control of a lens-specific promoter restores the formation of a normal retinal vascular network in Ndp(y/-) mutant mice. The improvement in structure correlates with restoration of neuronal function in the retina. In addition, lenses of transgenic mice with ectopic expression of norrin show significantly more capillaries in the hyaloid vasculature that surrounds the lens during development. In vitro, lenses of transgenic mice in coculture with microvascular endothelial cells induce proliferation of the cells. Transgenic mice with ectopic expression of norrin show more bromodeoxyuridine-labeled retinal progenitor cells at embryonic day 14.5 and thicker retinas at postnatal life than wild-type littermates, indicating a putative direct neurotrophic effect of norrin. These data provide direct evidence that norrin induces growth of ocular capillaries and that pharmacologic modulation of norrin might be used for treatment of the vascular abnormalities associated with Norrie disease or other vascular disorders of the retina.

Vascular Aging: Lessons From Pediatric Hypertension.

PubMed

Litwin, Mieczyslaw; Feber, Janusz; Ruzicka, Marcel

2016-05-01

Hypertension (HTN) in children is associated with early vascular aging (EVA) and underlying immunologic-metabolic abnormalities and accelerated biological maturation. Morphologic and functional vascular changes underlying EVA and HTN in children resemble those seen in the elderly including but not limited to an increase in intima-media thickness (IMT) and arterial stiffness and endothelial dysfunction. Although progeria syndrome leading to EVA and the development of clinically manifested cardiovascular (CV) disease in the second decade of life is a rare hereditary disorder, primary HTN, which is also associated with EVA, is much more common (reported in up to 10% in adolescents). EVA associated with HTN in children leads to the premature development of target organ injury in childhood and CV events in early adulthood. Limited evidence from prospective observational studies in children and adolescents indicates that early lifestyle measures (low salt/low sugar intake and exercise) or pharmacologic treatment of HTN, or both, partially reverses morphologic and functional changes underlying EVA such as an increase in carotid IMT and pulse wave velocity, a decrease in flow-mediated dilation of the brachial artery, and an increase in oxidative stress and visceral fat. Future mechanistic and therapeutic clinical trials are desirable to assess the mechanisms and treatment strategies of EVA in the context of HTN in children and their effect on CV events in early adulthood. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Evaluation of cardiovascular anomalies in patients with asymptomatic turner syndrome using multidetector computed tomography.

PubMed

Lee, Sun Hee; Jung, Ji Mi; Song, Min Seob; Choi, Seok jin; Chung, Woo Yeong

2013-08-01

Turner syndrome is well known to be associated with significant cardiovascular abnormalities. This paper studied the incidence of cardiovascular abnormalities in asymptomatic adolescent patients with Turner syndrome using multidetector computed tomography (MDCT) instead of echocardiography. Twenty subjects diagnosed with Turner syndrome who had no cardiac symptoms were included. Blood pressure and electrocardiography (ECG) was checked. Cardiovascular abnormalities were checked by MDCT. According to the ECG results, 11 had a prolonged QTc interval, 5 had a posterior fascicular block, 3 had a ventricular conduction disorder. MDCT revealed vascular abnormalities in 13 patients (65%). Three patients had an aberrant right subclavian artery, 2 had dilatation of left subclavian artery, and others had an aortic root dilatation, aortic diverticulum, and abnormal left vertebral artery. As for venous abnormalities, 3 patients had partial anomalous pulmonary venous return and 2 had a persistent left superior vena cava. This study found cardiovascular abnormalities in 65% of asymptomatic Turner syndrome patients using MDCT. Even though, there are no cardiac symptoms in Turner syndrome patients, a complete evaluation of the heart with echocardiography or MDCT at transition period to adults must be performed.

Predictors of Outcome following Acquired Brain Injury in Children

ERIC Educational Resources Information Center

Johnson, Abigail R.; DeMatt, Ellen; Salorio, Cynthia F.

2009-01-01

Acquired brain injury (ABI) in children and adolescents can result from multiple causes, including trauma, central nervous system infections, noninfectious disorders (epilepsy, hypoxia/ischemia, genetic/metabolic disorders), tumors, and vascular abnormalities. Prediction of outcomes is important, to target interventions, allocate resources,…

Familial Idiopathic Cranial Neuropathy in a Chinese Family.

PubMed

Zhang, Li; Liang, Jianfeng; Yu, Yanbing

Cranial neuropathy is usually idiopathic and familial cases are uncommon. We describe a family with 5 members with cranial neuropathy over 3 generations. All affected patients were women, indicating an X-linked dominant or an autosomal dominant mode of inheritance. Our cases and a review of the literature suggest that familial idiopathic cranial neuropathy is a rare condition which may be related to autosomal dominant vascular disorders (e.g. vascular tortuosity, sclerosis, elongation or extension), small posterior cranial fossas, anatomical variations of the posterior circulation, hypersensitivity of cranial nerves and other abnormalities. Moreover, microvascular decompression is the treatment of choice because vascular compression is the main factor in the pathogenesis. To the best of our knowledge, this is the first report of familial cranial neuropathy in China.

Dilatation of the Virchow-Robin spaces as an indicator of unilateral carotid artery stenosis: correlation with white matter lesions.

PubMed

Sahin, Neslin; Solak, Aynur; Genc, Berhan; Akpinar, Mehmet Besir

2015-07-01

Virchow-Robin space (VRS) dilatation is related to many pathologic conditions, mostly associated with vascular abnormalities. White matter lesions (WMLs) are commonly seen on brain magnetic resonance imaging (MRI) with advancing age and generally considered as potential markers for vascular disease. To investigate if asymmetric dilatation of VRSs and WMLs are associated with unilateral internal carotid artery stenosis (ICAS) and to test the relationship between dilated VRSs and common vascular risk factors. Twenty-nine patients (18 men, 11 women; mean age, 68.62 years) with unilateral ICAS (≥70% carotid stenosis) undergoing carotid endarterectomy were identified for this Health Insurance Portability and Accountability Act (HIPAA) compliant prospective study and assessed with brain MRI. Two experienced radiologists scored VRSs and WMLs and evaluated old infarcts, chronic lacunar infarcts, and cerebral atrophy. Asymmetry of WML and VRS scores between two cerebral hemispheres was assessed and associations between VRS scores, WML scores, and explanatory variables (e.g. age, sex, vascular risk factors, and atrophy) were tested. In this study, WMLs and basal ganglia VRSs were significantly greater in the unilateral hemisphere with ICA stenosis than contralateral hemisphere. Basal ganglia VRSs were associated with WMLs and internal cerebral atrophy. No association between the severity of VRSs and vascular risk factors was found. ICA stenosis may contribute as a factor in the development of WMLs and dilatation of VRSs by causing chronic hypoperfusion. VRS dilatation may be an additional MRI marker of ICAS. © The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Mechanisms of vascular aging: What can we learn from Hutchinson-Gilford progeria syndrome?

PubMed

Del Campo, Lara; Hamczyk, Magda R; Andrés, Vicente; Martínez-González, José; Rodríguez, Cristina

Aging is the main risk factor for cardiovascular disease (CVD). The increased prevalence of CVD is partly due to the global increase in life expectancy. In this context, it is essential to identify the mechanisms by which aging induces CVD, with the ultimate aim of reducing its incidence. Both atherosclerosis and heart failure significantly contribute to age-associated CVD morbidity and mortality. Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by the synthesis of progerin, which is noted for accelerated aging and CVD. This mutant form of prelamin A induces generalised atherosclerosis, vascular calcification, and cardiac electrophysiological abnormalities, leading to premature aging and death, mainly due to myocardial infarction and stroke. This review discusses the main vascular structural and functional abnormalities during physiological and premature aging, as well as the mechanisms involved in the exacerbated CVD and accelerated aging induced by the accumulation of progerin and prelamin A. Both proteins are expressed in non-HGPS individuals, and physiological aging shares many features of progeria. Research into HGPS could therefore shed light on novel mechanisms involved in the physiological aging of the cardiovascular system. Copyright © 2018 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

Limiting chest computed tomography in the evaluation of pediatric thoracic trauma.

PubMed

Golden, Jamie; Isani, Mubina; Bowling, Jordan; Zagory, Jessica; Goodhue, Catherine J; Burke, Rita V; Upperman, Jeffrey S; Gayer, Christopher P

2016-08-01

Computed tomography (CT) of the chest (chest CT) is overused in blunt pediatric thoracic trauma. Chest CT adds to the diagnosis of thoracic injury but rarely changes patient management. We sought to identify a subset of blunt pediatric trauma patients who would benefit from a screening chest CT based on their admission chest x-ray (CXR) findings. We hypothesize that limiting chest CT to patients with an abnormal mediastinal silhouette identifies intrathoracic vascular injuries not otherwise seen on CXR. All blunt trauma activations that underwent an admission CXR at our Level 1 pediatric trauma center from 2005 to 2013 were retrospectively reviewed. Patients who had a chest CT were evaluated for added diagnoses and change in management after CT. An admission CXR was performed in 1,035 patients. One hundred thirty-nine patients had a CT, and the diagnosis of intra-thoracic injury was added in 42% of patients. Chest CT significantly increased the diagnosis of contusion or atelectasis (30.3% vs 60.4%; p < 0.05), pneumothorax (7.2% vs 18.7%; p < 0.05), and other fractures (4.3% vs 10.8%; p < 0.05) on CXR compared to chest CT. Chest CT changed the management of only 4 patients (2.9%). Two patients underwent further radiologic evaluation that was negative for injury, one had a chest tube placed for an occult pneumothorax before exploratory laparotomy, and one patient had a thoracotomy for repair of aortic injury. Chest CT for select patients with an abnormal mediastinal silhouette on CXR would have decreased CT scans by 80% yet still identified patients with an intrathoracic vascular injury. The use of chest CT should be limited to the identification of intrathoracic vascular injuries in the setting of an abnormal mediastinal silhouette on CXR. Therapeutic study, level IV; diagnostic study, level III.

Vascular signaling abnormalities in Alzheimer disease.

PubMed

Grammas, Paula; Sanchez, Alma; Tripathy, Debjani; Luo, Ester; Martinez, Joseph

2011-08-01

Our laboratory has documented that brain microvessels derived from patients with Alzheimer disease (AD) express or release a myriad of factors that have been implicated in vascular activation and angiogenesis. In addition, we have documented that signaling cascades associated with vascular activation and angiogenesis are upregulated in AD-derived brain microvessels. These results are consistent with emerging data suggesting that factors and processes characteristic of vascular activation and angiogenesis are found in the AD brain. Despite increases in proangiogenic factors and signals in the AD brain, however, evidence for increased vascularity in AD is lacking. Cerebral hypoperfusion/hypoxia, a potent stimulus for vascular activation and angiogenesis, triggers hypometabolic, cognitive, and degenerative changes in the brain. In our working model, hypoxia stimulates the angiogenic process; yet, there is no new vessel growth. Therefore, there are no feedback signals to shut off vascular activation, and endothelial cells become irreversibly activated. This activation results in release of a large number of proteases, inflammatory proteins, and other gene products with biologic activity that can injure or kill neurons. Pathologic activation of brain vasculature may contribute noxious mediators that lead to neuronal injury and disease processes in AD brains. This concept is supported by preliminary experiments in our laboratory, which show that pharmacologic blockade of vascular activation improves cognitive function in an animal model of AD. Thus, "vascular activation" could be a novel, unexplored therapeutic target in AD.

Using NASA's GeneLab for VESGEN Systems Analysis of Vascular Phenotypes from Stress and Other Signaling Pathways

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, P.; Weitzel, Alexander; Vyas, R. J.; Murray, M. C.; Vickerman, M. B.; Bhattacharya, S.; Wyatt, S. E.

2016-01-01

One fundamental requirement shared by humans with all higher terrestrial life forms, including other vertebrates, insects, and higher land plants, is a complex, fractally branching vascular system. NASA's VESsel GENeration Analysis (VESGEN) software maps and quantifies vascular trees, networks, and tree-network composites according to weighted physiological rules such as vessel connectivity, tapering and bifurcational branching. According to fluid dynamics, successful vascular transport requires a complex distributed system of highly regulated laminar flow. Microvascular branching rules within vertebrates, dicot leaves and the other organisms therefore display many similarities. A unifying perspective is that vascular patterning offers a useful readout of molecular signaling that necessarily integrates these complex pathways. VESGEN has elucidated changes in vascular pattern resulting from inflammatory, developmental and other signaling within numerous tissues and major model organisms studied for Space Biology. For a new VESGEN systems approach, we analyzed differential gene expression in leaves of Arabidopsis thaliana reported by GeneLab (GLDS-7) for spaceflight. Vascularrelated changes in leaf gene expression were identified that can potentially be phenocopied by mutants in ground-based experiments. To link transcriptional, protein and other molecular change with phenotype, alterations in the spatial and dynamic dimensions of vascular patterns for Arabidopsis leaves and other model species are being co-localized with signaling patterns of single molecular expression analyzed as information dimensions. Previously, Drosophila microarray data returned from space suggested significant changes in genes related to wing venation development that include EGF, Notch, Hedghog, Wingless and Dpp signaling. Phenotypes of increasingly abnormal ectopic wing venation in the (non-spaceflight) Drosophila wing generated by overexpression of a Notch antagonist were analyzed by VESGEN. Other VESGEN research applications include the mouse retina, GI and coronary vessels, avian placental analogs and translational studies in the astronaut retina related to health challenges for long-duration missions.

Coronary vasomotor abnormalities in insulin-resistant individuals.

PubMed

Quiñones, Manuel J; Hernandez-Pampaloni, Miguel; Schelbert, Heinrich; Bulnes-Enriquez, Isabel; Jimenez, Xochitl; Hernandez, Gustavo; De La Rosa, Roxana; Chon, Yun; Yang, Huiying; Nicholas, Susanne B; Modilevsky, Tamara; Yu, Katherine; Van Herle, Katja; Castellani, Lawrence W; Elashoff, Robert; Hsueh, Willa A

2004-05-04

Insulin resistance is a metabolic spectrum that progresses from hyperinsulinemia to the metabolic syndrome, impaired glucose tolerance, and finally type 2 diabetes mellitus. It is unclear when vascular abnormalities begin in this spectrum of metabolic effects. To evaluate the association of insulin resistance with the presence and reversibility of coronary vasomotor abnormalities in young adults at low cardiovascular risk. Cross-sectional study followed by prospective, open-label treatment study. University hospital. 50 insulin-resistant and 22 insulin-sensitive, age-matched Mexican-American participants without glucose intolerance or traditional risk factors for or evidence of coronary artery disease. 3 months of thiazolidinedione therapy for 25 insulin-resistant patients. Glucose infusion rate in response to insulin infusion was used to define insulin resistance (glucose infusion rate < or = 4.00 mg/kg of body weight per minute [range, 0.90 to 3.96 mg/kg per minute]) and insulin sensitivity (glucose infusion rate > or = 7.50 mg/kg per minute [range, 7.52 to 13.92 mg/kg per minute]). Myocardial blood flow was measured by using positron emission tomography at rest, during cold pressor test (largely endothelium-dependent), and after dipyridamole administration (largely vascular smooth muscle-dependent). Myocardial blood flow responses to dipyridamole were similar in the insulin-sensitive and insulin-resistant groups. However, myocardial blood flow response to cold pressor test increased by 47.6% from resting values in insulin-sensitive patients and by 14.4% in insulin-resistant patients. During thiazolidinedione therapy in a subgroup of insulin-resistant patients, insulin sensitivity improved, fasting plasma insulin levels decreased, and myocardial blood flow responses to cold pressor test normalized. The study was not randomized, and it included only 1 ethnic group. Insulin-resistant patients who do not have hypercholesterolemia or hypertension and do not smoke manifest coronary vasomotor abnormalities. Insulin-sensitizing thiazolidinedione therapy normalized these abnormalities. These results suggest an association between insulin resistance and abnormal coronary vasomotor function, a relationship that requires confirmation in larger studies.

Hypoxia and fetal heart development.

PubMed

Patterson, A J; Zhang, L

2010-10-01

Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not the only gene involved in adaptation to hypoxia, its role places it as a central figure in orchestrating events needed for adaptation to hypoxic stress. Although "normal" hypoxia (lower oxygen tension in the fetus as compared with the adult) is essential in heart formation, further abnormal hypoxia in utero adversely affects cardiogenesis. Prenatal hypoxia alters myocardial structure and causes a decline in cardiac performance. Not only are the effects of hypoxia apparent during the perinatal period, but prolonged hypoxia in utero also causes fetal programming of abnormality in the heart's development. The altered expression pattern of cardioprotective genes such as protein kinase c epsilon, heat shock protein 70, and endothelial nitric oxide synthase, likely predispose the developing heart to increased vulnerability to ischemia and reperfusion injury later in life. The events underlying the long-term changes in gene expression are not clear, but likely involve variation in epigenetic regulation.

A stochastic model for early placental development†

PubMed Central

Cotter, Simon L.; Klika, Václav; Kimpton, Laura; Collins, Sally; Heazell, Alexander E. P.

2014-01-01

In the human, placental structure is closely related to placental function and consequent pregnancy outcome. Studies have noted abnormal placental shape in small-for-gestational-age infants which extends to increased lifetime risk of cardiovascular disease. The origins and determinants of placental shape are incompletely understood and are difficult to study in vivo. In this paper, we model the early development of the human placenta, based on the hypothesis that this is driven by a chemoattractant effect emanating from proximal spiral arteries in the decidua. We derive and explore a two-dimensional stochastic model, and investigate the effects of loss of spiral arteries in regions near to the cord insertion on the shape of the placenta. This model demonstrates that disruption of spiral arteries can exert profound effects on placental shape, particularly if this is close to the cord insertion. Thus, placental shape reflects the underlying maternal vascular bed. Abnormal placental shape may reflect an abnormal uterine environment, predisposing to pregnancy complications. Through statistical analysis of model placentas, we are able to characterize the probability that a given placenta grew in a disrupted environment, and even able to distinguish between different disruptions. PMID:24850904

The lung in liver disease: old problem, new concepts.

PubMed

Fallon, Michael B; Zhang, Junlan

2013-01-01

Liver dysfunction has been recognized to influence the lung in many different clinical situations, although the mechanisms for these effects are not well understood. One increasingly recognized interaction, the hepatopulmonary syndrome (HPS) occurs in the context of cirrhosis and results when alveolar microvascular dilation causes arterial gas exchange abnormalities and hypoxemia. HPS occurs in up to 30% of patients with cirrhosis and significantly increases mortality in affected patients. Currently, liver transplantation is the only curative therapy. Experimental biliary cirrhosis induced by common bile duct ligation (CBDL) in the rat reproduces the pulmonary vascular and gas exchange abnormalities of human HPS and has been contrasted with other experimental models of cirrhosis in which HPS does not develop. Microvascular dilation, intravascular monocyte infiltration, and angiogenesis in the lung have been identified as pathologic features that drive gas exchange abnormalities in experimental HPS. Our recent studies have identified biliary epithelium and activation and interaction between the endothelin-1 (ET-1)/endothelial endothelin B (ETB) receptor and CX3CL1/CX3CR1 pathways as important mechanisms for the observed pathologic events. These studies define novel interactions between the lung and liver in cirrhosis and may lead to effective medical therapies.

Molecular Regulation of Endothelial Cells by NF-1

DTIC Science & Technology

2013-01-01

cancer progression. The mammalian target of rapamycin (mTOR) is a serine threonine kinase, that exists in two distinct signaling complexes: mTORC1 and...abnormalities such as diabetes , with known vascular complications. Thus mTOR may be a significant regulator of endothelial cell functions

Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction

PubMed Central

Barton, Matthias; Baretella, Oliver; Meyer, Matthias R

2012-01-01

Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the world's population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease, obesity has deleterious effects on metabolic homeostasis, and affects numerous organ systems including heart, kidney and the vascular system. Thus, obesity is now regarded as an independent risk factor for atherosclerosis-related diseases such as coronary artery disease, myocardial infarction and stroke. In the arterial system, endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium-derived vasoactive factors favouring vasoconstriction, cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally, because of the similarities of the vascular pathomechanisms activated, obesity can be considered to cause accelerated, ‘premature’ vascular aging. Here, we will review some of the pathomechanisms involved in obesity-related activation of endothelium-dependent vasoconstriction, the clinical relevance of obesity-associated vascular risk, and therapeutic interventions using ‘endothelial therapy’ aiming at maintaining or restoring vascular endothelial health. LINKED ARTICLES This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3 PMID:21557734

Clinical image: MRI during migraine with aura

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNeal, A.C.

1996-03-01

Migraine refers to severe headaches that are usually unilateral, throbbing, and associated with nausea, vomiting, photophobia, and phonophobia. Migraine with aura (formerly called {open_quotes}classic migraine{close_quotes}) consists of the headache preceded or accompanied by neurological dysfunction. This dysfunction (aura) usually involves visual and sensory symptoms. The patient described herein experienced migraine with aura. MRI during and after the attack showed a reversible abnormality of the right posterior cerebral artery, with no parenchymal lesions. This appears to be the first report of abnormal MR vascular imaging during migraine with aura. 10 refs., 2 figs.

CT Angiography after 20 Years

PubMed Central

Rubin, Geoffrey D.; Leipsic, Jonathon; Schoepf, U. Joseph; Fleischmann, Dominik; Napel, Sandy

2015-01-01

Through a marriage of spiral computed tomography (CT) and graphical volumetric image processing, CT angiography was born 20 years ago. Fueled by a series of technical innovations in CT and image processing, over the next 5–15 years, CT angiography toppled conventional angiography, the undisputed diagnostic reference standard for vascular disease for the prior 70 years, as the preferred modality for the diagnosis and characterization of most cardiovascular abnormalities. This review recounts the evolution of CT angiography from its development and early challenges to a maturing modality that has provided unique insights into cardiovascular disease characterization and management. Selected clinical challenges, which include acute aortic syndromes, peripheral vascular disease, aortic stent-graft and transcatheter aortic valve assessment, and coronary artery disease, are presented as contrasting examples of how CT angiography is changing our approach to cardiovascular disease diagnosis and management. Finally, the recently introduced capabilities for multispectral imaging, tissue perfusion imaging, and radiation dose reduction through iterative reconstruction are explored with consideration toward the continued refinement and advancement of CT angiography. PMID:24848958

Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity

PubMed Central

Kyriakides, Themis R.; Leach, Kathleen J.; Hoffman, Allan S.; Ratner, Buddy D.; Bornstein, Paul

1999-01-01

Disruption of the thrombospondin 2 gene (Thbs2) in mice results in a complex phenotype characterized chiefly by abnormalities in fibroblasts, connective tissues, and blood vessels. Consideration of this phenotype suggested to us that the foreign body reaction (FBR) might be altered in thrombospondin 2 (TSP2)-null mice. To investigate the participation of TSP2 in the FBR, polydimethylsiloxane (PDMS) and oxidized PDMS (ox-PDMS) disks were implanted in TSP2-null and control mice. Growth of TSP2-null and control skin fibroblasts in vitro also was evaluated on both types of disks. Normal fibroblasts grew as a monolayer on both surfaces, but attachment of the cells to ox-PDMS was weak and sensitive to movement. TSP2-null fibroblasts grew as aggregates on both surfaces, and their attachment was further compromised on ox-PDMS. After a 4-week implantation period, both types of PDMS elicited a similar FBR with a collagenous capsule in both TSP2-null and control mice. However, strikingly, the collagenous capsule that formed in TSP2-null mice was highly vascularized and thicker than that formed in normal mice. In addition, abnormally shaped collagen fibers were observed in capsules from mutant mice. These observations indicate that the presence or absence of an extracellular matrix component, TSP2, can influence the nature of the FBR, in particular its vascularity. The expression of TSP2 therefore could represent a molecular target for local inhibitory measures when vascularization of the tissue surrounding an implanted device is desired. PMID:10200282

Association of vascular physical examination findings and arteriographic lesions in large vessel vasculitis.

PubMed

Grayson, Peter C; Tomasson, Gunnar; Cuthbertson, David; Carette, Simon; Hoffman, Gary S; Khalidi, Nader A; Langford, Carol A; McAlear, Carol A; Monach, Paul A; Seo, Philip; Warrington, Kenneth J; Ytterberg, Steven R; Merkel, Peter A

2012-02-01

To assess the utility of the vascular physical examination to detect arteriographic lesions in patients with established large vessel vasculitis (LVV), including Takayasu's arteritis (TAK) and giant cell arteritis (GCA). In total, 100 patients (TAK = 68, GCA = 32) underwent standardized physical examination and angiography of the carotid, subclavian, and axillary arteries. Sensitivity and specificity were calculated for the association between findings on physical examination focusing on the vascular system (absent pulse, bruit, and blood pressure difference) and arteriographic lesions defined as stenosis, occlusion, or aneurysm. We found 67% of patients had at least 1 abnormality on physical examination (74% TAK, 53% GCA). Arteriographic lesions were seen in 76% of patients (82% TAK, 63% GCA). Individual physical examination findings had poor sensitivity (range 14%-50%) and good-excellent specificity (range 71%-98%) to detect arteriographic lesions. Even when considering physical examination findings in combination, at least 30% of arteriographic lesions were missed. Specificity improved (range 88%-100%) if individual physical examination findings were compared to a broader region of vessels rather than specific anatomically correlated vessels and if ≥ 1 physical examination findings were combined. In patients with established LVV, physical examination alone is worthwhile to detect arterial disease but does not always localize or reveal the full extent of arteriographic lesions. Abnormal vascular system findings on physical examination are highly associated with the presence of arterial lesions, but normal findings on physical examination do not exclude the possibility of arterial disease. Serial angiographic assessment is advisable to monitor arterial disease in patients with established LVV.

Pediatric head and neck lesions: assessment of vascularity by MR digital subtraction angiography.

PubMed

Chooi, Weng Kong; Woodhouse, Neil; Coley, Stuart C; Griffiths, Paul D

2004-08-01

Pediatric head and neck lesions can be difficult to characterize on clinical grounds alone. We investigated the use of dynamic MR digital subtraction angiography as a noninvasive adjunct for the assessment of the vascularity of these abnormalities. Twelve patients (age range, 2 days to 16 years) with known or suspected vascular abnormalities were studied. Routine MR imaging, time-of-flight MR angiography, and MR digital subtraction angiography were performed in all patients. The dynamic sequence was acquired in two planes at one frame per second by using a thick section (6-10 cm) selective radio-frequency spoiled fast gradient-echo sequence and an IV administered bolus of contrast material. The images were subtracted from a preliminary mask sequence and viewed as a video-inverted cine loop. In all cases, MR digital subtraction angiography was successfully performed. The technique showed the following: 1) slow flow lesions (two choroidal angiomas, eyelid hemangioma, and scalp venous malformation); 2) high flow lesions that were not always suspected by clinical examination alone (parotid hemangioma, scalp, occipital, and eyelid arteriovenous malformations plus a palatal teratoma); 3) a hypovascular tumor for which a biopsy could be safely performed (Burkitt lymphoma); and 4) a hypervascular tumor of the palate (cystic teratoma). Our early experience suggests that MR digital subtraction angiography can be reliably performed in children of all ages without complication. The technique provided a noninvasive assessment of the vascularity of each lesion that could not always have been predicted on the basis of clinical examination or routine MR imaging alone.

Ultra-high-sensitive optical micro-angiography provides depth resolved visualization of microcirculations within human skin under psoriatic conditions

NASA Astrophysics Data System (ADS)

Qin, Jia; An, Lin; Wang, Ruikang

2011-03-01

Adequate functioning of the peripheral micro vascular in human skin is necessary to maintain optimal tissue perfusion and preserve normal hemodynamic function. There is a growing body of evidence suggests that vascular abnormalities may directly related to several dermatologic diseases, such as psoriasis, port-wine stain, skin cancer, etc. New in vivo imaging modalities to aid volumetric microvascular blood perfusion imaging are there for highly desirable. To address this need, we demonstrate the capability of ultra-high sensitive optical micro angiography to allow blood flow visualization and quantification of vascular densities of lesional psoriasis area in human subject in vivo. The microcirculation networks of lesion and non-lesion skin were obtained after post processing the data sets captured by the system. With our image resolution (~20 μm), we could compare these two types of microcirculation networks both qualitatively and quantitatively. The B-scan (lateral or x direction) cross section images, en-face (x-y plane) images and the volumetric in vivo perfusion map of lesion and non-lesion skin areas were obtained using UHS-OMAG. Characteristic perfusion map features were identified between lesional and non-lesional skin area. A statistically significant difference between vascular densities of lesion and non-lesion skin area was also found using a histogram based analysis. UHS-OMAG has the potential to differentiate the normal skin microcirculation from abnormal human skin microcirculation non-invasively with high speed and sensitivity. The presented data demonstrates the great potential of UHS-OMAG for detecting and diagnosing skin disease such as psoriasis in human subjects.

Association of Vascular Physical Examination Findings and Arteriographic Lesions in Large Vessel Vasculitis

PubMed Central

GRAYSON, PETER C.; TOMASSON, GUNNAR; CUTHBERTSON, DAVID; CARETTE, SIMON; HOFFMAN, GARY S.; KHALIDI, NADER A.; LANGFORD, CAROL A.; McALEAR, CAROL A.; MONACH, PAUL A.; SEO, PHILIP; WARRINGTON, KENNETH J.; YTTERBERG, STEVEN R.; MERKEL, PETER A.

2013-01-01

Objective To assess the utility of the vascular physical examination to detect arteriographic lesions in patients with established large vessel vasculitis (LVV), including Takayasu’s arteritis (TAK) and giant cell arteritis (GCA). Methods In total, 100 patients (TAK = 68, GCA = 32) underwent standardized physical examination and angiography of the carotid, subclavian, and axillary arteries. Sensitivity and specificity were calculated for the association between findings on physical examination focusing on the vascular system (absent pulse, bruit, and blood pressure difference) and arteriographic lesions defined as stenosis, occlusion, or aneurysm. Results We found 67% of patients had at least 1 abnormality on physical examination (74% TAK, 53% GCA). Arteriographic lesions were seen in 76% of patients (82% TAK, 63% GCA). Individual physical examination findings had poor sensitivity (range 14%–50%) and good-excellent specificity (range 71%–98%) to detect arteriographic lesions. Even when considering physical examination findings in combination, at least 30% of arteriographic lesions were missed. Specificity improved (range 88%–100%) if individual physical examination findings were compared to a broader region of vessels rather than specific anatomically correlated vessels and if ≥ 1 physical examination findings were combined. Conclusion In patients with established LVV, physical examination alone is worthwhile to detect arterial disease but does not always localize or reveal the full extent of arteriographic lesions. Abnormal vascular system findings on physical examination are highly associated with the presence of arterial lesions, but normal findings on physical examination do not exclude the possibility of arterial disease. Serial angiographic assessment is advisable to monitor arterial disease in patients with established LVV. PMID:22174204

Metaherpetic corneal disease in a dog associated with partial limbal stem cell deficiency and neurotrophic keratitis.

PubMed

Ledbetter, Eric C; Marfurt, Carl F; Dubielzig, Richard R

2013-07-01

To describe clinical, in vivo confocal microscopic, histopathologic, and immunohistochemical features of a dog with metaherpetic corneal disease that developed subsequent to a protracted episode of canine herpesvirus-1 (CHV-1) dendritic ulcerative keratitis. A 7-year-old, spayed-female, Miniature Schnauzer was treated for bilateral CHV-1 dendritic ulcerative keratitis. Following resolution of ulcerative keratitis, sectoral peripheral superficial corneal gray opacification, vascularization, and pigmentation slowly migrated centripetally to the axial cornea of both eyes. Corneal sensitivity measured with a Cochet-Bonnet esthesiometer was dramatically and persistently reduced. In vivo corneal confocal microscopic examination revealed regions of epithelium with a conjunctival phenotype. In these areas, the surface epithelium was thin, disorganized, and composed of hyper-reflective epithelial cells. Goblet cells and Langerhans cells were frequent, and the subbasal nerve plexus was completely absent or markedly diminished. Histopathologic abnormalities in the globes were restricted to the superficial cornea and included sectoral corneal conjunctivalization, increased anterior stromal spindle cells, and vascularization. Immunohistochemical evaluation of the corneas with anti-neurotublin antibody demonstrated attenuation of the epithelial and subbasal nerve plexuses with marked stromal hyperinnervation and increased numbers of morphologically abnormal neurites. Similar to herpes simplex virus keratitis in humans, CHV-1 ulcerative keratitis may be associated with the development of chronic degenerative corneal disease in dogs. In the described dog, this chronic corneal disease included progressive corneal opacification because of partial limbal stem cell deficiency and neurotrophic keratitis. Long-term monitoring of dogs following resolution of active CHV-1 keratitis may be indicated, particularly when ulcerations persist for an extended period. © 2012 American College of Veterinary Ophthalmologists.

Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction

PubMed Central

Gonzales, Marcelino; Rodriguez, Armando; Bellido, Diva; Salmon, Carlos Salinas; Ladenburger, Anne; Reardon, Lindsay; Vargas, Enrique; Moore, Lorna G.

2015-01-01

Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects ∼10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600–4,100 m) residents aged 18–25 yr with excessive erythrocytosis (EE, Hb concentration ≥18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey (n = 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio = 5.25, P = 0.05 and odds ratio = 6.44, P = 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension. PMID:26092986

Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction.

PubMed

Julian, Colleen Glyde; Gonzales, Marcelino; Rodriguez, Armando; Bellido, Diva; Salmon, Carlos Salinas; Ladenburger, Anne; Reardon, Lindsay; Vargas, Enrique; Moore, Lorna G

2015-08-15

Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects ∼10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600-4,100 m) residents aged 18-25 yr with excessive erythrocytosis (EE, Hb concentration ≥18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey (n = 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio = 5.25, P = 0.05 and odds ratio = 6.44, P = 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension. Copyright © 2015 the American Physiological Society.

The potential relationship between Flammer and Sjögren syndromes: the chime of dysfunction.

PubMed

Baban, Babak; Golubnitschaja, Olga

2017-12-01

Flammer syndrome (FS) is a term to blanket a cluster of vascular and nonvascular signs and symptoms linked to primary vascular dysregulation (PVD), increased sensitivity to various stimuli (stress, drugs, etc.) and altered sense regulation such as pain, smell and thirst perception. On one hand, disruption of blood barrier and homeostasis of the body are the main targets of vascular irregularity. Inflammation and immune disorders including autoimmunity are considered as a consequence of the abnormal vascular regulation processes. On the other hand, decreased thirst feeling typical for FS-affected individuals may lead to extensive body dehydration resulting in dry eye appearance and breast cancer (BC) risk, amongst others. To this end, recent research demonstrated FS as linked to BC development and progression into the metastatic disease. On the other side, Sjögren syndrome (SS) is an autoimmune disease characterised by a progressive sicca syndrome associated with the dry eye symptoms, specific immunologic complex and/or significant infiltrate at minor salivary gland biopsy. SS is relatively frequent, with a clinical diagnosis predominantly amongst women. Its physiopathology is a complex battery of both environmental and genetic factors. If left untreated, SS may be associated with and/or resulted in severe arthritis and the development of B cell lymphoma. In this mini-review, we summarise the facts and hypotheses connecting FS and SS symptoms together and mechanisms potentially overlapping in both syndromes. Unraveling the common denominators between these two syndromes not only providing more evidence for interaction between altered sense regulation, vascular dysregulation, immune system dysfunction but also focusing on the individual outcomes in terms of severity grade and potential complications exploring novel diagnostic, prognostic and treatment modalities. Multi-professional considerations presented here are an example how to effectively enter the new era of preventive, predictive and personalised medicine benefiting the patients and healthcare system as the whole.

Thrombocytopenia and Platelet Dysfunction in Acute Tropical Infectious Diseases.

PubMed

Hapsari Putri, Indri; Tunjungputri, Rahajeng N; De Groot, Philip G; van der Ven, Andre J; de Mast, Quirijn

2018-06-18

Thrombocytopenia is a well-known manifestation of acute tropical infectious diseases. The role of platelets in infections has received much attention recently because of their emerging activities in modulation of inflammatory responses, host defense, and vascular integrity. However, while many studies have addressed thrombocytopenia in tropical infections, abnormalities in platelet function have been largely overlooked. This is an important research gap, as platelet dysfunction may contribute to the bleeding tendency that characterizes some tropical infections. The development of novel platelet function assays that can be used in thrombocytopenic conditions (e.g., flow cytometry assays) has contributed to important new insights in recent years. In this review, the importance of platelets in tropical infections is discussed with special emphasis on the underlying mechanisms and consequences of thrombocytopenia and platelet dysfunction in these infections. Special attention is paid to malaria, a disease characterized by microvascular obstruction in which bleeding is rare, and to infections in which bleeding is common, such as dengue, other viral hemorrhagic fevers, and the bacterial infection leptospirosis. Given the importance of platelet function abnormalities in these infections, the development of affordable assays for monitoring of platelet function in low-resource countries, as well as pharmacologic interventions to prevent or reverse platelet function abnormalities, might improve clinical care and the prognosis of these infections. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein.

PubMed

Allen, R C; Russell, S R; Streb, L M; Alsheikheh, A; Stone, E M

2006-02-01

To determine the molecular pathology and clinical severity of two pedigrees with a history of early retinal detachment and peripheral retinal vascular abnormalities. Longitudinal cohort study. A longitudinal clinical study and DNA analysis was performed on 49 family members of two pedigrees. Nine individuals were found to be hemizygous for a mutation at codon 112 (Gly112Glu) of the Norrie disease protein (NDP) in one pedigree. Significant phenotypic heterogeneity was found. The proband presented with a unilateral subtotal retinal detachment at the age of 3 years, and subsequently developed a slowly progressive tractional retinal detachment involving the macula in the contralateral eye at the age of 4 years. One individual had only mild peripheral retinal pigmentary changes with normal vision at the age of 79 years. The remaining seven individuals had varying degrees of peripheral retinal vascular abnormalities and anterior segment findings. Seven affected members of a second pedigree affected by a previously reported mutation, Arg74Cys, also demonstrated wide ocular phenotypic variation. A novel mutation (Gly112Glu), which represents the most carboxy located, NDP mutation reported, results in significant phenotypic heterogeneity. These data support the contention that the spectrum of ocular disease severity associated with these NDP mutations is broad. Use of terms that characterize this entity by phenotypic appearance, such as familial exudative vitreoretinopathy, do not adequately communicate the potential spectrum of severity of this disorder to affected or carrier family members.

Effects of antibacterial nanostructured composite films on vascular stents: hemodynamic behaviors, microstructural characteristics, and biomechanical properties.

PubMed

Cheng, Han-Yi; Hsiao, Wen-Tien; Lin, Li-Hsiang; Hsu, Ya-Ju; Sinrang, Andi Wardihan; Ou, Keng-Liang

2015-01-01

The purpose of this research was to investigate stresses resulting from different thicknesses and compositions of hydrogenated Cu-incorporated diamond-like carbon (a-C:H/Cu) films at the interface between vascular stent and the artery using three-dimensional reversed finite element models (FEMs). Blood flow velocity variation in vessels with plaques was examined by angiography, and the a-C:H/Cu films were characterized by transmission electron microscopy to analyze surface morphology. FEMs were constructed using a computer-aided reverse design system, and the effects of antibacterial nanostructured composite films in the stress field were investigated. The maximum stress in the vascular stent occurred at the intersections of net-like structures. Data analysis indicated that the stress decreased by 15% in vascular stents with antibacterial nanostructured composite films compared to the control group, and the stress decreased with increasing film thickness. The present results confirmed that antibacterial nanostructured composite films improve the biomechanical properties of vascular stents and release abnormal stress to prevent restenosis. The results of the present study offer the clinical benefit of inducing superior biomechanical behavior in vascular stents. © 2014 Wiley Periodicals, Inc.

Vascular Abnormalities Associated with Thermal and Electrical Trauma,

DTIC Science & Technology

1992-01-01

Knippenberg, R,W.: Temporal relationships among immunologic alterations in a guinea pig model of thermal injury. J. Infect, Dis., 153:1098, 1986. 7...decompression venous access to 72 hr in thermally injured patients of the stomach and alimentation provided either by is supported by the documented

Down Syndrome: A Cardiovascular Perspective

ERIC Educational Resources Information Center

Vis, J. C.; Duffels, M. G. J.; Winter, M. M.; Weijerman, M. E.; Cobben, J. M.; Huisman, S. A.; Mulder, B. J. M.

2009-01-01

This review focuses on the heart and vascular system in patients with Down syndrome. A clear knowledge on the wide spectrum of various abnormalities associated with this syndrome is essential for skillful management of cardiac problems in patients with Down syndrome. Epidemiology of congenital heart defects, cardiovascular aspects and…

Morning glory disk anomaly with ipsilateral capillary hemangioma, agenesis of the internal carotid artery, and Horner syndrome: a variant of PHACES syndrome?

PubMed

Puvanachandra, Narman; Heran, Manraj K; Lyons, Christopher J

2008-10-01

We describe a 6-week-old girl with a right upper lid capillary hemangioma, ipsilateral morning glory disk anomaly, microphthalmos, Mittendorf dot, and Horner syndrome. The ipsilateral internal carotid artery was also found to be absent. To our knowledge, this is the first patient to be reported with this group of findings. We suggest that this represents an overlap between morning glory disk and intracranial vascular abnormalities, a recognized association, and PHACES syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye, and sternal abnormalities). We discuss the common embryological basis for these abnormalities, which point to a widespread but highly variable disorder of mesodermal differentiation.

The neurovascular relation in oxygen-induced retinopathy.

PubMed

Akula, James D; Mocko, Julie A; Benador, Ilan Y; Hansen, Ronald M; Favazza, Tara L; Vyhovsky, Tanya C; Fulton, Anne B

2008-01-01

Longitudinal studies in rat models of retinopathy of prematurity (ROP) have demonstrated that abnormalities of retinal vasculature and function change hand-in-hand. In the developing retina, vascular and neural structures are under cooperative molecular control. In this study of rats with oxygen-induced retinopathy (OIR) models of ROP, mRNA expression of vascular endothelial growth factor (VEGF), semaphorin (Sema), and their neuropilin receptor (NRP) were examined during the course of retinopathy to evaluate their roles in the observed neurovascular congruency. Oxygen exposures designed to induce retinopathy were delivered to Sprague-Dawley rat pups (n=36) from postnatal day (P) 0 to P14 or from P7 to P14. Room-air-reared controls (n=18) were also studied. Sensitivities of the rod photoreceptors (S(rod)) and the postreceptor cells (Sm) were derived from electroretinographic (ERG) records. Arteriolar tortuosity, T(A), was derived from digital fundus images using Retinal Image multi-Scale Analysis (RISA) image analysis software. mRNA expression of VEGF(164), semaphorin IIIA (Sema3A), and neuropilin-1 (NRP-1) was evaluated by RT-PCR of retinal extracts. Tests were performed at P15-P16, P18-P19, and P25-P26. Relations among ERG, RISA, and PCR parameters were evaluated using linear regression on log transformed data. Sm was low and T(A) was high at young ages, then both resolved by P25-P26. VEGF(164) and Sema3A mRNA expression were also elevated early and decreased with age. Low Sm was significantly associated with high VEGF(164) and Sema3A expression. Low S(rod) was also significantly associated with high VEGF(164). S(rod) and Sm were both correlated with T(A). NRP-1 expression was little affected by OIR. The postreceptor retina appears to mediate the vascular abnormalities that characterize OIR. Because of the relationships revealed by these data, early treatment that targets the neural retina may mitigate the effects of ROP.

The neurovascular relation in oxygen-induced retinopathy

PubMed Central

Akula, James D.; Mocko, Julie A.; Benador, Ilan Y.; Hansen, Ronald M.; Favazza, Tara L.; Vyhovsky, Tanya C.

2008-01-01

Purpose Longitudinal studies in rat models of retinopathy of prematurity (ROP) have demonstrated that abnormalities of retinal vasculature and function change hand-in-hand. In the developing retina, vascular and neural structures are under cooperative molecular control. In this study of rats with oxygen-induced retinopathy (OIR) models of ROP, mRNA expression of vascular endothelial growth factor (VEGF), semaphorin (Sema), and their neuropilin receptor (NRP) were examined during the course of retinopathy to evaluate their roles in the observed neurovascular congruency. Methods Oxygen exposures designed to induce retinopathy were delivered to Sprague-Dawley rat pups (n=36) from postnatal day (P) 0 to P14 or from P7 to P14. Room-air-reared controls (n=18) were also studied. Sensitivities of the rod photoreceptors (Srod) and the postreceptor cells (Sm) were derived from electroretinographic (ERG) records. Arteriolar tortuosity, TA, was derived from digital fundus images using Retinal Image multi-Scale Analysis (RISA) image analysis software. mRNA expression of VEGF164, semaphorin IIIA (Sema3A), and neuropilin-1 (NRP-1) was evaluated by RT–PCR of retinal extracts. Tests were performed at P15–P16, P18–P19, and P25–P26. Relations among ERG, RISA, and PCR parameters were evaluated using linear regression on log transformed data. Results Sm was low and TA was high at young ages, then both resolved by P25–P26. VEGF164 and Sema3A mRNA expression were also elevated early and decreased with age. Low Sm was significantly associated with high VEGF164 and Sema3A expression. Low Srod was also significantly associated with high VEGF164. Srod and Sm were both correlated with TA. NRP-1 expression was little affected by OIR. Conclusions The postreceptor retina appears to mediate the vascular abnormalities that characterize OIR. Because of the relationships revealed by these data, early treatment that targets the neural retina may mitigate the effects of ROP. PMID:19112532

Anomalous vascularization in a Wnt medulloblastoma: a case report.

PubMed

Di Giannatale, Angela; Carai, Andrea; Cacchione, Antonella; Marrazzo, Antonio; Dell'Anna, Vito Andrea; Colafati, Giovanna Stefania; Diomedi-Camassei, Francesca; Miele, Evelina; Po, Agnese; Ferretti, Elisabetta; Locatelli, Franco; Mastronuzzi, Angela

2016-07-15

Medulloblastoma is the most common malignant brain tumor in children. To date only few cases of medulloblastoma with hemorrhages have been reported in the literature. Although some studies speculate on the pathogenesis of this anomalous increased vascularization in medulloblastoma, the specific mechanism is still far from clearly understood. A correlation between molecular medulloblastoma subgroups and hemorrhagic features has not been reported, although recent preliminary studies described that WNT-subtype tumors display increased vascularization and hemorrhaging. Herein, we describe a child with a Wnt-medulloblastoma presenting as cerebellar-vermian hemorrhagic lesion. Brain magnetic resonance imaging (MRI) showed the presence of a midline posterior fossa mass with a cystic hemorrhagic component. The differential diagnosis based on imaging included cavernous hemangioma, arteriovenous malformation and traumatic lesion. At surgery, the tumor appeared richly vascularized as documented by the preoperative angiography. The case we present showed that Wnt medulloblastoma may be associated with anomalous vascularization. Further studies are needed to elucidate if there is a link between the hypervascularization and the Wnt/β-catenin signaling activation and if this abnormal vasculature might influence drug penetration contributing to good prognosis of this medulloblastoma subgroup.

Whole-mount Confocal Microscopy for Adult Ear Skin: A Model System to Study Neuro-vascular Branching Morphogenesis and Immune Cell Distribution.

PubMed

Yamazaki, Tomoko; Li, Wenling; Mukouyama, Yoh-Suke

2018-03-29

Here, we present a protocol of a whole-mount adult ear skin imaging technique to study comprehensive three-dimensional neuro-vascular branching morphogenesis and patterning, as well as immune cell distribution at a cellular level. The analysis of peripheral nerve and blood vessel anatomical structures in adult tissues provides some insights into the understanding of functional neuro-vascular wiring and neuro-vascular degeneration in pathological conditions such as wound healing. As a highly informative model system, we have focused our studies on adult ear skin, which is readily accessible for dissection. Our simple and reproducible protocol provides an accurate depiction of the cellular components in the entire skin, such as peripheral nerves (sensory axons, sympathetic axons, and Schwann cells), blood vessels (endothelial cells and vascular smooth muscle cells), and inflammatory cells. We believe this protocol will pave the way to investigate morphological abnormalities in peripheral nerves and blood vessels as well as the inflammation in the adult ear skin under different pathological conditions.

Pulmonary physiology during pulmonary embolism.

PubMed

Elliott, C G

1992-04-01

Acute pulmonary thromboembolism produces a number of pathophysiologic derangements of pulmonary function. Foremost among these alterations is increased pulmonary vascular resistance. For patients without preexistent cardiopulmonary disease, increased pulmonary vascular resistance is directly related to the degree of vascular obstruction demonstrated on the pulmonary arteriogram. Vasoconstriction, either reflexly or biochemically mediated, may contribute to increased pulmonary vascular resistance. Acute pulmonary thromboembolism also disturbs matching of ventilation and blood flow. Consequently, some lung units are overventilated relative to perfusion (increased dead space), while other lung units are underventilated relative to perfusion (venous admixture). True right-to-left shunting of mixed venous blood can occur through the lungs (intrapulmonary shunt) or across the atrial septum (intracardiac shunt). In addition, abnormalities of pulmonary gas exchange (carbon monoxide transfer), pulmonary compliance and airway resistance, and ventilatory control may accompany pulmonary embolism. Thrombolytic therapy can reverse the hemodynamic derangements of acute pulmonary thromboembolism more rapidly than anticoagulant therapy. Limited data suggest a sustained benefit of thrombolytic treatment on the pathophysiologic alterations of pulmonary vascular resistance and pulmonary gas exchange produced by acute pulmonary emboli.

Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease.

PubMed

Aliev, Gjumrakch; Palacios, Hector H; Walrafen, Brianna; Lipsitt, Amanda E; Obrenovich, Mark E; Morales, Ludis

2009-10-01

Alzheimer's disease (AD) and cerebrovascular accidents are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. In this regard, hypoperfusion appears to induce oxidative stress (OS), which is largely due to reactive oxygen species (ROS), and over time initiates mitochondrial failure which is known as an initiating factor of AD. Recent evidence indicates that chronic injury stimulus induces hypoperfusion seen in vulnerable brain regions. This reduced regional cerebral blood flow (CBF) then leads to energy failure within the vascular endothelium and associated brain parenchyma, manifested by damaged mitochondrial ultrastructure (the formation of large number of immature, electron-dense "hypoxic" mitochondria) and by overproduction of mitochondrial DNA (mtDNA) deletions. Additionally, these mitochondrial abnormalities co-exist with increased redox metal activity, lipid peroxidation, and RNA oxidation. Interestingly, vulnerable neurons and glial cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels, and, moreover, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We summarize the large body of evidence which indicates that sporadic, late-onset AD results from a vascular etiology by briefly reviewing mitochondrial damage and vascular risk factors associated with the disease and then we discuss the cerebral microvascular changes reason for the energy failure that occurs in normal aging and, to a much greater extent, AD.

Developing Therapies for Heart Failure with Preserved Ejection Fraction: Current State and Future Directions

PubMed Central

Butler, Javed; Fonarow, Gregg C.; Zile, Michael R.; Lam, Carolyn S.; Roessig, Lothar; Schelbert, Erik B.; Shah, Sanjiv J.; Ahmed, Ali; Bonow, Robert O.; Cleland, John GF; Cody, Robert J.; Chioncel, Ovidiu; Collins, Sean P.; Dunnmon, Preston; Filippatos, Gerasimos; Lefkowitz, Martin P.; Marti, Catherine N.; McMurray, John J.; Misselwitz, Frank; Nodari, Savina; O’Connor, Christopher; Pfeffer, Marc A.; Pieske, Burkert; Pitt, Bertram; Rosano, Guiseppe; Sabbah, Hani N.; Senni, Michele; Solomon, Scott D.; Stockbridge, Norman; Teerlink, John R.; Georgiopoulou, Vasiliki V.; Gheorghiade, Mihai

2014-01-01

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the FDA and included representatives from academia, industry and regulatory agencies. This document summarizes the proceedings from this meeting. PMID:24720916

Hemorrhagic fever of bunyavirus etiology: disease models and progress towards new therapies.

PubMed

Gowen, Brian B; Hickerson, Brady T

2017-03-01

A growing number of bunyaviruses are known to cause viral hemorrhagic fever (VHF), a severe febrile illness which can progress to hypovolemic shock and multi-organ failure and is characterized by hematologic abnormalities and vascular leak. At present, there are no approved vaccines or antiviral therapies to effectively prevent or treat VHF caused by pathogenic bunyaviruses. Advances in the modeling of bunyaviral infections have facilitated efforts towards the development of novel post-exposure prophylactic and therapeutic countermeasures, several of which may some day be approved for human use. Here, we review recent progress in animal models of severe bunyaviral infections essential to this mission, as well as promising antivirals and biologicals that are at various stages of the development process.

Fibrosis and diseases of the eye

PubMed Central

Friedlander, Martin

2007-01-01

Most diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis and wound healing, often in response to tissue ischemia or inflammation. Disruption of the highly ordered tissue architecture in the eye caused by vascular leakage, hemorrhage, and concomitant fibrosis can lead to mechanical disruption of the visual axis and/or biological malfunctioning. An increased understanding of inflammation, wound healing, and angiogenesis has led to the development of drugs effective in modulating these biological processes and, in certain circumstances, the preservation of vision. Unfortunately, such pharmacological interventions often are too little, too late, and progression of vision loss frequently occurs. The recent development of progenitor and/or stem cell technologies holds promise for the treatment of currently incurable ocular diseases. PMID:17332885

Fenestrations and Various Duplications of the Posterior Communicating Artery in the Prenatal and Postnatal Periods.

PubMed

Trandafilović, Milena; Vasović, Ljiljana; Vlajković, Slobodan; Đorđević, Gordana; Stojanović, Borisav; Mladenović, Marija

2016-07-01

The 2 paired arteries-the posterior communicating arteries (PCoAs) and the precommunicating parts of the posterior cerebral arteries-form the so-called posterior segment of the cerebral arterial circle on the base of the brain. A number of (ab)normal morphologic features were described in the literature (e.g., unusual kinking, or extreme elongations, hypoplasia, duplications, fenestrations, the infundibular widening, or aplasia of the PCoA in the prenatal and/or postnatal periods). The aim of this study was to analyze an incidence of various fenestrations and duplications of the PCoA, and describe their general features and their association with other vascular abnormalities. The research was performed on the brains of 200 human fetuses and 377 adult cadavers of both genders and different ages using microdissection and macrodissection methods. There were 0.34% cases with PCoA fenestrations and 3.12% cases with various PCoA duplications. Their morphologic features were described and compared with the similar PCoA abnormalities recorded in the scientific literature. There was no association between the PCoA and either duplication or aneurysm in adult cases. After thorough examination, the fenestrations and duplications of the PCoA are distinguished as 2 special forms of vascular abnormalities, and the PCoA duplications are characterized as partial and total. Furthermore, whereas the low incidence of a fenestration of the PCoA suggests it to be a sufficiently rare phenomenon, the duplications of the PCoA trunk are fairly frequent, especially concerning its terminal segment. Copyright © 2016 Elsevier Inc. All rights reserved.

Remote thalamic microstructural abnormalities related to cognitive function in ischemic stroke patients.

PubMed

Fernández-Andújar, Marina; Doornink, Fleur; Dacosta-Aguayo, Rosalía; Soriano-Raya, Juan José; Miralbell, Júlia; Bargalló, Núria; López-Cancio, Elena; Pérez de la Ossa, Natalia; Gomis, Meritxell; Millán, Mònica; Barrios, Maite; Cáceres, Cynthia; Pera, Guillem; Forés, Rosa; Clemente, Imma; Dávalos, Antoni; Mataró, Maria

2014-11-01

Ischemic stroke can lead to a continuum of cognitive sequelae, ranging from mild vascular cognitive impairment to vascular dementia. These cognitive deficits can be influenced by the disruption of cortico-subcortical circuits. We sought to explore remote thalamic microstructural abnormalities and their association with cognitive function after ischemic stroke. Seventeen patients with right hemispheric ischemic stroke and 17 controls matched for age, sex, and years of education were included. All participants underwent neurological, neuropsychological, and diffusion tensor image examination. Patients were assessed 3 months poststroke. Voxel-wise analysis was used to study thalamic diffusion differences between groups. Mean fractional anisotropy (FA) and mean diffusivity (MD) values in significant thalamic areas were calculated for each subject and correlated with cognitive performance. Stroke patients showed lower FA values and higher MD values in specific areas of both the left and right thalamus compared with controls. In patients, decreased FA values were associated with lower verbal fluency performance in the right thalamus (R(2) = 0.45, β = 0.74) and the left thalamus (R(2) = 0.57, β = 0.77) after adjusting for diabetes mellitus. Moreover, increased MD values were associated with lower verbal fluency performance in the right thalamus (R(2) = 0.27, β = -0.54) after adjusting for diabetes mellitus. In controls, thalamic FA and MD values were not related to any cognitive function. Our findings support the hypothesis that ischemic stroke lesions are associated with remote thalamic diffusion abnormalities, and that these abnormalities can contribute to cognitive dysfunction 3 months after a cerebrovascular event. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Endothelial Progenitor Cells in Diabetic Microvascular Complications: Friends or Foes?

PubMed

Yu, Cai-Guo; Zhang, Ning; Yuan, Sha-Sha; Ma, Yan; Yang, Long-Yan; Feng, Ying-Mei; Zhao, Dong

2016-01-01

Despite being featured as metabolic disorder, diabetic patients are largely affected by hyperglycemia-induced vascular abnormality. Accumulated evidence has confirmed the beneficial effect of endothelial progenitor cells (EPCs) in coronary heart disease. However, antivascular endothelial growth factor (anti-VEGF) treatment is the main therapy for diabetic retinopathy and nephropathy, indicating the uncertain role of EPCs in the pathogenesis of diabetic microvascular disease. In this review, we first illustrate how hyperglycemia induces metabolic and epigenetic changes in EPCs, which exerts deleterious impact on their number and function. We then discuss how abnormal angiogenesis develops in eyes and kidneys under diabetes condition, focusing on "VEGF uncoupling with nitric oxide" and "competitive angiopoietin 1/angiopoietin 2" mechanisms that are shared in both organs. Next, we dissect the nature of EPCs in diabetic microvascular complications. After we overview the current EPCs-related strategies, we point out new EPCs-associated options for future exploration. Ultimately, we hope that this review would uncover the mysterious nature of EPCs in diabetic microvascular disease for therapeutics.

Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue.

PubMed

Toussaint, Nigel D; Elder, Grahame J; Kerr, Peter G

2009-01-01

Cardiovascular disease is highly prevalent in chronic kidney disease (CKD) and is often associated with increased vascular stiffness and calcification. Recent studies have suggested a complex interaction between vascular calcification and abnormalities of bone and mineral metabolism, with an inverse relationship between arterial calcification and bone mineral density (BMD). Although osteoporosis is recognized and treated in CKD 1 to 3, the interpretation of BMD levels in the osteoporotic range is controversial in CKD 4, 5, and 5D when renal osteodystrophy is generally present. In addition, there is a paucity of data for patients with CKD mineral and bone disorder (MBD), because studies using bisphosphonates in postmenopausal and glucocorticoid-induced osteoporosis have generally excluded patients with significant CKD. For these patients, treatment of low BMD using standard therapies for osteoporosis is not without potential for harm due to the possibility of worsening low bone turnover, osteomalacia, mixed uraemic osteodystrophy, and of exacerbated hyperparathyroidism; and bisphosphonates should only be used selectively and with caution. Some experimental and clinical studies have also suggested that bisphosphonates may reduce progression of extra-osseous calcification and inhibit the development of atherosclerosis. The authors review the potential benefits and risks associated with bisphosphonate use for bone protection in CKD, and assess their effect on vascular calcification and atherosclerosis.

Altered feto-placental vascularization, feto-placental malperfusion and fetal growth restriction in mice with Egfl7 loss of function.

PubMed

Lacko, Lauretta A; Hurtado, Romulo; Hinds, Samantha; Poulos, Michael G; Butler, Jason M; Stuhlmann, Heidi

2017-07-01

EGFL7 is a secreted angiogenic factor produced by embryonic endothelial cells. To understand its role in placental development, we established a novel Egfl7 knockout mouse. The mutant mice have gross defects in chorioallantoic branching morphogenesis and placental vascular patterning. Microangiography and 3D imaging revealed patchy perfusion of Egfl7 -/- placentas marked by impeded blood conductance through sites of narrowed vessels. Consistent with poor feto-placental perfusion, Egfl7 knockout resulted in reduced placental weight and fetal growth restriction. The placentas also showed abnormal fetal vessel patterning and over 50% reduction in fetal blood space. In vitro , placental endothelial cells were deficient in migration, cord formation and sprouting. Expression of genes involved in branching morphogenesis, Gcm1 , Syna and Synb , and in patterning of the extracellular matrix, Mmrn1 , were temporally dysregulated in the placentas. Egfl7 knockout did not affect expression of the microRNA embedded within intron 7. Collectively, these data reveal that Egfl7 is crucial for placental vascularization and embryonic growth, and may provide insight into etiological factors underlying placental pathologies associated with intrauterine growth restriction, which is a significant cause of infant morbidity and mortality. © 2017. Published by The Company of Biologists Ltd.

The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems.

PubMed

Wu, Min; Frieboes, Hermann B; Chaplain, Mark A J; McDougall, Steven R; Cristini, Vittorio; Lowengrub, John S

2014-08-21

Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the response slows down as the tumor shrinks due to the heterogeneity and low concentration of agents in the tumor interior compared with the cases where other pathological effects may combine to flatten the IFP and thus reduce the heterogeneity. We conclude that dual normalizations of the micronevironment - both the vasculature and the interstitium - are needed to maximize the effects of chemotherapy, while normalization of only one of these may be insufficient to overcome the physical resistance and may thus lead to sub-optimal outcomes. Copyright © 2014 Elsevier Ltd. All rights reserved.

The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems

PubMed Central

Wu, Min; Frieboes, Hermann B.; Chaplain, Mark A.J.; McDougall, Steven R.; Cristini, Vittorio; Lowengrub, John

2014-01-01

Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but leads to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the response slows down as the tumor shrinks due to the heterogeneity and low concentration of agents in the tumor interior compared with the cases where other pathological effects may combine to flatten the IFP and thus reduce the heterogeneity. We conclude that dual normalizations of the micronevironment - both the vasculature and the interstitium - are needed to maximize the effects of chemotherapy, while normalization of only one of these may be insufficient to overcome the physical resistance and thus leads to sub-optimal outcomes. PMID:24751927

[Writing disorder using a word processor: role of the left hand].

PubMed

Lemesle, M; Sieroff, E; Virat-Brassaud, M E; Graule-Petot, A; Giroud, M; Dumas, R

1999-12-01

A young female secretary developed a writing disorder, exclusively expressed when using a word processor, following an ischemic vascular event involving the insula and the right posterior parietal region. There was no disturbance of laterality. The neurological examination, completed by neuropsychological tests eliminated any persistent phasic or gnostic disorders. The analysis of the text produced revealed abnormalities leading to the conclusion that the left hand was responsible for all the errors observed. A sensorimotor integration disorder produced a melokinetic apraxia which appeared to be the cause of the writing disorder which would have most likely remained unknown had the subject not been a secretary.

Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection.

PubMed

Hashimoto, Takahiro; Sakata, Yasushi; Fukushima, Kentaro; Maeda, Tetsuo; Arita, Yoh; Shioyama, Wataru; Nakaoka, Yoshikazu; Hori, Yumiko; Morii, Eiichi; Aozasa, Katsuyuki; Kanakura, Yuzuru; Yamauchi-Takihara, Keiko; Komuro, Issei

2011-01-01

A 45-year-old man with chronic active Epstein-Barr virus (EBV) infection (CAEBV) with natural killer cell type developed pulmonary arterial hypertension (PAH). After chemotherapy, he showed marked depression of the EBV DNA genome in the peripheral blood, but PAH sustained. He died of heart failure due to PAH, and the histo-pathological examination revealed pulmonary vascular abnormalities without lung disease on autopsy. Although the EBV DNA genome and the infiltrating lymphocytes were not detected in the lung, his clinical course suggested that his PAH might be caused by CAEBV. This is the first reported case of PAH associated CAEBV in an adult.

Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits.

PubMed Central

Keaney, J F; Gaziano, J M; Xu, A; Frei, B; Curran-Celentano, J; Shwaery, G T; Loscalzo, J; Vita, J A

1993-01-01

Recent evidence suggests that dietary therapy with lipid-soluble antioxidants may be beneficial for patients with atherosclerotic vascular disease but the potential mechanism(s) for these observations remain obscure. Abnormalities in endothelium-dependent control of vascular tone develop early in the course of atherosclerosis and may result from oxidative modification of low density lipoproteins. We examined the role of dietary antioxidants in preserving normal endothelial cell vasodilator function in cholesterol-fed rabbits with particular attention to possible effects on serum lipoproteins, low density lipoprotein oxidation, and atherogenesis. Male New Zealand White rabbits were fed diets containing no additive (controls), 1% cholesterol (cholesterol group), or 1% cholesterol chow supplemented with either beta-carotene (0.6 g/kg of chow) or alpha-tocopherol (1000 international units/kg of chow) for a 28-day period. After dietary therapy, thoracic aortae were harvested for assay of vascular function and for pathologic examination and tissue antioxidant levels. Compared to controls, acetylcholine- and A23187-mediated endothelium-dependent relaxations were significantly impaired in vessels from the cholesterol group (P < 0.001), whereas vessels from animals treated with beta-carotene or alpha-tocopherol demonstrated normal endothelium-dependent arterial relaxation. Preservation of endothelial function was associated with vascular incorporation of alpha-tocopherol and beta-carotene but was unrelated to plasma lipoprotein levels, smooth muscle cell function, or the extent of atherosclerosis. Increased low density lipoprotein resistance to ex vivo copper-mediated oxidation was observed only in the alpha-tocopherol group. Our results suggest that dietary antioxidants may benefit patients with atherosclerosis by preserving endothelial vasodilator function through a mechanism related to vascular tissue antioxidant content and not reflected by assay of low density lipoprotein resistance to ex vivo oxidation. PMID:8265642

Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood-brain barrier disruption, and progressive white matter damage.

PubMed

Glushakova, Olena Y; Johnson, Danny; Hayes, Ronald L

2014-07-01

Traumatic brain injury (TBI) is a significant risk factor for chronic traumatic encephalopathy (CTE), Alzheimer's disease (AD), and Parkinson's disease (PD). Cerebral microbleeds, focal inflammation, and white matter damage are associated with many neurological and neurodegenerative disorders including CTE, AD, PD, vascular dementia, stroke, and TBI. This study evaluates microvascular abnormalities observed at acute and chronic stages following TBI in rats, and examines pathological processes associated with these abnormalities. TBI in adult rats was induced by controlled cortical impact (CCI) of two magnitudes. Brain pathology was assessed in white matter of the corpus callosum for 24 h to 3 months following injury using immunohistochemistry (IHC). TBI resulted in focal microbleeds that were related to the magnitude of injury. At the lower magnitude of injury, microbleeds gradually increased over the 3 month duration of the study. IHC revealed TBI-induced focal abnormalities including blood-brain barrier (BBB) damage (IgG), endothelial damage (intercellular adhesion molecule 1 [ICAM-1]), activation of reactive microglia (ionized calcium binding adaptor molecule 1 [Iba1]), gliosis (glial fibrillary acidic protein [GFAP]) and macrophage-mediated inflammation (cluster of differentiation 68 [CD68]), all showing different temporal profiles. At chronic stages (up to 3 months), apparent myelin loss (Luxol fast blue) and scattered deposition of microbleeds were observed. Microbleeds were surrounded by glial scars and co-localized with CD68 and IgG puncta stainings, suggesting that localized BBB breakdown and inflammation were associated with vascular damage. Our results indicate that evolving white matter degeneration following experimental TBI is associated with significantly delayed microvascular damage and focal microbleeds that are temporally and regionally associated with development of punctate BBB breakdown and progressive inflammatory responses. Increased understanding of mechanisms underlying delayed microvascular damage following TBI could provide novel insights into chronic pathological responses to TBI and potential common mechanisms underlying TBI and neurodegenerative diseases.

Abnormal placental development and early embryonic lethality in EpCAM-null mice.

PubMed

Nagao, Keisuke; Zhu, Jianjian; Heneghan, Mallorie B; Hanson, Jeffrey C; Morasso, Maria I; Tessarollo, Lino; Mackem, Susan; Udey, Mark C

2009-12-31

EpCAM (CD326) is encoded by the tacstd1 gene and expressed by a variety of normal and malignant epithelial cells and some leukocytes. Results of previous in vitro experiments suggested that EpCAM is an intercellular adhesion molecule. EpCAM has been extensively studied as a potential tumor marker and immunotherapy target, and more recent studies suggest that EpCAM expression may be characteristic of cancer stem cells. To gain insights into EpCAM function in vivo, we generated EpCAM -/- mice utilizing an embryonic stem cell line with a tacstd1 allele that had been disrupted. Gene trapping resulted in a protein comprised of the N-terminus of EpCAM encoded by 2 exons of the tacstd1 gene fused in frame to betageo. EpCAM +/- mice were viable and fertile and exhibited no obvious abnormalities. Examination of EpCAM +/- embryos revealed that betageo was expressed in several epithelial structures including developing ears (otocysts), eyes, branchial arches, gut, apical ectodermal ridges, lungs, pancreas, hair follicles and others. All EpCAM -/- mice died in utero by E12.5, and were small, developmentally delayed, and displayed prominent placental abnormalities. In developing placentas, EpCAM was expressed throughout the labyrinthine layer and by spongiotrophoblasts as well. Placentas of EpCAM -/- embryos were compact, with thin labyrinthine layers lacking prominent vascularity. Parietal trophoblast giant cells were also dramatically reduced in EpCAM -/- placentas. EpCAM was required for differentiation or survival of parietal trophoblast giant cells, normal development of the placental labyrinth and establishment of a competent maternal-fetal circulation. The findings in EpCAM-reporter mice suggest involvement of this molecule in development of vital organs including the gut, kidneys, pancreas, lungs, eyes, and limbs.

The Dynamic Actin Cytoskeleton in Smooth Muscle.

PubMed

Tang, Dale D

2018-01-01

Smooth muscle contraction requires both myosin activation and actin cytoskeletal remodeling. Actin cytoskeletal reorganization facilitates smooth muscle contraction by promoting force transmission between the contractile unit and the extracellular matrix (ECM), and by enhancing intercellular mechanical transduction. Myosin may be viewed to serve as an "engine" for smooth muscle contraction whereas the actin cytoskeleton may function as a "transmission system" in smooth muscle. The actin cytoskeleton in smooth muscle also undergoes restructuring upon activation with growth factors or the ECM, which controls smooth muscle cell proliferation and migration. Abnormal smooth muscle contraction, cell proliferation, and motility contribute to the development of vascular and pulmonary diseases. A number of actin-regulatory proteins including protein kinases have been discovered to orchestrate actin dynamics in smooth muscle. In particular, Abelson tyrosine kinase (c-Abl) is an important molecule that controls actin dynamics, contraction, growth, and motility in smooth muscle. Moreover, c-Abl coordinates the regulation of blood pressure and contributes to the pathogenesis of airway hyperresponsiveness and vascular/airway remodeling in vivo. Thus, c-Abl may be a novel pharmacological target for the development of new therapy to treat smooth muscle diseases such as hypertension and asthma. © 2018 Elsevier Inc. All rights reserved.

Medical management of moyamoya disease and recurrent stroke in an infant with Majewski osteodysplastic primordial dwarfism type II (MOPD II).

PubMed

Kılıç, Esra; Utine, Eda; Unal, Sule; Haliloğlu, Göknur; Oğuz, Kader Karli; Cetin, Mualla; Boduroğlu, Koray; Alanay, Yasemin

2012-10-01

We report an infant diagnosed with Majewski osteodysplastic primordial dwarfism type II at age 8 months, who experienced cerebrovascular morbidities related to this entity. Molecular analysis identified c.2609+1 G>A, intron 14, homozygous splice site mutation in the pericentrin gene. At age 18 months, she developed recurrent strokes and hemiparesis. Brain magnetic resonance imaging and magnetic resonance angiography showed abnormal gyral pattern, cortical acute infarcts, bilateral stenosis of the internal carotid arteries and reduced flow on the cerebral arteries, consistent with moyamoya disease. In Majewski osteodysplastic primordial dwarfism type II, life expectancy is reduced because of high risk of stroke secondary to cerebral vascular anomalies (aneurysms, moyamoya disease). Periodic screening for vascular events is recommended in individuals with Majewski osteodysplastic primordial dwarfism type II every 12-18 months following diagnosis. Our patient was medically managed with low molecular weight heparin followed with aspirin prophylaxis, in addition to carbamazepine and physical rehabilitation. We report an infant with moyamoya disease and recurrent stroke presenting 10 months after diagnosis (at age 18 months), and discuss the outcome of nonsurgical medical management. The presented case is the second youngest case developing stroke and moyamoya disease.

Folic Acid Supplementation Improves Vascular Function in Professional Dancers With Endothelial Dysfunction

PubMed Central

Hoch, Anne Z.; Papanek, Paula; Szabo, Aniko; Widlansky, Michael E.; Gutterman, David D.

2012-01-01

Objective To determine if folic acid supplementation improves vascular function (brachial artery flow-mediated dilation [FMD]) in professional dancers with known endothelial dysfunction. Design Prospective cross-sectional study. Setting Academic institution in the Midwestern United States. Subjects Twenty-two professional ballet dancers volunteered for this study. Main Outcome Measures Subjects completed a 3-day food record to determine caloric and micronutrient intake. Menstrual status was determined by interview and questionnaire. Endothelial function was determined as flow-induced vasodilation measured by high-frequency ultrasound of the brachial artery. A change in brachial diameter of <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Subjects with abnormal FMD took 10 mg of folic acid daily for 4 weeks, and FMD testing was then repeated. Serum whole blood was measured for folic acid levels before and after supplementation. Results Sixty-four percent of dancers (n = 14) had abnormal brachial artery FMD (<5%) (mean ± standard deviation, 2.9% ± 1.5%). After 4 weeks of folic acid supplementation (10 mg/day), FMD improved in all the subjects (7.1% ± 2.3%; P < .0001). Conclusions This study reveals that vascular endothelial function improves in dancers after supplementation with folic acid (10 mg/day) for at least 4 weeks. This finding may have clinically important implications for future cardiovascular disease risk prevention. PMID:21715240

Evidence for Post-Translational Processing of Vascular Endothelial (VE)-Cadherin in Brain Tumors: Towards a Candidate Biomarker

PubMed Central

Vilgrain, Isabelle; Sidibé, Adama; Polena, Helena; Cand, Francine; Mannic, Tiphaine; Arboleas, Mélanie; Boccard, Sandra; Baudet, Antoine; Gulino-Debrac, Danielle; Bouillet, Laurence; Quesada, Jean-Louis; Mendoza, Christophe; Lebas, Jean-François; Pelletier, Laurent; Berger, François

2013-01-01

Vessel abnormalities are among the most important features in malignant glioma. Vascular endothelial (VE)-cadherin is of major importance for vascular integrity. Upon cytokine challenge, VE-cadherin structural modifications have been described including tyrosine phosphorylation and cleavage. The goal of this study was to examine whether these events occurred in human glioma vessels. We demonstrated that VE-cadherin is highly expressed in human glioma tissue and tyrosine phosphorylated at site Y685, a site previously found phosphorylated upon VEGF challenge, via Src activation. In vitro experiments showed that VEGF-induced VE-cadherin phosphorylation, preceded the cleavage of its extracellular adhesive domain (sVE, 90 kDa). Interestingly, metalloproteases (MMPs) secreted by glioma cell lines were responsible for sVE release. Because VEGF and MMPs are important components of tumor microenvironment, we hypothesized that VE-cadherin proteolysis might occur in human brain tumors. Analysis of glioma patient sera prior treatment confirmed the presence of sVE in bloodstream. Furthermore, sVE levels studied in a cohort of 53 glioma patients were significantly predictive of the overall survival at three years (HR 0.13 [0.04; 0.40] p≤0.001), irrespective to histopathological grade of tumors. Altogether, these results suggest that VE-cadherin structural modifications should be examined as candidate biomarkers of tumor vessel abnormalities, with promising applications in oncology. PMID:24358106

Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction.

PubMed

Barton, Matthias; Baretella, Oliver; Meyer, Matthias R

2012-02-01

Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the world's population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease, obesity has deleterious effects on metabolic homeostasis, and affects numerous organ systems including heart, kidney and the vascular system. Thus, obesity is now regarded as an independent risk factor for atherosclerosis-related diseases such as coronary artery disease, myocardial infarction and stroke. In the arterial system, endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium-derived vasoactive factors favouring vasoconstriction, cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally, because of the similarities of the vascular pathomechanisms activated, obesity can be considered to cause accelerated, 'premature' vascular aging. Here, we will review some of the pathomechanisms involved in obesity-related activation of endothelium-dependent vasoconstriction, the clinical relevance of obesity-associated vascular risk, and therapeutic interventions using 'endothelial therapy' aiming at maintaining or restoring vascular endothelial health. This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Optical coherence tomography based angiography [Invited

PubMed Central

Chen, Chieh-Li; Wang, Ruikang K.

2017-01-01

Optical coherence tomography (OCT)-based angiography (OCTA) provides in vivo, three-dimensional vascular information by the use of flowing red blood cells as intrinsic contrast agents, enabling the visualization of functional vessel networks within microcirculatory tissue beds non-invasively, without a need of dye injection. Because of these attributes, OCTA has been rapidly translated to clinical ophthalmology within a short period of time in the development. Various OCTA algorithms have been developed to detect the functional micro-vasculatures in vivo by utilizing different components of OCT signals, including phase-signal-based OCTA, intensity-signal-based OCTA and complex-signal-based OCTA. All these algorithms have shown, in one way or another, their clinical values in revealing micro-vasculatures in biological tissues in vivo, identifying abnormal vascular networks or vessel impairment zones in retinal and skin pathologies, detecting vessel patterns and angiogenesis in eyes with age-related macular degeneration and in skin and brain with tumors, and monitoring responses to hypoxia in the brain tissue. The purpose of this paper is to provide a technical oriented overview of the OCTA developments and their potential pre-clinical and clinical applications, and to shed some lights on its future perspectives. Because of its clinical translation to ophthalmology, this review intentionally places a slightly more weight on ophthalmic OCT angiography. PMID:28271003

The use of breast ultrasound color Doppler vascular pattern morphology improves diagnostic sensitivity with minimal change in specificity.

PubMed

Svensson, W E; Pandian, A J; Hashimoto, H

2010-10-01

The aim of this study was to evaluate the use of vascular morphology, around and within the B-mode region of abnormality, for improving the diagnostic accuracy of two of the most common solid breast pathologies. The B-mode and Doppler images of 117 breast cancers and 366 fibroadenomas and lesions with a fibroadenoma-like appearance were reviewed retrospectively and the morphology of the vascular pattern was evaluated. The ratio of external to internal color Doppler, the external vascular pattern and the connecting vessels to internal vessels were assessed and differentiated into benign and malignant vascular patterns. These patterns were correlated with the histological diagnosis. Vascularity was demonstrated in 95 % of cancers and in 46 % of benign lesions with a trend to increasing vascularity in cancers. This provided poor specificity for excluding cancer in fibroadenomas. Variations in vascular pattern were recorded. The observed benign vascular patterns were avascularity, vascularity in the periphery and peripheral marginal vessels connecting with internal vascularity. The observed malignant vascular patterns were radially aligned external vessels with internal vessels being more numerous than external vessels which connected to radial vessels. (Fisher exact test p < 0.0001). Analysis of the vascular morphology improved the sensitivity for identifying cancers from 97 % (B-mode) to 99 % (B-mode and color Doppler) with a minimal reduction in specificity (93.7 to 92.6 %) or accuracy (94.6 to 94.2 %). The presence of vascularity within a lesion, by itself, is no longer a good predictor of malignancy because of the increase in Doppler sensitivity associated with improvements in ultrasound technology. The color Doppler ultrasound vascular pattern morphology improves the accuracy and sensitivity of B-mode image diagnosis, breast cancers and fibroadenomas with a minimal loss of specificity. Any breast lesion with radial rather than marginal connecting vessels should be regarded with suspicion. © Georg Thieme Verlag KG Stuttgart · New York.

Launch Conditions Might Affect the Formation of Blood Vessel in the Quail Chorioallantoic Membrane

NASA Technical Reports Server (NTRS)

Henry, M. K.; Unsworth, B. R.; Sychev, B. R.; Guryeva, T. S.; Dadasheva, O. A.; Piert, S. J.; Lagel, K. E.; Dubrovin, L. C.; Jahns, G. C.; Boda, K.;

Evaluation of interobserver variability and diagnostic performance of developed MRI-based radiological scoring system for invasive placenta previa.

PubMed

Ueno, Yoshiko; Maeda, Tetsuo; Tanaka, Utaru; Tanimura, Kenji; Kitajima, Kazuhiro; Suenaga, Yuko; Takahashi, Satoru; Yamada, Hideto; Sugimura, Kazuro

2016-09-01

To evaluate the interobserver variability and diagnostic performance of a developed magnetic resonance imaging (MRI)-based scoring system for invasive placenta previa. Prenatal MR images of 70 women were retrospectively evaluated, 18 of whom were diagnosed with invasive placenta. The six MR features (dark band on T2 -weighted images, intraplacental abnormal vascularity, placental bulge, heterogeneous placenta, myometrial thinning, and placental protrusion sign) were scored on 5-point Likert scale separately, and the cumulative radiological score (CRS) was defined as the sum of each score. Two more experienced radiologists (readers A and B) and two less experienced residents (readers C and D) calculated the CRS. Interobserver variability was assessed by measuring the intraclass correlation coefficient. Diagnostic performance was evaluated by means of receiver operating characteristic (ROC) analysis. Interobserver variability for CRS was excellent for the more experienced radiologists (0.85), and good for all readers (0.72) and the less experienced residents (0.66). The area under the ROC curve (Az) and accuracy (Acc) for CRS were significantly higher or equivalent to those of other MR features for all readers (Az and Acc for reader A; CRS, 0.92, 91.4%; intraplacental T2 dark band, 0.83, P = 0.009, 81.4%, P = 0.03; intraplacental abnormal vascularity, 0.9, P = 0.3, 90.0%, P = 1.00; placental bulge, 0.81, P = 0.0008, 80.0%, P = 0.02; heterogeneous placenta, 0.85, P = 0.11, 74.3%, P = 0.002; myometrial thinning, 0.84, P = 0.06, 60.0%, P < 0.0001; placental protrusion sign, 0.81, P = 0.01, 81.4%, P = 0.26). This developed MRI-based scoring system demonstrated excellent or good interobserver variability, and good diagnostic performance for invasive placenta previa. J. Magn. Reson. Imaging 2016;44:573-583. © 2016 International Society for Magnetic Resonance in Medicine.

Magnitude of dyslipedemia and its association with micro and macro vascular complications in type 2 diabetes: a hospital based study from Bikaner (Northwest India).

PubMed

Agrawal, R P; Sharma, Poornima; Pal, Mahender; Kochar, A; Kochar, D K

2006-08-01

Type 2 diabetes is not only associated with hyperglycemia but also with disorders of lipid metabolism. The aim of this study was to investigate the association of dyslipedemia with micro and macro vascular complications of diabetes. Population based cross sectional study included 4067 diabetic patients who visited hospital during January 2000 to December 2002. Lipid profile was estimated by semi autoanalyser, Retinopathy was assessed by fundoscopy, Nephropathy by microalbuminurea, coronary artery disease (CAD) by electro cardiogram (ECG) changes, peripheral vascular disease (PVD) by doppler study and neuropathy by clinical examinations. The association of dyslipedemia with micro and macro vascular complications was assessed by regression analysis. The prevalence of dyslipedemia is high in diabetic population with high serum cholesterol >240mg/dl was seen in 15%, serum triglycerides >160mg/dl was seen in 42.41%, raised LDL >130mg/dl in 45.26%, VLDL >40mg/dl in 24.09% and low levels of HDL-C <40mg/dl were seen in 52.27%. On regression analysis, CAD had strong correlation with high levels of VLDL (0.76), triglycerides (0.82), LDL (0.23) and low HDL (-0.81). Similar association was seen with PVD. Diabetic retinopathy and nephropathy were found to have significant correlation with low HDL (-0.43) and raised LDL (0.37), respectively. Neuropathy was not found to have any significant correlation with lipid profile abnormalities. Lipid profile abnormalities are very common in type 2 diabetes and it has great influence on CAD and PVD. Hence, appropriate preventive and treatment strategies should be considered timely.

Inflammation and premature aging in advanced chronic kidney disease.

PubMed

Kooman, Jeroen P; Dekker, Marijke J; Usvyat, Len A; Kotanko, Peter; van der Sande, Frank M; Schalkwijk, Casper G; Shiels, Paul G; Stenvinkel, Peter

2017-10-01

Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed. Copyright © 2017 the American Physiological Society.

Biomarkers of World Trade Center Particulate Matter Exposure: Physiology of distal airway and blood biomarkers that predict FEV1 decline

PubMed Central

Weiden, Michael D.; Kwon, Sophia; Caraher, Erin; Berger, Kenneth I.; Reibman, Joan; Rom, William N.; Prezant, David J.; Nolan, Anna

2016-01-01

Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung’s normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after World Trade Center (WTC) exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1

Differential diagnosis of bilateral parietal abnormalities in I-123 IMP SPECT imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuwabara, Y.; Ichiya, Y.; Otsuka, M.

1990-12-01

This report discusses the clinical significance of bilateral parietal abnormalities on I-123 IMP SPECT imaging in 158 patients with cerebral disorders. This pattern was seen in 15 out of 21 patients with Alzheimer's disease; it was also seen in 4 out of 5 patients with Parkinson's disease with dementia, in 3 out of 17 patients with vascular dementia, in 1 out of 36 patients with cerebral infarction without dementia, in 1 out of 2 patients with hypoglycemia, and in 1 out of 2 patients with CO intoxication. Detection of bilateral parietal abnormalities is a useful finding in the diagnosis ofmore » Alzheimer's disease, but one should keep in mind that other cerebral disorders may also show a similar pattern with I-123 IMP SPECT imaging.« less

Gastroschisis, destructive brain lesions, and placental infarction in the second trimester suggest a vascular pathogenesis.

PubMed

Folkerth, Rebecca D; Habbe, Donald M; Boyd, Theonia K; McMillan, Kristin; Gromer, Jessica; Sens, Mary Ann; Elliott, Amy J

2013-01-01

The cause and pathogenesis of gastroschisis are uncertain. We report the autopsy and placental pathology of a stillbirth at 20 gestational weeks, in which gastroschisis was accompanied by destructive lesions in the cerebral cortex and brainstem, as well as cardiac calcification, consistent with ischemic injury during the 2nd trimester. An important potential underlying mechanism explaining the fetal abnormalities is the presence of infarcts in the placenta, indicative at this gestational age of maternal vascular underperfusion. The association of gastroschisis with ischemic lesions in the brain, heart, and placenta in this case supports the concept that gastroschisis, at least in some instances, may result from vascular event(s) causing disruption of the fetal abdominal wall and resulting in the extrusion of the abdominal organs, as well as hypoxic-ischemic brain and cardiac injury.

VEGF can protect against blood brain barrier dysfunction, dendritic spine loss and spatial memory impairment in an experimental model of diabetes.

PubMed

Taylor, Stephanie L; Trudeau, Dustin; Arnold, Brendan; Wang, Joshua; Gerrow, Kim; Summerfeldt, Kieran; Holmes, Andrew; Zamani, Akram; Brocardo, Patricia S; Brown, Craig E

2015-06-01

Clinical and experimental studies have shown a clear link between diabetes, vascular dysfunction and cognitive impairment. However, the molecular underpinnings of this association remain unclear. Since vascular endothelial growth factor (VEGF) signaling is important for maintaining vascular integrity and function, we hypothesized that vascular and cognitive impairment in the diabetic brain could be related to a deficiency in VEGF signaling. Here we show that chronic hyperglycemia (~8weeks) in a mouse model of type 1 diabetes leads to a selective reduction in the expression of VEGF and its cognate receptor (VEGF-R2) in the hippocampus. Correlating with this, diabetic mice showed selective deficits in spatial memory in the Morris water maze, increased vessel area, width and permeability in the dentate gyrus/CA1 region of the hippocampus and reduced spine densities in CA1 neurons. Chronic low dose infusion of VEGF in diabetic mice was sufficient to restore VEGF signaling, protect them from memory deficits, as well as vascular and synaptic abnormalities in the hippocampus. These findings suggest that a hippocampal specific reduction in VEGF signaling and resultant vascular/neuronal defects may underlie early manifestations of cognitive impairment commonly associated with diabetes. Furthermore, restoring VEGF signaling may be a useful strategy for preserving hippocampal-related brain circuitry in degenerative vascular diseases. Copyright © 2015. Published by Elsevier Inc.

Overgrowth syndromes with vascular anomalies.

PubMed

Blei, Francine

2015-04-01

Overgrowth syndromes with vascular anomalies encompass entities with a vascular anomaly as the predominant feature vs those syndromes with predominant somatic overgrowth and a vascular anomaly as a more minor component. The focus of this article is to categorize these syndromes phenotypically, including updated clinical criteria, radiologic features, evaluation, management issues, pathophysiology, and genetic information. A literature review was conducted in PubMed using key words "overgrowth syndromes and vascular anomalies" as well as specific literature reviews for each entity and supportive genetic information (e.g., somatic mosaicism). Additional searches in OMIM and Gene Reviews were conducted for each syndrome. Disease entities were categorized by predominant clinical features, known genetic information, and putative affected signaling pathway. Overgrowth syndromes with vascular anomalies are a heterogeneous group of disorders, often with variable clinical expression, due to germline or somatic mutations. Overgrowth can be focal (e.g., macrocephaly) or generalized, often asymmetrically (and/or mosaically) distributed. All germ layers may be affected, and the abnormalities may be progressive. Patients with overgrowth syndromes may be at an increased risk for malignancies. Practitioners should be attentive to patients having syndromes with overgrowth and vascular defects. These patients require proactive evaluation, referral to appropriate specialists, and in some cases, early monitoring for potential malignancies. Progress in identifying vascular anomaly-related overgrowth syndromes and their genetic etiology has been robust in the past decade and is contributing to genetically based prenatal diagnosis and new therapies targeting the putative causative genetic mutations. Copyright © 2015 Mosby, Inc. All rights reserved.

Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1α-hydroxylase

PubMed Central

Ohnishi, Mutsuko; Nakatani, Teruyo; Lanske, Beate; Razzaque, M. Shawkat

2011-01-01

Changes in the expression of klotho, a β-glucuronidase, contribute to the development of features that resemble those of premature aging, as well as chronic renal failure. Klotho knockout mice have increased expression of the sodium/phosphate cotransporter (NaPi2a) and 1α-hydroxylase in their kidneys, along with increased serum levels of phosphate and 1,25-dihydroxyvitamin D. These changes are associated with widespread soft-tissue calcifications, generalized tissue atrophy, and a shorter lifespan in the knockout mice. To determine the role of the increased vitamin D activities in klotho knockout animals, we generated klotho and 1α-hydroxylase double-knockout mice. These double mutants regained body weight and developed hypophosphatemia with a complete elimination of the soft-tissue and vascular calcifications that were routinely found in klotho knockout mice. The markedly increased serum fibroblast growth factor 23 and the abnormally low serum parathyroid hormone levels, typical of klotho knockout mice, were significantly reversed in the double-knockout animals. These in vivo studies suggest that vitamin D has a pathologic role in regulating abnormal mineral ion metabolism and soft-tissue anomalies of klotho-deficient mice. PMID:19225558

c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma

PubMed Central

Huang, Menggui; Liu, Tianrun; Ma, Peihong; Mitteer, R. Alan; Zhang, Zhenting; Kim, Hyun Jun; Yeo, Eujin; Zhang, Duo; Cai, Peiqiang; Li, Chunsheng; Zhang, Lin; Zhao, Botao; Roccograndi, Laura; O’Rourke, Donald M.; Dahmane, Nadia; Gong, Yanqing; Koumenis, Constantinos

2016-01-01

Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase–14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor–derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors. PMID:27043280

Acute dystonic reaction leading to lingual hematoma mimicking angioedema

PubMed Central

Sezer, Özgür; Aydin, Ali Attila; Bilge, Sedat; Arslan, Fatih; Arslan, Hasan

2017-01-01

Lingual hematoma is a severe situation, which is rare and endangers the airway. It can develop due to trauma, vascular abnormalities, and coagulopathy. Due to its sudden development, it can be clinically confused with angioedema. In patients who applied to the doctor with complaints of a swollen tongue, lingual hematoma can be confused with angioedema, in particular, at the beginning if the symptoms occurred after drug use. It should especially be considered that dystonia in the jaw can present as drug-induced hyperkinetic movement disorder. Early recognition of this rare clinical condition and taking precautions for providing airway patency are essential. In this case report, we will discuss mimicking angioedema and caused by a bite due to dystonia and separation of the tongue from the base of the mouth developing concurrently with lingual hematoma. PMID:29326495

Alterations in brain temperatures as a possible cause of migraine headache.

PubMed

Horváth, Csilla

2014-05-01

Migraine is a debilitating disease with a recurring generally unilateral headache and concomitant symptoms of nausea, vomiting and photo- and/or phonophobia that affects some 11-18% of the population. Most of the mechanisms previously put forward to explain the attacks have been questioned or give an explanation only some of the symptoms. Moreover, the best drugs for treatment are still the 20-year-old triptans, which have serious limitations as regards both efficacy and tolerability. As the dura and some cranial vessels are the only intracranial structures capable of pain sensations, a vascular theory of migraine emerged, but has been debated. Recent theories identified the hyperexcitability of structures involved in pain transmission, such as the trigeminal system or the cortex, or an abnormal modulatory function of the brainstem. However, there is ongoing scientific debate concerning these theories, neither of which is fully capable of explaining the occurrence of a migraine attack. The present article puts forward a hypothesis of the possibility of abnormal temperature regulation in certain regions or the overall brain in migraineurs, the attack being a defense mechanism to prevent neuronal damage. Few examinations have been made of temperature regulation in the human brain. It lacks the carotid rete, a vascular heat exchanger that serves in many animals to provide constant brain temperature. The human brain contains a high density of neurons with a considerable energy demand that is converted to heat. The human brain has a higher temperature than other parts of the body and needs continuous cooling. Recent studies revealed unexpectedly great variations in temperature of various structures of the brain and considerable changes in response to functional activation. There is various evidence in support of the hypothesis that accumulated heat in some structure or the overall brain may be behind the symptoms observed, such as a platelet abnormality, a decreased serotonin content, and dural "inflammation" including vasodilation and brainstem activation. The hypothesis postulates that a migraine attack serves to restore the brain temperature. Abnormally low temperatures in the brain can also result in headache. Surprisingly, no systematic examination of brain temperature changes in migraineurs has been published. Certain case reports support the present hypothesis. Various noninvasive technologies (e.g. MR) capable of monitoring brain temperature are available. If a systematic examination of local brain temperature revealed abnormalities in structures presumed to be involved in migraine, that would increase our understanding of the disease and trigger the development of improved treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

Abnormalities of the umbilico-portal venous system in Down syndrome: a report of two new patients.

PubMed

Pipitone, Salvatore; Garofalo, Caterina; Corsello, Giovanni; Mongiovì, Maurizio; Piccione, Maria; Maresi, Emiliano; Sperandeo, Velio

2003-08-01

Congenital anomalies of the umbilical and portal venous system are rare vascular malformations which are often associated with anomalies of the heart and gastrointestinal tract. Association with chromosomal disorders has been sporadically reported. We now report on two patients with trisomy 21 and congenital anomalies of the umbilico-portal system. A male fetus showed absence of the intrahepatic portal vein (PV) and ductus venosus with a direct communication between portal sinus and inferior vena cava exhibiting an umbilicosystemic total shunt during the fetal life and a portosystemic total shunt after birth. A female infant showed absence of the intrahepatic PV and a total portocaval shunt. Both patients also had heart defects. As previously documented in other reports, our cases demonstrated that this association may be causally-related to the chromosomal aberration. In addition, the umbilico-portal venous system abnormalities seems to be the most frequent congenital vascular malformation in Down syndrome. A presumptive pathogenetic mechanism could be a trisomy 21-related altered angiogenesis of the vitelloumbilical plexus. Copyright 2003 Wiley-Liss, Inc.

CXCL12-CXCR4 signalling plays an essential role in proper patterning of aortic arch and pulmonary arteries.

PubMed

Kim, Bo-Gyeong; Kim, Yong Hwan; Stanley, Edward L; Garrido-Martin, Eva M; Lee, Young Jae; Oh, S Paul

2017-11-01

Chemokine CXCL12 (stromal derived factor 1: SDF1) has been shown to play important roles in various processes of cardiovascular development. In recent avian studies, CXCL12 signalling has been implicated in guidance of cardiac neural crest cells for their participation in the development of outflow tract and cardiac septum. The goal of this study is to investigate the extent to which CXCL12 signalling contribute to the development of aortic arch and pulmonary arteries in mammals. Novel Cxcl12-LacZ reporter and conditional alleles were generated. Using whole mount X-gal staining with the reporter allele and vascular casting techniques, we show that the domain branching pattern of pulmonary arteries in Cxcl12-null mice is completely disrupted and discordant with that of pulmonary veins and airways. Cxcl12-null mice also displayed abnormal and superfluous arterial branches from the aortic arch. The early steps of pharyngeal arch remodelling in Cxcl12-null mice appeared to be unaffected, but vertebral arteries were often missing and prominent aberrant arteries were present parallel to carotid arteries or trachea, similar to aberrant vertebral artery or thyroid ima artery, respectively. Analysis with computed tomography not only confirmed the results from vascular casting studies but also identified abnormal systemic arterial supply to lungs in the Cxcl12-null mice. Tie2-Cre mediated Cxcr4 deletion phenocopied the Cxcl12-null phenotypes, indicating that CXCR4 is the primary receptor for arterial patterning, whereas Cxcl12 or Cxcr4 deletion by Wnt1-Cre did not affect aortic arch patterning. CXCL12-CXCR4 signalling is essential for the correct patterning of aortic arches and pulmonary arteries during development. Superfluous arteries in Cxcl12-null lungs and the aortic arch infer a role of CXCL12 in protecting arteries from uncontrolled sprouting during development of the arterial system. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.

Pulmonary vasculature in COPD: The silent component.

PubMed

Blanco, Isabel; Piccari, Lucilla; Barberà, Joan Albert

2016-08-01

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that results from an inflammatory process affecting the airways and lung parenchyma. Despite major abnormalities taking place in bronchial and alveolar structures, changes in pulmonary vessels also represent an important component of the disease. Alterations in vessel structure are highly prevalent and abnormalities in their function impair gas exchange and may result in pulmonary hypertension (PH), an important complication of the disease associated with reduced survival and worse clinical course. The prevalence of PH is high in COPD, particularly in advanced stages, although it remains of mild to moderate severity in the majority of cases. Endothelial dysfunction, with imbalance between vasodilator/vasoconstrictive mediators, is a key determinant of changes taking place in pulmonary vasculature in COPD. Cigarette smoke products may perturb endothelial cells and play a critical role in initiating vascular changes. The concurrence of inflammation, hypoxia and emphysema further contributes to vascular damage and to the development of PH. The use of drugs that target endothelium-dependent signalling pathways, currently employed in pulmonary arterial hypertension, is discouraged in COPD due to the lack of efficacy observed in randomized clinical trials and because there is compelling evidence indicating that these drugs may worsen pulmonary gas exchange. The subgroup of patients with severe PH should be ideally managed in centres with expertise in both PH and chronic lung diseases because alterations of pulmonary vasculature might resemble those observed in pulmonary arterial hypertension. Because this condition entails poor prognosis, it warrants specialist treatment. © 2016 Asian Pacific Society of Respirology.

Systemic sclerosis patients with and without pulmonary arterial hypertension: a nailfold capillaroscopy study.

PubMed

Riccieri, Valeria; Vasile, Massimiliano; Iannace, Nicoletta; Stefanantoni, Katia; Sciarra, Iliana; Vizza, Carmine D; Badagliacca, Roberto; Poscia, Roberto; Papa, Silvia; Mezzapesa, Mario; Nocioni, Martina; Valesini, Guido

2013-08-01

Pulmonary arterial hypertension (PAH) is a complication of SSc due to increased vascular resistance, and abnormal vascularity is a well-known feature of the disease as shown by nailfold videocapillaroscopy (NVC). This study investigated for specific NVC changes in SSc patients with and without PAH to assess any useful difference. Twenty-four SSc patients, 12 with PAH and 12 without, entered the study. Evidence of PAH was defined as increased systolic pulmonary artery pressure (PAP) (≥35 mmHg), indirectly assessed by echocardiography and confirmed by right heart catheterization (mPAP > 25 mmHg). NVC was performed, and a semi-quantitative rating scale, a rating system for avascular areas and a specific NVC pattern evaluation, namely early, active and late, were used. An NVC score >1 was more frequently found in patients with PAH than those without, 11 cases (92%) vs 5 cases (42%) (P = 0.03); an avascular areas grade >1 was present in 10 (83%) and 2 (17%) cases, respectively (P = 0.003); and a more severe NC pattern (active/late) was described in 11 (92%) and 5 (42%) patients, respectively (P = 0.03). When we compared the mPAP with NVC parameters, we found significant correlations between mPAP values and the NVC score (P < 0.005) and with the avascular areas score (P < 0.001). Our results underline the relevance of early microvascular assessment in patients at risk of developing a severe complication such as PAH that can amplify the systemic microvascular impairment in SSc. More severe NVC abnormalities should lead to strict cardiopulmonary surveillance and a complete NVC study is indicated.

Taurine protects methamphetamine-induced developmental angiogenesis defect through antioxidant mechanism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shao, Xue; Hu, Zhengtao; Hu, Chunyan

Investigations have characterized addictive drug-induced developmental cardiovascular malformation in human, non-human primate and rodent. However, the underlying mechanism of malformation caused by drugs during pregnancy is still largely unknown, and preventive and therapeutic measures have been lacking. Using {sup 1}H NMR spectroscopy, we profiled the metabolites from human embryo endothelial cells exposed to methamphetamine (METH) and quantified a total of 226 peaks. We identified 11 metabolites modified robustly and found that taurine markedly increased. We then validated the hypothesis that this dramatic increase in taurine could attribute to its effect in inhibiting METH-induced developmental angiogenesis defect. Taurine supplement showed amore » more significant potential than other metabolites in protecting against METH-induced injury in endothelial cells. Taurine strongly attenuated METH-induced inhibition of proliferation and migration in endothelial cells. Furthermore, death rate and vessel abnormality of zebrafish embryos treated with METH were greatly reversed by taurine. In addition, taurine supplement caused a rapid decrease in reactive oxygen species generation and strongly attenuated the excitable arise of antioxidase activities in the beginning of METH exposure prophase. Dysregulations of NF-κB, p-ERK as well as Bax, which reflect apoptosis, cell cycle arrest and oxidative stress in vascular endothelium, were blocked by taurine. Our results provide the first evidence that taurine prevents METH-caused developmental angiogenesis defect through antioxidant mechanism. Taurine could serve as a potential therapeutic or preventive intervention of developmental vascular malformation for the pregnant women with drug use. Highlights: ► Metabonomics findings. ► Abnormal development. ► Dysregulations of key proteins.« less

Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study.

PubMed

Reinstein, Eyal; Pariani, Mitchel; Bannykh, Serguei; Rimoin, David L; Schievink, Wouter I

2013-04-01

We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities.

The importance of sphingolipids and reactive oxygen species in cardiovascular development.

PubMed

de Faria Poloni, Joice; Chapola, Henrique; Feltes, Bruno César; Bonatto, Diego

2014-06-01

The heart is the first organ in the embryo to form. Its structural and functional complexity is the result of a thorough developmental program, where sphingolipids play an important role in cardiogenesis, heart maturation, angiogenesis, the regulation of vascular tone and vessel permeability. Sphingolipids are necessary for signal transduction and membrane microdomain formation. In addition, recent evidence suggests that sphingolipid metabolism is directly interconnected to the modulation of oxidative stress. However, cardiovascular development is highly sensitive to excessive reactive species production, and disturbances in sphingolipid metabolism can lead to abnormal development and cardiac disease. Therefore, in this review, we address the molecular link between sphingolipids and oxidative stress, connecting these pathways to cardiovascular development and cardiovascular disease. © 2014 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

Zebrafish as a model for monocarboxyl transporter 8-deficiency.

PubMed

Vatine, Gad David; Zada, David; Lerer-Goldshtein, Tali; Tovin, Adi; Malkinson, Guy; Yaniv, Karina; Appelbaum, Lior

2013-01-04

Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor retardation characterized by neurological impairment and abnormal thyroid hormone (TH) levels. Mutations in the TH transporter, monocarboxylate transporter 8 (MCT8), are associated with AHDS. MCT8 knock-out mice exhibit impaired TH levels; however, they lack neurological defects. Here, the zebrafish mct8 gene and promoter were isolated, and mct8 promoter-driven transgenic lines were used to show that, similar to humans, mct8 is primarily expressed in the nervous and vascular systems. Morpholino-based knockdown and rescue experiments revealed that MCT8 is strictly required for neural development in the brain and spinal cord. This study shows that MCT8 is a crucial regulator during embryonic development and establishes the first vertebrate model for MCT8 deficiency that exhibits a neurological phenotype.

Features of the temperature response to a double cuff-occlusion of the upper limbs: remote ischemic preconditioning aspect

NASA Astrophysics Data System (ADS)

Sagaidachnyi, A. A.; Fomin, A. V.; Mayskov, D. I.; Skripal, A. V.; Usanov, D. A.

2018-04-01

The essence of the phenomenon of ischemic preconditioning is increasing myocardium resistance to long periods of ischemia that occurs after several short ischemia-reperfusion periods. The aim of this pilot study was to determine the temperature and vascular response in double brachial occlusions and to assess the prospects of using this maneuver for remote ischemic preconditioning. Infrared thermography-based measurements were used to assess hemodynamics both left and right hands during the baseline, ischemia and hyperemia periods. Double ischemia with a period of 2 min was implemented by a cuff compression of the brachial artery of the right hand. A study group was constituted of eight men and six women without cardiovascular abnormalities at the age of 22 to 35 years. As a result, we have determined that a temperature and vascular response to ischemia of right hand is accompanied by the vascular reaction of the contralateral left hand, especially after the inflation and deflation of the cuff. These vascular reactions are reproducible, systemic and appear to be at least neurological in nature. An experimental confirmation of the systemic vascular «training effect» after multiple brachial ischemia-reperfusion periods is a subject of further investigations.

Brain cytoplasmic RNA 1 suppresses smooth muscle differentiation and vascular development in mice.

PubMed

Wang, Yung-Chun; Chuang, Ya-Hui; Shao, Qiang; Chen, Jian-Fu; Chen, Shi-You

2018-04-13

The cardiovascular system develops during the early stages of embryogenesis, and differentiation of smooth muscle cells (SMCs) is essential for that process. SMC differentiation is critically regulated by transforming growth factor (TGF)-β/SMAD family member 3 (SMAD3) signaling, but other regulators may also play a role. For example, long noncoding RNAs (lncRNAs) regulate various cellular activities and events, such as proliferation, differentiation, and apoptosis. However, whether long noncoding RNAs also regulate SMC differentiation remains largely unknown. Here, using the murine cell line C3H10T1/2, we found that brain cytoplasmic RNA 1 (BC1) is an important regulator of SMC differentiation. BC1 overexpression suppressed, whereas BC1 knockdown promoted, TGF-β-induced SMC differentiation, as indicated by altered cell morphology and expression of multiple SMC markers, including smooth muscle α-actin (αSMA), calponin, and smooth muscle 22α (SM22α). BC1 appeared to block SMAD3 activity and inhibit SMC marker gene transcription. Mechanistically, BC1 bound to SMAD3 via RNA SMAD-binding elements (rSBEs) and thus impeded TGF-β-induced SMAD3 translocation to the nucleus. This prevented SMAD3 from binding to SBEs in SMC marker gene promoters, an essential event in SMC marker transcription. In vivo , BC1 overexpression in mouse embryos impaired vascular SMC differentiation, leading to structural defects in the artery wall, such as random breaks in the elastic lamina, abnormal collagen deposition on SM fibers, and disorganized extracellular matrix proteins in the media of the neonatal aorta. Our results suggest that BC1 is a suppressor of SMC differentiation during vascular development. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Down-regulation of N-deacetylase-N-sulfotransferase-1 signaling in the developing diaphragmatic vasculature of nitrofen-induced congenital diaphragmatic hernia.

PubMed

Takahashi, Toshiaki; Friedmacher, Florian; Zimmer, Julia; Puri, Prem

2017-06-01

Congenital diaphragmatic hernia (CDH) has been attributed to various developmental abnormalities of the underlying tissue components. N-deacetylase-N-sulfotransferase-1 (Ndst1) is a strongly expressed biosynthetic enzyme in endothelial cells, which has recently been identified as an important factor during diaphragmatic vascularization. Loss of endothelial Ndst1 has been demonstrated to cause angiogenic defects in the developing diaphragm and disrupt normal diaphragmatic development. Furthermore, deficiency of Ndst1 diminishes the expression of slit homolog 3 (Slit3), a known CDH-related gene that has been associated with reduced vascular density and muscle defects in the diaphragm of Slit3 -/- mice. We hypothesized that expression of Ndst1 and Slit3 is decreased in the diaphragmatic vasculature of fetal rats with nitrofen-induced CDH. Time-mated rats received either nitrofen or vehicle on gestational day 9 (D9). Fetal diaphragms were microdissected on D13, D15 and D18, and divided into control and nitrofen-exposed specimens. Gene expression levels of Ndst1 and Slit3 were assessed using qRT-PCR. Immunofluorescence-double-staining for Ndst1 and Slit3 was performed to evaluate protein expression and localization. Relative mRNA expression of Ndst1 and Slit3 was significantly decreased in pleuroperitoneal folds (D13), developing diaphragms (D15) and fully muscularized diaphragms (D18) of nitrofen-exposed fetuses compared to controls. Confocal-laser-scanning-microscopy revealed markedly diminished Ndst1 and Slit3 expression in endothelial cells within the diaphragmatic vasculature on D13, D15 and D18 compared to controls. Down-regulation of Ndst1 signaling in the developing diaphragm may impair endothelial cell migration and angiogenesis, thus leading to defective diaphragmatic vascular development and CDH. Ib. Copyright © 2017 Elsevier Inc. All rights reserved.

Preoperative clinical and diagnostic characteristics of patients who require delayed IPP after primary Peyronies repair.

PubMed

Alphs, Hannah H; Navai, Neema; Köhler, Tobias S; McVary, Kevin T

2010-03-01

Penile vascular abnormalities occur in a high proportion of patients with Peyronie's disease (PD). Penile duplex ultrasonography (PDU) and dynamic infusion cavernosometry and cavernosography (DICC) are tools that can be used to help tailor individualized treatment for patients undergoing surgical intervention for their PD. However, precisely which parameters can be used to predict those patients with PD at risk for developing erectile dysfunction (ED) after intervention without inflatable penile prosthesis (IPP) has not been previously elucidated. To evaluate preoperative vascular parameters that predispose PD patients for developing ED after intervention without IPP. Twenty-six patients receiving surgical intervention for their PD at a single center were retrospectively identified. Of these, 11 (42.3%) opted for primary repair without placement of an IPP. Three (27.2%) of these 11 patients went on to develop ED postoperatively. We compared various demographic, PDU, and DICC parameters between patients who did and did not fail primary repair of their PD. Mean age and follow-up of patients who went on to develop ED after repair of PD without IPP were not significantly different (P < 0.05). Resistive index (RI) and end diastolic volume were significantly different between these two groups (P < 0.05), while peak systolic volume, flow to maintain, and pressure decay were not significantly different. An RI cutoff of <0.80 was found to identify all patients who would later develop ED and fail primary repair without IPP. Penile vascular assessment can aid in counseling patients about their risk of developing delayed ED after primary repair of PD. In our cohort of patients, PDU provided preoperative risk stratification for postoperative erectile dysfunction in men undergoing Peyronie's repair without IPP. We propose the prospective study of an RI cutoff to identify patients at risk of failing primary PD repair without IPP.

Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.

PubMed

Khalil, Raouf A

2013-12-15

Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. Copyright © 2013 Elsevier Inc. All rights reserved.

Estrogen, Vascular Estrogen Receptor and Hormone Therapy in Postmenopausal Vascular Disease

PubMed Central

Khalil, Raouf A.

2013-01-01

Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women’s Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject’s age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. PMID:24099797

[Simvastatin therapy and effect on hiperlipidemia and vascular status in nephrotic children with sustained dyslipidemia].

PubMed

Ksiazek, Joanna; Niemirska, Anna; Lipka, Maria; Wierzbicka, Aldona; Syczewska, Małgorzata; Grenda, Ryszard

2009-03-01

Dyslipidemia is common in nephrotic children and persistent lipid abnormalities are risk factor of late vascular complications. The aim of the study was evaluation of efficacy and safety of 12-months simvastatin therapy in nephrotic children with lipid profile abnormalities present despite clinical remission lasting for at least 8 weeks, including ultrasonographic assessment of carotid and femoral arteries. Overall 52 children (40 steroid-dependent and 12 steroid-resistant) were initially introduced to the study and 29 of them were treated with simvastatin. Normalisation of lipid profile was achieved in 19/29 (65.5%) and improvement in 9/29 (31%). Significant reduction in total cholesterol (p < 0.00001), LDL-C (p < 0.000003), VLDL- (p < 0.0123), oxy-LDL-C fractions (p < 0.0002) and triglycerides (TG) (p < 0.0005) serum concentration was achieved in non-proteinuric patients. Analysis of the intima-media thickness (IMT) of the common carotid (c) and superficial femoral (f) arteries values revealed positive correlation between baseline cIMT and VLDL-C (p = 0.038) and TG concentration (p = 0.008), as well as positive correlation between fIMT and baseline creatinine (p = 0.04) and LDL-C serum concentration (p = 0.032) after simvastatine treatment. Number of children with significant vessels pathology (Z-score > 2.0) was small. Increased cIMT was seen at baseline in 4 patients and in 5 after simvastatin treatment, however average and Z-score values in children under simvastatin treatment have decreased. Increased fIMT values were seen at baseline in 2 and in one case after simvastatin treatment. Tolerance of simvastation was very good in all cases but one. Simvastatin therapy was effective and safe in nephrotic non-proteinuric children with abnormal lipid profile. Fair estimation of impact of the 12-months simvastatin therapy on vascular status was not available due to limited number of children with significantly increased IMT at baseline.

VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors.

PubMed

Röhrig, F; Vorlová, S; Hoffmann, H; Wartenberg, M; Escorcia, F E; Keller, S; Tenspolde, M; Weigand, I; Gätzner, S; Manova, K; Penack, O; Scheinberg, D A; Rosenwald, A; Ergün, S; Granot, Z; Henke, E

2017-01-05

The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor's vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors. We demonstrate that, in anti-VEGF-refractory murine tumors, vascular changes after VEGF ablation result in reduced delivery leading to therapeutic failure. In these tumors, the impaired response after anti-VEGF treatment is directly linked to strong deposition of fibrillar extracellular matrix (ECM) components and high expression of lysyl oxidases. The resulting condensed, highly crosslinked ECM impeded drug permeation, protecting tumor cells from exposure to small-molecule drugs. The reduced vascular density after anti-VEGF treatment further decreased delivery in these tumors, an effect not compensated by the improved vessel quality. Pharmacological inhibition of lysyl oxidases improved drug delivery in various tumor models and reversed the negative effect of VEGF ablation on drug delivery and therapeutic response in anti-VEGF-resistant tumors. In conclusion, the vascular changes after anti-VEGF therapy can have a context-dependent negative impact on overall therapeutic efficacy. A determining factor is the tumor ECM, which strongly influences the effect of anti-VEGF therapy. Our results reveal the prospect to revert a possible negative effect and to potentiate responsiveness to antiangiogenic therapy by concomitantly targeting ECM-modifying enzymes.

VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors

PubMed Central

Röhrig, F; Vorlová, S; Hoffmann, H; Wartenberg, M; Escorcia, F E; Keller, S; Tenspolde, M; Weigand, I; Gätzner, S; Manova, K; Penack, O; Scheinberg, D A; Rosenwald, A; Ergün, S; Granot, Z; Henke, E

2017-01-01

The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor's vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors. We demonstrate that, in anti-VEGF-refractory murine tumors, vascular changes after VEGF ablation result in reduced delivery leading to therapeutic failure. In these tumors, the impaired response after anti-VEGF treatment is directly linked to strong deposition of fibrillar extracellular matrix (ECM) components and high expression of lysyl oxidases. The resulting condensed, highly crosslinked ECM impeded drug permeation, protecting tumor cells from exposure to small-molecule drugs. The reduced vascular density after anti-VEGF treatment further decreased delivery in these tumors, an effect not compensated by the improved vessel quality. Pharmacological inhibition of lysyl oxidases improved drug delivery in various tumor models and reversed the negative effect of VEGF ablation on drug delivery and therapeutic response in anti-VEGF-resistant tumors. In conclusion, the vascular changes after anti-VEGF therapy can have a context-dependent negative impact on overall therapeutic efficacy. A determining factor is the tumor ECM, which strongly influences the effect of anti-VEGF therapy. Our results reveal the prospect to revert a possible negative effect and to potentiate responsiveness to antiangiogenic therapy by concomitantly targeting ECM-modifying enzymes. PMID:27270432

Aneurysms in vascular access: state of the art and future developments.

PubMed

Inston, Nicholas; Mistry, Hiren; Gilbert, James; Kingsmore, David; Raza, Zahid; Tozzi, Matteo; Azizzadeh, Ali; Jones, Robert; Deane, Colin; Wilkins, Jason; Davidson, Ingemar; Ross, John; Gibbs, Paul; Huang, Dean; Valenti, Domenico

2017-11-17

A master class was held at the Vascular Access at Charing Cross (VA@CX2017) conference in April 2017 with invited experts and active audience participation to discuss arteriovenous (AV) vascular access aneurysms, a serious and common complication of vascular access (VA). The natural history of aneurysms in VA is poorly defined, and although classifications exist they are not uniformly applied in studies or clinical practice. True and pseudo aneurysms of AV access occur. Whilst an AV fistula by definition is an abnormal dilatation of a blood vessel, an agreed definition of 18 mm, or 3 times accepted maturation diameter, is proposed. The mechanism of aneurysmal dilatation is unknown but appears to be a combination of excessive external remodeling, wall changes due to injury, and obstruction of outflow. Diagnosis of AV aneurysms is based on physical examination and ultrasound. Venography and cross-sectional imaging may assist and be required for the investigation of outflow stenosis. Treatment of pseudo aneurysms and true aneurysms of VA (AVA) is not evidence-based, but relies on clinical experience and available facilities. In many AVA, a conservative approach with surveillance is suitable, although intervals and modalities are unclear. Avoidance of rupture is imperative and preemptive treatment should aim for access preservation, ideally with avoidance of prosthetic materials. Different techniques of aneurysmorrhaphy are described with good results in published series. Although endovascular approaches and stenting are described with good short-term results, issues with cannulation of stented areas occur and, while possible, this is not recommended, and long-term access revision is recommended.

Signal transduction in the development of pulmonary arterial hypertension

PubMed Central

Malenfant, Simon; Neyron, Anne-Sophie; Paulin, Roxane; Potus, François; Meloche, Jolyane; Provencher, Steeve; Bonnet, Sébastien

2013-01-01

Pulmonary arterial hypertension (PAH) is a unique disease. Properly speaking, it is not a disease of the lung. It can be seen more as a microvascular disease occurring mainly in the lungs and affecting the heart. At the cellular level, the PAH paradigm is characterized by inflammation, vascular tone imbalance, pulmonary arterial smooth muscle cell proliferation and resistance to apoptosis and the presence of in situ thrombosis. At a clinical level, the aforementioned abnormal vascular properties alter physically the pulmonary circulation and ventilation, which greatly influence the right ventricle function as it highly correlates with disease severity. Consequently, right heart failure remains the principal cause of death within this cohort of patients. While current treatment modestly improve patients’ conditions, none of them are curative and, as of today, new therapies are lacking. However, the future holds potential new therapies that might have positive influence on the quality of life of the patient. This article will first review the clinical presentation of the disease and the different molecular pathways implicated in the pathobiology of PAH. The second part will review tomorrow's future putative therapies for PAH. PMID:24015329

Restraint of angiogenesis by zinc finger transcription factor CTCF-dependent chromatin insulation

PubMed Central

Tang, Ming; Chen, Bo; Pardo, Carolina; Pampo, Christine; Chen, Jing; Lien, Ching-Ling; Wu, Lizi; Wang, Heiman; Yao, Kai; Oh, S. Paul; Seto, Edward; Smith, Lois E. H.; Siemann, Dietmar W.; Kladde, Michael P.; Cepko, Constance L.; Lu, Jianrong

2011-01-01

Angiogenesis is meticulously controlled by a fine balance between positive and negative regulatory activities. Vascular endothelial growth factor (VEGF) is a predominant angiogenic factor and its dosage is precisely regulated during normal vascular formation. In cancer, VEGF is commonly overproduced, resulting in abnormal neovascularization. VEGF is induced in response to various stimuli including hypoxia; however, very little is known about the mechanisms that confine its induction to ensure proper angiogenesis. Chromatin insulation is a key transcription mechanism that prevents promiscuous gene activation by interfering with the action of enhancers. Here we show that the chromatin insulator-binding factor CTCF binds to the proximal promoter of VEGF. Consistent with the enhancer-blocking mode of chromatin insulators, CTCF has little effect on basal expression of VEGF but specifically affects its activation by enhancers. CTCF knockdown cells are sensitized for induction of VEGF and exhibit elevated proangiogenic potential. Cancer-derived CTCF missense mutants are mostly defective in blocking enhancers at the VEGF locus. Moreover, during mouse retinal development, depletion of CTCF causes excess angiogenesis. Therefore, CTCF-mediated chromatin insulation acts as a crucial safeguard against hyperactivation of angiogenesis. PMID:21896759

Fluid dynamics in flexible tubes: An application to the study of the pulmonary circulation

NASA Technical Reports Server (NTRS)

Kuchar, N. R.

1971-01-01

Based on an analysis of unsteady, viscous flow through distensible tubes, a lumped-parameter model for the dynamics of blood flow through the pulmonary vascular bed was developed. The model is nonlinear, incorporating the variation of flow resistance with transmural pressure. Solved using a hybrid computer, the model yields information concerning the time-dependent behavior of blood pressures, flow rates, and volumes in each important class of vessels in each lobe of each lung in terms of the important physical and environmental parameters. Simulations of twenty abnormal or pathological situations of interest in environmental physiology and clinical medicine were performed. The model predictions agree well with physiological data.

Glyoxalase 1 Modulation in Obesity and Diabetes.

PubMed

Rabbani, Naila; Thornalley, Paul J

2018-01-02

Obesity and type 2 diabetes mellitus are increasing globally. There is also increasing associated complications, such as non-alcoholic fatty liver disease (NAFLD) and vascular complications of diabetes. There is currently no licensed treatment for NAFLD and no recent treatments for diabetic complications. New approaches are required, particularly those addressing mechanism-based risk factors for health decline and disease progression. Recent Advances: Dicarbonyl stress is the abnormal accumulation of reactive dicarbonyl metabolites such as methylglyoxal (MG) leading to cell and tissue dysfunction. It is a potential driver of obesity, diabetes, and related complications that are unaddressed by current treatments. Increased formation of MG is linked to increased glyceroneogenesis and hyperglycemia in obesity and diabetes and also down-regulation of glyoxalase 1 (Glo1)-which provides the main enzymatic detoxification of MG. Glo1 functional genomics studies suggest that increasing Glo1 expression and activity alleviates dicarbonyl stress; slows development of obesity, related insulin resistance; and prevents development of diabetic nephropathy and other microvascular complications of diabetes. A new therapeutic approach constitutes small-molecule inducers of Glo1 expression-Glo1 inducers-exploiting a regulatory antioxidant response element in the GLO1 gene. A prototype Glo1 inducer, trans-resveratrol (tRES)-hesperetin (HESP) combination, in corrected insulin resistance, improved glycemic control and vascular inflammation in healthy overweight and obese subjects in clinical trial. tRES and HESP synergize pharmacologically, and HESP likely overcomes the low bioavailability of tRES by inhibition of intestinal glucuronosyltransferases. Glo1 inducers may now be evaluated in Phase 2 clinical trials for treatment of NAFLD and vascular complications of diabetes. Antioxid. Redox Signal. 00, 000-000.

Use of 3D printer technology to facilitate surgical correction of a complex vascular anomaly with esophageal entrapment in a dog.

PubMed

Dundie, A; Hayes, G; Scrivani, P; Campoy, L; Fletcher, D; Ash, K; Oxford, E; Moïse, N S

2017-04-01

A 10 week old female intact Staffordshire terrier was presented with a total of five congenital cardio-thoracic vascular anomalies consisting of a patent ductus arteriosus (PDA) with an aneurysmic dilation, pulmonic stenosis, persistent right aortic arch, aberrant left subclavian artery and persistent left cranial vena cava. These abnormalities were identified with a combination of echocardiogram and computed tomography angiography (CTA). The abnormalities were associated with esophageal entrapment, regurgitation, and volume overload of the left heart with left atrial and ventricular enlargement. A 2 cm diameter aneurysmic dilation at the junction of the PDA, right aortic arch and aberrant left subclavian artery presented an unusual surgical challenge and precluded simple circumferential ligation and transection of the structure. A full scale three dimensional model of the heart and vasculature was constructed from the CTA and plasma sterilized. The model was used preoperatively to facilitate surgical planning and enhance intraoperative communication and coordination between the surgical and anesthesia teams. Intraoperatively the model facilitated spatial orientation, atraumatic vascular dissection, instrument sizing and positioning. A thoracoabdominal stapler was used to close the PDA aneurysm prior to transection. At the four-month postoperative follow-up the patient was doing well. This is the first reported application of new imaging and modeling technology to enhance surgical planning when approaching correction of complex cardiovascular anomalies in a dog. Copyright © 2016 Elsevier B.V. All rights reserved.

Disturbed angiogenesis in systemic sclerosis: high levels of soluble endoglin.

PubMed

Wipff, J; Avouac, J; Borderie, D; Zerkak, D; Lemarechal, H; Kahan, A; Boileau, C; Allanore, Y

2008-07-01

SSc is a CTD characterized by early generalized microangiopathy with disturbed angiogenesis. Soluble endoglin (sENG), a serum anti-angiogenic protein, has recently been described as a major actor in pre-eclampsia, another severe vascular disease with abnormal angiogenesis. The aim of this study was to investigate, in a cross-sectional study, sENG levels together with other serum vascular markers. Serum levels of sENG were assessed by ELISA in consecutive SSc patients and controls matched for age and sex. We also measured by ELISA serum levels of VEGF and asymmetric dimethylarginine (ADMA), as respective markers of angiogenesis and endothelial dysfunction. We included 235 unrelated subjects: 187 SSc patients and 48 controls. Higher concentrations of sENG (P = 0.002) and sVEGF (P < 0.0001) were found in SSc patients compared with controls whereas there was no difference for ADMA. In multivariate analysis, sENG levels were significantly increased in SSc patients with cutaneous ulcerations (P = 0.0003), positive for ACAs (P = 0.009) and with abnormal diffusing capacity for carbon monoxide divided by alveolar volume (P = 0.03). Soluble ENG levels negatively correlated with ADMA, but no relationship was found between sENG and sVEGF. This study shows increased values of sENG in a large SSc cohort and a relevant association with a vascular phenotype. The predictive value of the biomarker sENG and its potential role on cellular endothelial disturbances remain to be determined.

Ehlers-Danlos Syndrome in Orthopaedics

PubMed Central

Shirley, Eric D.; DeMaio, Marlene; Bodurtha, Joanne

2012-01-01

Ehlers-Danlos syndrome is a heterogeneous connective tissue condition characterized by varying degrees of skin hyperextensibility, joint hypermobility, and vascular fragility. Joint dislocations, musculoskeletal pain, atrophic scars, easy bleeding, vessel/viscera rupture, severe scoliosis, and obstetric complications may occur. These manifestations are secondary to abnormal collagen, with specific molecular defects in types I, III, and V collagen; they may also be related to tenascin-X, which has been identified in some patients. Ehlers-Danlos syndrome has been classified into 6 types, with variable degrees of joint instability, skin hyperextensibility, wound healing difficulty, and vascular fragility. Diagnosis begins with recognition of the signs and symptoms of global hypermobility and referring appropriate patients for genetic consultation. It is important to accurately identify patients with Ehlers-Danlos syndrome to initiate appropriate musculoskeletal treatment, optimize anesthetic and postoperative management, perform appropriate vascular screening, and help families address their concerns with other families and advocacy groups. PMID:23016112

Pathophysiology of hypertension: interactions between macro and microvascular alterations through endothelial dysfunction.

PubMed

Yannoutsos, Alexandra; Levy, Bernard I; Safar, Michel E; Slama, Gerard; Blacher, Jacques

2014-02-01

Hypertension is a multifactorial systemic chronic disorder through functional and structural macrovascular and microvascular alterations. Macrovascular alterations are featured by arterial stiffening, disturbed wave reflection and altered central to peripheral pulse pressure amplification. Microvascular alterations, including altered wall-to-lumen ratio of larger arterioles, vasomotor tone abnormalities and network rarefaction, lead to disturbed tissue perfusion and susceptibility to ischemia. Central arterial stiffness and microvascular alterations are common denominators of organ damages. Vascular alterations are intercorrelated, amplifying the haemodynamic load and causing further damage in the arterial network. A plausible precursor role of vascular alterations in incident hypertension provides new insights for preventive and therapeutic strategies targeting macro and microvasculature. Cumulative metabolic burden and oxidative stress lead to chronic endothelial injury, promoting structural and functional vascular alterations, especially in the microvascular network. Pathophysiology of hypertension may then be revisited, based on both macrovascular and microvascular alterations, with a precursor role of endothelial dysfunction for the latter.

Collagen IX is required for the integrity of collagen II fibrils and the regulation of vascular plexus formation in Zebrafish caudal fins

PubMed Central

Huang, Cheng-chen; Wang, Tai-Chuan; Lin, Bo-Hung; Wang, Yi-Wen; Johnson, Stephen L.; Yu, John

2013-01-01

Capillary plexuses form during both vasculogenesis and angiogenesis and are remodeled into mature vessel types and patterns which are delicately orchestrated with the sizes and shapes of other tissues and organs. We isolated a zebrafish mutation named prp (for persistent plexus) that causes persistent formation of vascular plexuses in the caudal fins and consequent mispatterning of bony fin rays and the fin shape. Detailed analyses revealed that the prp mutation causes a significant reduction in the size and dramatic structural defects in collagen II-rich extracellular matrices called actinotrichia of both embryonic finfolds and adult fins. prp was mapped to chromosome 19 and found to encode the zebrafish collagen9α1 (col9α1) gene which is abundantly expressed in developing finfolds. A point mutation resulting in a leucine-to-histidine change was detected in the thrombospondin domain of the col9α1 gene in prp. Morpholino-mediated knockdown of col9α1 phenocopied the prp small-finfold phenotype in wild-type embryos, and an injection of plasmids containing the col9α1 cDNA into prp embryos locally restored the finfold size. Furthermore, we found that osteoblasts in prp mutants were mispatterned apparently following the abnormal vascular plexus pattern, demonstrating that blood vessels play an important role in the patterning of bony rays in zebrafish caudal fins. PMID:19501583

Collagen IX is required for the integrity of collagen II fibrils and the regulation of vascular plexus formation in zebrafish caudal fins.

PubMed

Huang, Cheng-chen; Wang, Tai-Chuan; Lin, Bo-Hung; Wang, Yi-Wen; Johnson, Stephen L; Yu, John

2009-08-15

Capillary plexuses form during both vasculogenesis and angiogenesis and are remodeled into mature vessel types and patterns which are delicately orchestrated with the sizes and shapes of other tissues and organs. We isolated a zebrafish mutation named prp (for persistent plexus) that causes persistent formation of vascular plexuses in the caudal fins and consequent mispatterning of bony fin rays and the fin shape. Detailed analyses revealed that the prp mutation causes a significant reduction in the size and dramatic structural defects in collagen II-rich extracellular matrices called actinotrichia of both embryonic finfolds and adult fins. prp was mapped to chromosome 19 and found to encode the zebrafish collagen9alpha1 (col9alpha1) gene which is abundantly expressed in developing finfolds. A point mutation resulting in a leucine-to-histidine change was detected in the thrombospondin domain of the col9alpha1 gene in prp. Morpholino-mediated knockdown of col9alpha1 phenocopied the prp small-finfold phenotype in wild-type embryos, and an injection of plasmids containing the col9alpha1 cDNA into prp embryos locally restored the finfold size. Furthermore, we found that osteoblasts in prp mutants were mispatterned apparently following the abnormal vascular plexus pattern, demonstrating that blood vessels play an important role in the patterning of bony rays in zebrafish caudal fins.

Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia

PubMed Central

Park, Sung Ok; Wankhede, Mamta; Lee, Young Jae; Choi, Eun-Jung; Fliess, Naime; Choe, Se-Woon; Oh, Seh-Hoon; Walter, Glenn; Raizada, Mohan K.; Sorg, Brian S.; Oh, S. Paul

2009-01-01

Arteriovenous malformations (AVMs) are vascular anomalies where arteries and veins are directly connected through a complex, tangled web of abnormal arteries and veins instead of a normal capillary network. AVMs in the brain, lung, and visceral organs, including the liver and gastrointestinal tract, result in considerable morbidity and mortality. AVMs are the underlying cause of three major clinical symptoms of a genetic vascular dysplasia termed hereditary hemorrhagic telangiectasia (HHT), which is characterized by recurrent nosebleeds, mucocutaneous telangiectases, and visceral AVMs and caused by mutations in one of several genes, including activin receptor–like kinase 1 (ALK1). It remains unknown why and how selective blood vessels form AVMs, and there have been technical limitations to observing the initial stages of AVM formation. Here we present in vivo evidence that physiological or environmental factors such as wounds in addition to the genetic ablation are required for Alk1-deficient vessels to develop to AVMs in adult mice. Using the dorsal skinfold window chamber system, we have demonstrated for what we believe to be the first time the entire course of AVM formation in subdermal blood vessels by using intravital bright-field images, hyperspectral imaging, fluorescence recordings of direct arterial flow through the AV shunts, and vascular casting techniques. We believe our data provide novel insights into the pathogenetic mechanisms of HHT and potential therapeutic approaches. PMID:19805914

Imaging Keratitis-Icthyosis-Deafness (KID) syndrome with FDG-PET (F18-fluorodeoxiglucose-Positron Emission Tomography).

PubMed

Aparici, Carina Mari; Arcienega, Daniela; Cho, Eric; Hawkins, Randy

2010-01-01

Keratitis-Icthyosis-Deafness (KID) syndrome is a rare dysplasia characterized by vascularizing keratitis, congenital sensorineural hearing-loss, and progressive erythrokeratoderma. To our knowledge, this is the first KID syndrome imaged with FDG-PET in the literature. This paper is intended to help familiarize with the FDG abnormalities related to this rare entity.

Abnormalities of vascular histology and collagen fiber configuration in patients with advanced chronic kidney disease.

PubMed

Allon, Michael; Litovsky, Silvio H; Tey, Jason Chieh Sheng; Sundberg, Chad A; Zhang, Yingying; Chen, Zhen; Fang, Yun; Cheung, Alfred K; Shiu, Yan-Ting

2018-05-01

Several histologic features have been identified in the upper-extremity arteries and veins of patients with advanced chronic kidney disease, which may affect arteriovenous fistula maturation. However, it is unclear whether these chronic kidney disease vascular features are abnormal. We obtained upper-extremity arterial and venous specimens from 125 advanced chronic kidney disease patients undergoing arteriovenous fistula creation and from 15 control subjects. We quantified medial fibrosis, micro-calcification, and intimal hyperplasia with appropriate histology stains. We characterized medial collagen fiber configuration in second-harmonic-generation microscopy images for the fiber anisotropy index and the dominant fiber direction. The advanced chronic kidney disease patients were significantly younger than control subjects (53 ± 14 years vs 76 ± 11 years, p < 0.001). After controlling for age, the chronic kidney disease patients had greater arterial medial fibrosis (69% ± 14% vs 51% ± 10%, p < 0.001) and greater arterial micro-calcification (3.03% ± 5.17% vs 0.01% ± 0.03%, p = 0.02), but less arterial intimal thickness (30 ± 25 µm vs 63 ± 25 µm, p < 0.001), as compared to control subjects. The anisotropy index of medial collagen fibers was lower in both arteries (0.24 ± 0.10 vs 0.44 ± 0.04, p < 0.001) and veins (0.28 ± 0.09 vs 0.53 ± 0.10, p < 0.001) in chronic kidney disease patients, indicating that orientation of the fibers was more disordered. The dominant direction of medial collagen fibers in chronic kidney disease patients was greater in the arteries (49.3° ± 23.6° vs 4.0° ± 2.0°, p < 0.001) and the veins (30.0° ± 19.6° vs 3.9° ± 2.1°, p < 0.001), indicating that the fibers in general were aligned more perpendicular to the lumen. Advanced chronic kidney disease is associated with several abnormalities in vascular histology and collagen fiber configuration. Future research is needed to investigate whether these abnormalities affect the maturation outcomes of arteriovenous fistulas.

[Accuracy of placenta accreta prenatal diagnosis by ultrasound and MRI in a high-risk population].

PubMed

Daney de Marcillac, F; Molière, S; Pinton, A; Weingertner, A-S; Fritz, G; Viville, B; Roedlich, M-N; Gaudineau, A; Sananes, N; Favre, R; Nisand, I; Langer, B

2016-02-01

Main objective was to compare accuracy of ultrasonography and MRI for antenatal diagnosis of placenta accreta. Secondary objectives were to specify the most common sonographic and RMI signs associated with diagnosis of placenta accreta. This retrospective study used data collected from all potential cases of placenta accreta (patients with an anterior placenta praevia with history of scarred uterus) admitted from 01/2010 to 12/2014 in a level III maternity unit in Strasbourg, France. High-risk patients beneficiated antenatally from ultrasonography and MRI. Sonographic signs registered were: abnormal placental lacunae, increased vascularity on color Doppler, absence of the retroplacental clear space, interrupted bladder line. MRI signs registered were: abnormal uterine bulging, intraplacental bands of low signal intensity on T2-weighted images, increased vascularity, heterogeneous signal of the placenta on T2-weighed, interrupted bladder line, protrusion of the placenta into the cervix. Diagnosis of placenta accreta was confirmed histologically after hysterectomy or clinically in case of successful conservative treatment. Twenty-two potential cases of placenta accreta were referred to our center and underwent both ultrasonography and MRI. All cases of placenta accreta had a placenta praevia associated with history of scarred uterus. Sensibility and specificity for ultrasonography were, respectively, 0.92 and 0.67, for MRI 0.84 and 0.78 without significant difference (p>0.05). The most relevant signs associated with diagnosis of placenta accreta in ultrasonography were increased vascularity on color Doppler (sensibility 0.85/specificity 0.78), abnormal placental lacunae (sensibility 0.92/specificity 0.55) and loss of retroplacental clear space (sensibility 0.76/specificity 1.0). The most relevant signs in MRI were: abnormal uterine bulging (sensitivity 0.92/specificity 0.89), dark intraplacental bands on T2-weighted images (sensitivity 0.83/specificity 0.80) or placental heterogeneity (sensitivity 0.92/specificity 0.89). Association of two sonographic or MRI signs had the best sensitivity/specificity ratio. Ultrasonography and RMI represent two interesting and complementary diagnostic tools for antenatal diagnosis of placenta accreta. Because of its cost and accessibility, ultrasonography remains the first in line to be used for diagnosis. Use of an analytical grid for diagnosis of placenta accreta could be helpful. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Reimbursement Policies for Carotid Duplex Ultrasound that are Based on International Classification of Diseases Codes May Discourage Testing in High-Yield Groups.

PubMed

Go, Michael R; Masterson, Loren; Veerman, Brent; Satiani, Bhagwan

2016-02-01

To curb increasing volumes of diagnostic imaging and costs, reimbursement for carotid duplex ultrasound (CDU) is dependent on "appropriate" indications as documented by International Classification of Diseases (ICD) codes entered by ordering physicians. Historically, asymptomatic indications for CDU yield lower rates of abnormal results than symptomatic indications, and consensus documents agree that most asymptomatic indications for CDU are inappropriate. In our vascular laboratory, we perceived an increased rate of incorrect or inappropriate ICD codes. We therefore sought to determine if ICD codes were useful in predicting the frequency of abnormal CDU. We hypothesized that asymptomatic or nonspecific ICD codes would yield a lower rate of abnormal CDU than symptomatic codes, validating efforts to limit reimbursement in asymptomatic, low-yield groups. We reviewed all outpatient CDU done in 2011 at our institution. ICD codes were recorded, and each medical record was then reviewed by a vascular surgeon to determine if the assigned ICD code appropriately reflected the clinical scenario. CDU findings categorized as abnormal (>50% stenosis) or normal (<50% stenosis) were recorded. Each individual ICD code and group 1 (asymptomatic), group 2 (nonhemispheric symptoms), group 3 (hemispheric symptoms), group 4 (preoperative cardiovascular examination), and group 5 (nonspecific) ICD codes were analyzed for correlation with CDU results. Nine hundred ninety-four patients had 74 primary ICD codes listed as indications for CDU. Of assigned ICD codes, 17.4% were deemed inaccurate. Overall, 14.8% of CDU were abnormal. Of the 13 highest frequency ICD codes, only 433.10, an asymptomatic code, was associated with abnormal CDU. Four symptomatic codes were associated with normal CDU; none of the other high frequency codes were associated with CDU result. Patients in group 1 (asymptomatic) were significantly more likely to have an abnormal CDU compared to each of the other groups (P < 0.001, P < 0.001, P = 0.020, P = 0.002) and to all other groups combined (P < 0.001). Asymptomatic indications by ICD codes yielded higher rates of abnormal CDU than symptomatic indications. This finding is inconsistent with clinical experience and historical data, and we suggest that inaccurate coding may play a role. Limiting reimbursement for CDU in low-yield groups is reasonable. However, reimbursement policies based on ICD coding, for example, limiting payment for asymptomatic ICD codes, may impede use of CDU in high-yield patient groups. Copyright © 2016 Elsevier Inc. All rights reserved.

IR imaging of blood circulation of patients with vascular disease

NASA Astrophysics Data System (ADS)

Wang, Hsin; Wade, Dwight R., Jr.; Kam, Jack

2004-04-01

We conducted a preliminary IR imaging study of blood circulation in patients with peripheral vascular diseases. Abnormal blood flow is common in older adults, especially those with elevated blood lipids, diabetes, hypertension, and a history of smoking. All of these conditions have a high prevalence in our population, often with more than one condition in the same individual. The differences in blood flow is revealed by temperature differences in areas of the extremities as well as other regions of the body. However, what is needed is an imaging technique that is relatively inexpensive and can reveal the blood flow in real time. The IR imaging can show detailed venous system and small tempearture changes associated with blood flow. Six patients with vascular diseases were tested in a clinic set up. Their legs and feet were imaged. We observed large temperature differences (cooling of more than 10° C) at the foot, especially toes. More valuable information were obtained from the temperature distribution maps. IR thermography is potentially a very valuable tool for medical application, especially for vascular diseases.

Strategies for the Segmentation of Subcutaneous Vascular Patterns in Thermographic Images

NASA Astrophysics Data System (ADS)

Chan, Eric K. Y.; Pearce, John A.

1989-05-01

Computer-assisted segmentation of vascular patterns in thermographic images provides the clinician with graphic outlines of thermally significant subcutaneous blood vessels. Segmentation strategies compared here consist of image smoothing protocols followed by thresholding and zero-crossing edge detectors. Median prefiltering followed by the Frei-Chen algorithm gave the most reproducible results, with an execution time of 143 seconds for 256 X 256 images. The Laplacian of Gaussian operator was not suitable due to streak artifacts in the thermographic imaging system. This computerized process may be adopted in a fast paced clinical environment to aid in the diagnosis and assessment of peripheral circulatory diseases, Raynaud's Disease3, phlebitis, varicose veins, as well as diseases of the autonomic nervous system. The same methodology may be applied to enhance the appearance of abnormal breast vascular patterns, and hence serve as an adjunct to mammography in the diagnosis of breast cancer. The automatically segmented vascular patterns, which have a hand drawn appearance, may also be used as a data reduction precursor to higher level pattern analysis and classification tasks.

Arterial complications of vascular Ehlers-Danlos syndrome.

PubMed

Eagleton, Matthew J

2016-12-01

Vascular Ehlers-Danlos syndrome (EDS) is a relatively rare genetic syndrome that occurs owing to disorders in the metabolism of fibrillary collagen. These defects affect the soft connective tissues resulting in abnormalities in the skin, joints, hollow organs, and blood vessels. Patients with these defects frequently present at a young age with spontaneous arterial complications involving the medium-sized arteries. Complications involving the hollow organs, such as spontaneous colonic perforation, are observed as well. Given the fragility of the soft tissue, open and endovascular intervention on patients with vascular EDS is fraught with high complication rates. A PubMed search was performed to identify manuscripts published related to vascular EDS. This search included more than 747 articles. These findings were cross-referenced using key terms, including endovascular, embolization, surgery, genetics, pathophysiology, connective tissue disorders, vascular complications, systematic review, type III collagen, and COL3A1. The references in key articles and review articles were evaluated for additional resources not identified in the PubMed search. Care must be taken to balance the risk of intervention vs the risk of continued observation. Life-threatening hemorrhage, however, mandates intervention. With careful, altered approaches to tissue handling, endovascular approaches may provide a safer option for managing the arterial complications observed in patients with vascular EDS. Additional hope may also be found in the use of pharmacologic agents that reduce the incidence and severity of the arterial complications. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Computed tomographic features of idiopathic fibrosing interstitial pneumonia: comparison with pulmonary fibrosis related to collagen vascular disease.

PubMed

Hwang, Jeong-Hwa; Misumi, Shigeki; Sahin, Hakan; Brown, Kevin K; Newell, John D; Lynch, David A

2009-01-01

To compare the computed tomographic (CT) features of idiopathic fibrosing interstitial pneumonia with those of pulmonary fibrosis related to collagen vascular disease (CVD). We reviewed the CT scans of 177 patients with diffuse interstitial pulmonary fibrosis, of which 97 had idiopathic fibrosing interstitial pneumonia and 80 had CVD. The CT images were systematically scored for the presence and extent of pulmonary and extrapulmonary abnormalities. Computed tomographic diagnosis of usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) was assigned. A CT pattern of UIP was identified in 59 (60.8%) of patients with idiopathic fibrosing interstitial pneumonia compared with 15 (18.7%) of those patients with CVD; conversely, the CT diagnosis of NSIP was made in 51 (64%) of patients with CVD compared with 36 (37%) of patients with idiopathic disease (P < 0.01). In 113 patients who had lung biopsy, the CT diagnoses of UIP and NSIP were concordant with the histologic diagnoses in 36 of 50 patients and 34 of 41 patients, respectively. Pleural effusions, esophageal dilation, and pericardial abnormalities were more frequent in patients with CVD than in patients with idiopathic fibrosing interstitial pneumonia. Compared with patients with CVD, those patients with an idiopathic fibrosing interstitial pneumonia showed a higher prevalence of a UIP pattern and lower prevalence of an NSIP pattern as determined by CT. Identification of coexisting extrapulmonary abnormalities on CT can support a diagnosis of CVD.

Edaravone inhibits hypoxia-induced trophoblast-soluble Fms-like tyrosine kinase 1 expression: a possible therapeutic approach to preeclampsia.

PubMed

Zhao, Y; Zheng, Y F; Luo, Q Q; Yan, T; Liu, X X; Han, L; Zou, L

2014-07-01

To investigate the effects of edaravone, a potent free radical scavenger used clinically, on hypoxia-induced trophoblast-soluble Fms-like tyrosine kinase 1 (sFlt-1) expression. A trophoblast cell line (HRT-8/SVneo) impaired by cobalt chloride (CoCl2) was used as the cell model under hypoxic conditions. 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) was used to measure the viability of cells exposed to CoCl2 and edaravone. The levels of intracellular reactive oxygen species (ROS) were analyzed by flow cytometry. mRNA expression of sFlt-1, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) in trophoblasts was measured by real-time polymerase chain reaction, and the secretion of sFlt-1, VEGF, and PlGF proteins was analyzed by enzyme-linked immunosorbent assays (ELISAs). A human umbilical vein endothelial cell (HUVEC) tube-formation assay was performed to identify the effects of CoCl2 and edaravone on vascular development. CoCl2 treatment caused the loss of trophoblast viability, the formation of ROS, and sFlt-1 mRNA and protein expression in a dose-dependent manner. Pretreatment with edaravone significantly inhibited hypoxia-induced oxidative stress formation and sFlt-1 expression in trophoblasts. Neither PlGF nor VEGF mRNA or protein expression was increased by CoCl2. In the in vitro tube formation assay, edaravone showed a protective role in vascular development under hypoxic conditions. This study demonstrated that hypoxia leading to increased sFlt-1 release in trophoblasts may contribute to the placental vascular formation abnormalities observed in preeclampsia and suggested that the free radical scavenger edaravone could be a candidate for the effective treatment of preeclampsia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation.

PubMed

Hopper, Rachel K; Feinstein, Jeffrey A; Manning, Melanie A; Benitz, William; Hudgins, Louanne

2015-04-01

Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.

Continuous development precludes radioprotection in a colonial ascidian.

PubMed

Laird, Diana J; Weissman, Irving L

2004-03-01

Colonial organisms provide a unique experimental system for stem cell biology. The colonial Urochordate Botryllus schlosseri reproduces sexually as well as by continuous asexual budding. Adjacent colonies with a shared histocompatibility allele undergo vascular fusion and establish a common blood circulation, performing natural transplantation. Fused colonies become chimeras, often with complete somatic replacement of the host cell genotype by the fused parabiont. We attempted to establish a radioprotection assay for the somatic stem cells that induce long-term chimerism in Botryllus. We demonstrate over a range of radiation doses that neither autologous nor allogeneic cell transplantation enhances survival of host colonies. This suggests that high mitotic index associated with continuous asexual development leads to radiosensitivity of organs and structures essential to survival during engraftment. We observe that radiation induces uncontrolled epithelial cell proliferation in abnormally terminated buds, suggesting that stem cells are not required for the initial stages of bud development.

Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications

PubMed Central

Moran, Elizabeth P.; Wang, Zhongxiao; Chen, Jing; Sapieha, Przemyslaw; Smith, Lois E. H.

2016-01-01

Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in developed countries, and its prevalence will increase as the global incidence of diabetes grows exponentially. DR begins with an early nonproliferative stage in which retinal blood vessels and neurons degenerate as a consequence of chronic hyperglycemia, resulting in vasoregression and persistent retinal ischemia, metabolic disequilibrium, and inflammation. This is conducive to overcompensatory pathological neovascularization associated with advanced proliferative DR. Although DR is considered a microvascular complication, the retinal microvasculature is intimately associated with and governed by neurons and glia; neurodegeneration, neuroinflammation, and dysregulation of neurovascular cross talk are responsible in part for vascular abnormalities in both early nonproliferative DR and advanced proliferative DR. Neuronal activity directly regulates microvascular dilation and blood flow in the process of neurovascular coupling. Retinal neurons also secrete guidance cues in response to injury, ischemia, or metabolic stress that may either promote or suppress vascular outgrowth, either alleviating or exacerbating DR, contingent on the stage of disease and retinal microenvironment. Neurodegeneration, impaired neurovascular coupling, and dysregulation of neuronal guidance cues are key events in the pathogenesis of DR, and correcting these events may prevent or delay development of advanced DR. The review discusses the mechanisms of neurovascular cross talk and its dysregulation in DR, and their potential therapeutic implications. PMID:27473938

A clinical and experimental overview of sirenomelia: insight into the mechanisms of congenital limb malformations.

PubMed

Garrido-Allepuz, Carlos; Haro, Endika; González-Lamuño, Domingo; Martínez-Frías, María Luisa; Bertocchini, Federica; Ros, Maria A

2011-05-01

Sirenomelia, also known as sirenomelia sequence, is a severe malformation of the lower body characterized by fusion of the legs and a variable combination of visceral abnormalities. The causes of this malformation remain unknown, although the discovery that it can have a genetic basis in mice represents an important step towards the understanding of its pathogenesis. Sirenomelia occurs in mice lacking Cyp26a1, an enzyme that degrades retinoic acid (RA), and in mice that develop with reduced bone morphogenetic protein (Bmp) signaling in the caudal embryonic region. The phenotypes of these mutant mice suggest that sirenomelia in humans is associated with an excess of RA signaling and a deficit in Bmp signaling in the caudal body. Clinical studies of sirenomelia have given rise to two main pathogenic hypotheses. The first hypothesis, based on the aberrant abdominal and umbilical vascular pattern of affected individuals, postulates a primary vascular defect that leaves the caudal part of the embryo hypoperfused. The second hypothesis, based on the overall malformation of the caudal body, postulates a primary defect in the generation of the mesoderm. This review gathers experimental and clinical information on sirenomelia together with the necessary background to understand how deviations from normal development of the caudal part of the embryo might lead to this multisystemic malformation.

Antibody phage display technologies with special reference to angiogenesis.

PubMed

Smith, Julia; Kontermann, Roland E; Embleton, Jim; Kumar, Shant

2005-03-01

The presence of blood vessels is a prerequisite for normal development, tissue growth, and tissue repair. However, its abnormal occurrence or absence can also potentiate disease processes. Angiogenic therapies have been used to stimulate blood vessel growth in ischemic conditions such as severe end-stage peripheral vascular disease, ischemic heart disease and stroke and for inhibition of angiogenesis in tumors. The targeting and identification of novel endothelial cell (EC) markers that can ultimately be used in angiogenic strategies is an expanding field but is limited by the availability of reagents. For instance repeated injection of mouse monoclonal antibodies (Mabs) against angiogenic EC, can result in the production of autoantibodies. Therefore, these mouse Mabs cannot be used for therapeutic purposes. Phage display technology was employed in this context to select antibodies, proteins, and peptides against known or novel EC antigens. Furthermore, technologies have been developed that enable the specific targeting of epitopes on cells including the endothelium with high-affinity/avidity antibodies. The focus for these antibody targeting strategies are markers that are unique or up-regulated on angiogenic EC including the vascular endothelial growth factor receptor (VEGFR) KDR, endoglin (CD105), and the extracellular domain B (ED-B) domain of fibronectin (FN). These markers are reviewed herein.

Use of a polysulfone hemodialysis membrane may prevent recurrent posterior reversible encephalopathy syndrome in a patient undergoing hemodialysis.

PubMed

Mima, Akira; Matsubara, Takeshi; Endo, Shuichiro; Murakami, Taichi; Hashimoto, Yasuki

2014-01-01

A 71-year-old woman underwent hemodialysis (HD) treatment for chronic kidney disease. During HD, she developed headache, abnormalities in visual perception, and generalized convulsion. Brain magnetic resonance imaging (MRI) showed T2-hyperintensity lesions in the posterior lobe, and an electroencephalogram showed slow waves in all areas. Twenty days later, the T2-hyperintensity lesions had vanished. Furthermore, perfusion computed tomography (CT) and single-photon emission CT with N-isopropyl[(123)I]-p-iodoamphetamine (IMP-SPECT) showed no significant abnormalities. The patient was diagnosed with posterior reversible encephalopathy syndrome (PRES) because she displayed typical clinical symptoms and MRI findings. Although several antihypertensive and antiseizure medications were administered, the patient experienced recurrent PRES. Therefore, we used a polysulfone dialyzer to reduce the oxidative stress and inflammation while preserving vascular endothelial function. After use of a polysulfone dialyzer membrane, the patient had no PRES episodes during the clinical course. This is the first study to demonstrate that use of a polysulfone dialyzer membrane instead of a cellulose membrane may prevent recurrent PRES.

Early Detection of Diabetic Retinopathy.

PubMed

Safi, Hamid; Safi, Sare; Hafezi-Moghadam, Ali; Ahmadieh, Hamid

2018-04-18

Diabetic retinopathy (DR) is a primary cause of visual impairment worldwide. Diabetes mellitus may be associated with ophthalmoscopically nonvisible neurovascular damage that progresses before the first clinical signs of DR appear. Reduction of the inner neuroretinal layer thickness on macular optical coherence tomography (OCT), reduced contrast sensitivity primarily at low spatial frequencies, abnormal results in color vision and microperimetry tests, and a prolonged implicit time recorded by multifocal electroretinography have been proposed for detection of early functional and nonvisible structural neuroretinal changes. Vascular abnormalities such as changes in the retinal vessels caliber, architectural indices, and blood flow have been investigated to evaluate the early stages of DR. The results of OCT angiography, retinal vessel oxygen saturation patterns, and elevated levels of circulating blood markers and cytokines have been suggested as early signs of DR. Light-based molecular imaging in rodents has been developed to demonstrate changes in protein expressions in the retinal microvessels as diagnostic biomarkers. Future clinical studies will examine the safety and efficacy of this approach in humans. We summarize all studies related to subclinical DR biomarkers. Copyright © 2018 Elsevier Inc. All rights reserved.

Neuroimaging of Cerebrovascular Disease in the Aging Brain

PubMed Central

Gupta, Ajay; Nair, Sreejit; Schweitzer, Andrew D.; Kishore, Sirish; Johnson, Carl E.; Comunale, Joseph P.; Tsiouris, Apostolos J.; Sanelli, Pina C.

2012-01-01

Cerebrovascular disease remains a significant public health burden with its greatest impact on the elderly population. Advances in neuroimaging techniques allow detailed and sophisticated evaluation of many manifestations of cerebrovascular disease in the brain parenchyma as well as in the intracranial and extracranial vasculature. These tools continue to contribute to our understanding of the multifactorial processes that occur in the age-dependent development of cerebrovascular disease. Structural abnormalities related to vascular disease in the brain and vessels have been well characterized with CT and MRI based techniques. We review some of the pathophysiologic mechanisms in the aging brain and cerebral vasculature and the related structural abnormalities detectable on neuroimaging, including evaluation of age-related white matter changes, atherosclerosis of the cerebral vasculature, and cerebral infarction. In addition, newer neuroimaging techniques, such as diffusion tensor imaging, perfusion techniques, and assessment of cerebrovascular reserve, are also reviewed, as these techniques can detect physiologic alterations which complement the morphologic changes that cause cerebrovascular disease in the aging brain.Further investigation of these advanced imaging techniques has potential application to the understanding and diagnosis of cerebrovascular disease in the elderly. PMID:23185721

Red cell 2, 3-diphosphoglycerate levels among diabetic patents with and without vascular complications.

PubMed

Kanter, Y; Bessman, S P; Bessman, A

1975-08-01

There have been differences of opinion among authors concening in the levels of red cell 2,3-diphosphoglycerate (2,3-DPG) and nucleotides in nonacidotic diabetic patients. Our data suggest that abnormal levels of 2, 3-DPG in diabetic patients are related to the presence of vascular complications and not to the duration of the disease per sec. 2,3-DPG levels are normal in diabetic patients with no evidence of vascular complications (group A). In ambulatory patients with vascular complications (group B), significantly higher levels of 2,3-DPG are found than in normal subjects and patients in group A. In hospitalized diabetic patients with active peripheral vascular complications (group C), levels of 2,3-DPG are likewise significantly increased over those of normal subjects and patients of group A. 2,3-DPG was found to be significantly elevated in patients of group C as compared with group B. 2,3-DPG levels in venous blood from infected legs as compared with those of the peripheral venous blood were not significantly different, thereby ruling out local factors. There were no differences in the blood lactate levels in any of the group studied. The elevation of the 2,3-DPG levels may be a reflection of attempted red blood cell compensation for tissue hypoxia in the diabetic with vascular disease.

Ehlers-Danlos syndrome associated with fatal spontaneous vascular rupture in a dog.

PubMed

Uri, M; Verin, R; Ressel, L; Buckley, L; McEwan, N

2015-01-01

A 7-month-old male cross breed dog was presented with hyperextensible skin and atrophic scarring. A diagnosis of Ehlers-Danlos syndrome was made based on clinical signs, histopathology and electron microscopy. Two weeks after presentation, the dog died suddenly. Post-mortem examination revealed haemothorax and rupture of the left subclavian artery. Histological findings, including Goldner's modified Masson's trichrome staining and transmission electron microscopy of the subclavian artery, revealed abnormalities in the structure and arrangement of collagen fibrils, suggesting that the defective collagen formation extended to the vasculature. To the authors' knowledge, this is the first report of Ehlers-Danlos syndrome with vascular involvement in animals. Copyright © 2014 Elsevier Ltd. All rights reserved.

Embolic Strokes of Unknown Source and Cryptogenic Stroke: Implications in Clinical Practice

PubMed Central

Nouh, Amre; Hussain, Mohammed; Mehta, Tapan; Yaghi, Shadi

2016-01-01

Up to a third of strokes are rendered cryptogenic or of undetermined etiology. This number is specifically higher in younger patients. At times, inadequate diagnostic workups, multiple causes, or an under-recognized etiology contributes to this statistic. Embolic stroke of undetermined source, a new clinical entity particularly refers to patients with embolic stroke for whom the etiology of embolism remains unidentified despite through investigations ruling out established cardiac and vascular sources. In this article, we review current classification and discuss important clinical considerations in these patients; highlighting cardiac arrhythmias and structural abnormalities, patent foramen ovale, paradoxical sources, and potentially under-recognized, vascular, inflammatory, autoimmune, and hematologic sources in relation to clinical practice. PMID:27047443

Vascular defects and sensorineural deafness in a mouse model of Norrie disease.

PubMed

Rehm, Heidi L; Zhang, Duan-Sun; Brown, M Christian; Burgess, Barbara; Halpin, Chris; Berger, Wolfgang; Morton, Cynthia C; Corey, David P; Chen, Zheng-Yi

2002-06-01

Norrie disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature.

Lysophosphatidic Acid and Apolipoprotein A1 Predict Increased Risk of Developing World Trade Center Lung Injury: A Nested Case-Control Study

PubMed Central

Tsukiji, Jun; Cho, Soo Jung; Echevarria, Ghislaine C.; Kwon, Sophia; Joseph, Phillip; Schenck, Edward J.; Naveed, Bushra; Prezant, David J.; Rom, William N.; Schmidt, Ann Marie; Weiden, Michael D.; Nolan, Anna

2014-01-01

Rationale Metabolic syndrome, inflammatory and vascular injury markers measured in serum after WTC exposures predict abnormal FEV1. We hypothesized that elevated LPA levels predict FEV1

Effect of Caffeic Acid Phenethyl Ester on Vascular Damage Caused by Consumption of High Fructose Corn Syrup in Rats

PubMed Central

Gun, Aburrahman; Bilgic, Sedat; Kocaman, Nevin; Ozan, Gonca

2016-01-01

Fructose corn syrup is cheap sweetener and prolongs the shelf life of products, but fructose intake causes hyperinsulinemia, hypertriglyceridemia, and hypertension. All of them are referred to as metabolic syndrome and they are risk factors for cardiovascular diseases. Hence, the harmful effects of increased fructose intake on health and their prevention should take greater consideration. Caffeic Acid Phenethyl Ester (CAPE) has beneficial effects on metabolic syndrome and vascular function which is important in the prevention of cardiovascular disease. However, there are no known studies about the effect of CAPE on fructose-induced vascular dysfunction. In this study, we examined the effect of CAPE on vascular dysfunction due to high fructose corn syrup (HFCS). HFCS (6 weeks, 30% fed with drinking water) caused vascular dysfunction, but treatment with CAPE (50 micromol/kg i.p. for the last two weeks) effectively restored this problem. Additionally, hypertension in HFCS-fed rats was also decreased in CAPE supplemented rats. CAPE supplements lowered HFCS consumption-induced raise in blood glucose, homocysteine, and cholesterol levels. The aorta tissue endothelial nitric oxide synthase (eNOS) production was decreased in rats given HFCS and in contrast CAPE supplementation efficiently increased its production. The presented results showed that HFCS-induced cardiovascular abnormalities could be prevented by CAPE treatment. PMID:27042260

Ion channel remodeling in vascular smooth muscle during hypertension: Implications for novel therapeutic approaches

PubMed Central

Joseph, Biny K.; Thakali, Keshari M.; Moore, Christopher L.; Rhee, Sung W.

2013-01-01

Ion channels are multimeric, transmembrane proteins that selectively mediate ion flux across the plasma membrane in a variety of cells including vascular smooth muscle cells (VSMCs). The dynamic interplay of Ca2+ and K+ channels on the plasma membrane of VSMCs plays a pivotal role in modulating the vascular tone of small arteries and arterioles. The abnormally-elevated arterial tone observed in hypertension thus points to an aberrant expression and function of Ca2+ and K+ channels in the VSMCs. In this short review, we focus on the three well-studied ion channels in VSMCs, namely the L-type Ca2+ (CaV1.2) channels, the voltage-gated K+ (KV) channels, and the large-conductance Ca2+-activated K+ (BK) channels. First, we provide a brief overview on the physiological role of vascular CaV1.2, KV and BK channels in regulating arterial tone. Second, we discuss the current understanding of the expression changes and regulation of CaV1.2, KV and BK channels in the vasculature during hypertension. Third, based on available proof-of-concept studies, we describe the potential therapeutic approaches targeting these vascular ion channels in order to restore blood pressure to normotensive levels. PMID:23376354

Effect of Caffeic Acid Phenethyl Ester on Vascular Damage Caused by Consumption of High Fructose Corn Syrup in Rats.

PubMed

Gun, Aburrahman; Ozer, Mehmet Kaya; Bilgic, Sedat; Kocaman, Nevin; Ozan, Gonca

2016-01-01

Fructose corn syrup is cheap sweetener and prolongs the shelf life of products, but fructose intake causes hyperinsulinemia, hypertriglyceridemia, and hypertension. All of them are referred to as metabolic syndrome and they are risk factors for cardiovascular diseases. Hence, the harmful effects of increased fructose intake on health and their prevention should take greater consideration. Caffeic Acid Phenethyl Ester (CAPE) has beneficial effects on metabolic syndrome and vascular function which is important in the prevention of cardiovascular disease. However, there are no known studies about the effect of CAPE on fructose-induced vascular dysfunction. In this study, we examined the effect of CAPE on vascular dysfunction due to high fructose corn syrup (HFCS). HFCS (6 weeks, 30% fed with drinking water) caused vascular dysfunction, but treatment with CAPE (50 micromol/kg i.p. for the last two weeks) effectively restored this problem. Additionally, hypertension in HFCS-fed rats was also decreased in CAPE supplemented rats. CAPE supplements lowered HFCS consumption-induced raise in blood glucose, homocysteine, and cholesterol levels. The aorta tissue endothelial nitric oxide synthase (eNOS) production was decreased in rats given HFCS and in contrast CAPE supplementation efficiently increased its production. The presented results showed that HFCS-induced cardiovascular abnormalities could be prevented by CAPE treatment.

Doppler ultrasonography in living donor liver transplantation recipients: Intra- and post-operative vascular complications

PubMed Central

Abdelaziz, Omar; Attia, Hussein

2016-01-01

Living-donor liver transplantation has provided a solution to the severe lack of cadaver grafts for the replacement of liver afflicted with end-stage cirrhosis, fulminant disease, or inborn errors of metabolism. Vascular complications remain the most serious complications and a common cause for graft failure after hepatic transplantation. Doppler ultrasound remains the primary radiological imaging modality for the diagnosis of such complications. This article presents a brief review of intra- and post-operative living donor liver transplantation anatomy and a synopsis of the role of ultrasonography and color Doppler in evaluating the graft vascular haemodynamics both during surgery and post-operatively in accurately defining the early vascular complications. Intra-operative ultrasonography of the liver graft provides the surgeon with useful real-time diagnostic and staging information that may result in an alteration in the planned surgical approach and corrections of surgical complications during the procedure of vascular anastomoses. The relevant intra-operative anatomy and the spectrum of normal and abnormal findings are described. Ultrasonography and color Doppler also provides the clinicians and surgeons early post-operative potential developmental complications that may occur during hospital stay. Early detection and thus early problem solving can make the difference between graft survival and failure. PMID:27468207

Endothelial cell expression of adhesion molecules is induced by fetal plasma from pregnancies with umbilical placental vascular disease.

PubMed

Wang, Xin; Athayde, Neil; Trudinger, Brian

2002-07-01

To test the hypothesis that local production with spill into the fetal circulation of factor(s) injurious to endothelium is responsible for the vascular pathology present when the umbilical artery Doppler study is abnormal. Expression of adhesion molecules is a feature of endothelial cell activation. Case-control study. University teaching hospital. Fetal plasma was collected from 27 normal pregnancies, 39 pregnancies with umbilical placental vascular disease defined by abnormal umbilical artery Doppler and 11 pregnancies with pre-eclampsia and normal umbilical artery Doppler. Isolated and cultured human umbilical vein endothelial cells from normal pregnancies were incubated with fetal plasma from three study groups. mRNA expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) were assessed by reverse transcription-polymerase chain reaction. To confirm the occurrence of this in vivo, we measured the levels of soluble fractions of sICAM-1, sVCAM-1 and sPECAM-1 in the fetal circulation in the fetal plasma used for endothelial cell incubation. The mRNA expression of ICAM-1 [median 1.1 (interquartile range 0.5-1.9) vs 0.7 (0.3-1.2), P < 0.05] and PECAM-1 [2.1 (1.2-3.0) vs 1.5 (0.7-2.1), P < 0.05] was significantly higher following incubation with fetal plasma from umbilical placental vascular disease compared with the normal group. There was no difference in the expression of VCAM-1 [1.2 (0.9-1.8) vs 1.1 (0.8-1.6), ns]. The group with maternal pre-eclampsia and normal umbilical artery Doppler did not differ from the normal group. In the umbilical placental vascular disease group, the results were similar in the presence or absence of pre-eclampsia. For soluble fractions of the adhesion molecules released into the fetal circulation, we found the levels (ng/mL) of sICAM- I [median 248.5 (interquartile range 197.3-315.7) vs 174.2 (144.5-212.9), P < 0.05] and sPECAM-1 [9.3 (6.2-11.1) vs 6.1 (5.4-7.7), P < 0.05] in fetal plasma to be significantly increased in the presence of umbilical placental vascular disease compared with the normal. Vascular disease in the fetal umbilical placental circulation is associated with an elevation in mRNA expression by endothelial cells of ICAM-1 and PECAM-1. Our study provides evidence for endothelial cell activation and dysfunction in umbilical placental vascular disease. We speculate that the plasma factor(s) affecting the vessels of the umbilical villous tree is locally released by the trophoblast. The occurrence of the maternal syndrome of pre-eclampsia appears to be independent of this.

Imaging Keratitis-Icthyosis-Deafness (KID) syndrome with FDG-PET (F18-fluorodeoxiglucose-Positron Emission Tomography)

PubMed Central

Aparici, Carina Mari; Arcienega, Daniela; Cho, Eric; Hawkins, Randy

2010-01-01

Keratitis-Icthyosis-Deafness (KID) syndrome is a rare dysplasia characterized by vascularizing keratitis, congenital sensorineural hearing-loss, and progressive erythrokeratoderma. To our knowledge, this is the first KID syndrome imaged with FDG-PET in the literature. This paper is intended to help familiarize with the FDG abnormalities related to this rare entity. PMID:22470741

Congenital supratentorial meningeal arteriovenous malformation with hemangioma and massive arachnoid cell hyperplasia.

PubMed

Nabeel, Alnaghmoosh; Lach, Boleslaw; Al-Shail, Essam; Patay, Zoltan

2005-11-01

We describe the clinical, radiological and pathological findings of concurrent, congenital leptomeningeal arteriovenous malformation with hemangioma diagnosed in a newborn by prenatal and immediately postnatal magnetic resonance imaging. Vascular abnormalities were accompanied by massive arachnoidal cell hyperplasia reminiscent of meningioma. To the best of our knowledge, this is the first case of such a lesion reported in the literature.

A novel non-contrast-enhanced MRA using silent scan for evaluation of brain arteriovenous malformation: A case report and review of literature.

PubMed

Moon, Jin Il; Baek, Hye Jin; Ryu, Kyeong Hwa; Park, Hyun

2017-11-01

Brain arteriovenous malformations (AVMs) are congenital vascular abnormalities involving abnormal connections between arteries and veins. In clinical practice, imaging studies help evaluate feeding arteries, niduses, draining venous systems, and coexisting complications in patients with brain AVM. They also have an impact on decision-making regarding clinical management. We applied a novel non-contrast-enhanced MR angiography (MRA) technique, termed "silent MRA," for evaluating an incidental brain AVM. Here, we describe the clinical case with radiological review and highlight the technical background and clinical usefulness of silent MRA. A 60-year-old woman underwent neuroimaging study including MRA to evaluate intracranial cause of headache. The brain AVM, including its nidus and draining veins, was conspicuously delineated on silent MRA images; these findings correlated well with conventional angiographic findings. The patient did not receive interventional or surgical treatment. The patient is being followed up regularly at the outpatient department. The silent MRA can be a suitable imaging modality for repeated follow-up evaluation for not only brain AVMs but also various intracranial vascular diseases without the use of contrast materials.

A rare case of hidebound disease with dental implications.

PubMed

Bali, Vikram; Dabra, Sarita; Behl, Ashima Bali; Bali, Rajiv

2013-07-01

Systemic sclerosis (also called as Scleroderma or hidebound disease) is a chronic sclerotic disease of unknown etiology which causes diffuse, increased deposition of extra cellular matrix in connective tissue with vascular abnormalities, resulting in tissue hypoxia. The disease is characterized by diffuse fibrosis; degenerative changes; and vascular abnormalities in the skin (scleroderma), articular structures, and internal organs. Aesthetic and facial dysfunctions are followed by important oral and facial manifestations. Most oral manifestations begin with tongue rigidity and facial skin changes. Bone resorption of mandibular angle and widening of periodontal ligament space on periapical radiographs are important radiological findings. Other systemic changes include the involvement of internal organs, which lead to serious complications as well as disorders in the cardiac muscle and Raynaud΄s phenomenon. This is a case report of 30-year-old female patient with the classical features of this disease. This case is reported for its rarity and variable expressivity. The main aim of this article is to describe thorough presentation of the case report, various forms of scleroderma, pathogenesis, oral, extraoral, periodontal manifestations of scleroderma, and its treatment options. A brief review of the literature, focusing on dental alterations is also presented.

Hyperglycemia-induced PATZ1 negatively modulates endothelial vasculogenesis via repression of FABP4 signaling.

PubMed

Chen, Ren-An; Sun, Xiao-Mian; Yan, Chang-You; Liu, Li; Hao, Miao-Wang; Liu, Qiang; Jiao, Xi-Ying; Liang, Ying-Min

2016-09-02

Vascular endothelial dysfunction, a central hallmark of diabetes, predisposes diabetic patients to numerous cardiovascular complications. The POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1), is an important transcriptional regulatory factor and regulates divergent pathways depending on the cellular context, but its role in endothelial cells remains poorly understood. Herein, we report for the first time that endothelial PATZ1 expression was abnormally upregulated in diabetic endothelial cells (ECs) regardless of diabetes classification. This stimulatory effect was further confirmed in the high glucose-treated human umbilical vein endothelial cells (HUVECs). From a functional standpoint, transgenic overexpression of PATZ1 in endothelial colony forming cells (ECFCs) blunted angiogenesis in vivo and rendered endothelial cells unresponsive to established angiogenic factors. Mechanistically, PATZ1 acted as a potent transcriptional corepressor of fatty acid-binding protein 4 (FABP4), an essential convergence point for angiogenic and metabolic signaling pathways in ECs. Taken together, endothelial PATZ1 thus potently inhibits endothelial function and angiogenesis via inhibition of FABP4 expression, and abnormal induction of endothelial PATZ1 may contribute to multiple aspects of vascular dysfunction in diabetes. Copyright © 2016. Published by Elsevier Inc.

Therapeutic approaches for portal biliopathy: A systematic review

PubMed Central

Franceschet, Irene; Zanetto, Alberto; Ferrarese, Alberto; Burra, Patrizia; Senzolo, Marco

2016-01-01

Portal biliopathy (PB) is defined as the presence of biliary abnormalities in patients with non-cirrhotic/non-neoplastic extrahepatic portal vein obstruction (EHPVO) and portal cavernoma (PC). The pathogenesis of PB is due to ab extrinseco compression of bile ducts by PC and/or to ischemic damage secondary to an altered biliary vascularization in EHPVO and PC. Although asymptomatic biliary abnormalities can be frequently seen by magnetic resonance cholangiopancreatography in patients with PC (77%-100%), only a part of these (5%-38%) are symptomatic. Clinical presentation includes jaundice, cholangitis, cholecystitis, abdominal pain, and cholelithiasis. In this subset of patients is required a specific treatment. Different therapeutic approaches aimed to diminish portal hypertension and treat biliary strictures are available. In order to decompress PC, surgical porto-systemic shunt or transjugular intrahepatic porto-systemic shunt can be performed, and treatment on the biliary stenosis includes endoscopic (Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy, balloon dilation, stone extraction, stent placement) and surgical (bilioenteric anastomosis, cholecystectomy) approaches. Definitive treatment of PB often requires multiple and combined interventions both on vascular and biliary system. Liver transplantation can be considered in patients with secondary biliary cirrhosis, recurrent cholangitis or unsuccessful control of portal hypertension. PMID:28018098

Non-invasive detection and quantification of brain microvascular deficits by near-infrared spectroscopy in a rat model of Vascular Cognitive Impairment

NASA Astrophysics Data System (ADS)

Hallacoglu, Bertan; Sassaroli, Angelo M.; Rosenberg, Irwin H.; Troen, Aron; Fantini, Sergio

2011-02-01

Structural abnormalities in brain microvasculature are commonly associated with Alzheimer's Disease and other dementias. However, the extent to which structural microvascular abnormalities cause functional impairments in brain circulation and thereby to cognitive impairment is unclear. Non-invasive, near-infrared spectroscopy (NIRS) methods can be used to determine the absolute hemoglobin concentration and saturation in brain tissue, from which additional parameters such as cerebral blood volume (a theoretical correlate of brain microvascular density) can be derived. Validating such NIRS parameters in animal models, and understanding their relationship to cognitive function is an important step in the ultimate application of these methods to humans. To this end we applied a non-invasive multidistance NIRS method to determine the absolute concentration and saturation of cerebral hemoglobin in rat, by separately measuring absorption and reduced scattering coefficients without relying on pre- or post-correction factors. We applied this method to study brain circulation in folate deficient rats, which express brain microvascular pathology1 and which we have shown to develop cognitive impairment.2 We found absolute brain hemoglobin concentration ([HbT]) and oxygen saturation (StO2) to be significantly lower in folate deficient rats (n=6) with respect to control rats (n=5) (for [HbT]: 73+/-10 μM vs. 95+/-14 μM for StO2: 55%+/-7% vs. 66% +/-4%), implicating microvascular pathology and diminished oxygen delivery as a mechanism of cognitive impairment. More generally, our study highlights how noninvasive, absolute NIRS measurements can provide unique insight into the pathophysiology of Vascular Cognitive Impairment. Applying this method to this and other rat models of cognitive impairment will help to validate physiologically meaningful NIRS parameters for the ultimate goal of studying cerebral microvascular disease and cognitive decline in humans.

Role of Interventional Radiology in the Management of Peripheral Vascular Malformations: A Tertiary Care Center Experience.

PubMed

Tahir, Misbah; Mumtaz, Muhammad Anees; Sultan, Anum; Iqbal, Jawaid; Sayani, Raza

2018-03-16

Peripheral vascular malformations (PVMs) represent a wide spectrum of vascular abnormalities occurring due to anomalous connections between arteries, veins, capillaries, and lymphatic channels at the microscopic level, in different combinations. They are rare and challenging to treat. Different operators may have different approaches based on their experience and expertise. Sclerotherapy either alone or in combination with embolization has been used as an independent method for the treatment of PVMs. Purpose The aim of this study is to assess the safety and efficacy of sclerotherapy and embolization, with or without surgery, for the treatment of peripheral vascular malformations, based on our approach. Materials and methods A retrospective review of all patients with PVMs treated in our interventional radiology department from 2011 to 2017 was carried out. Medical records, imaging, and follow-up notes were reviewed to evaluate the response to treatment and post-procedure complications. Results Thirty-four sessions were performed in 15 patients (eight male, seven female) with PVMs. Low-flow lesions were identified in 10, intermediate flow in one, and high flow in four patients. Sodium tetradecyl sulfate (STS) was used as the sclerotherapeutic agent in 10 (66.67%), glue with lipoidal in three (20.0%), and bleomycin in one patient (6.67%). Coils with PVA and a covered stent were used in one and a combination of coil, PVA, and gel foam was used in one patient. A marked response was seen in 11 and a partial response in four patients. One patient developed foot gangrene. Stent thrombosis was noted in one patient with no clinical consequences. Recurrence was seen in two patients, who were lost to follow up. Conclusion PVMs are complex lesions. Sclerotherapy with or without embolization is a safe and effective treatment modality, with clinical response approaching 100%.

Prenatal alcohol exposure affects vasculature development in the neonatal brain.

PubMed

Jégou, Sylvie; El Ghazi, Faiza; de Lendeu, Pamela Kwetieu; Marret, Stéphane; Laudenbach, Vincent; Uguen, Arnaud; Marcorelles, Pascale; Roy, Vincent; Laquerrière, Annie; Gonzalez, Bruno José

2012-12-01

In humans, antenatal alcohol exposure elicits various developmental disorders, in particular in the brain. Numerous studies focus on the deleterious effects of alcohol on neural cells. Although recent studies suggest that alcohol can affect angiogenesis in adults, the impact of prenatal alcohol exposure on brain microvasculature remains poorly understood. We used a mouse model to investigate effects of prenatal alcohol exposure on the cortical microvascular network in vivo and ex vivo and the action of alcohol, glutamate, and vascular endothelial growth factor A (VEGF) on activity, plasticity, and survival of microvessels. We used quantitative reverse transcriptase polymerase chain reaction, Western blot, immunohistochemistry, calcimetry, and videomicroscopy. We characterized the effect of prenatal alcohol exposure on the cortical microvascular network in human controls and fetal alcohol syndrome (FAS)/partial FAS (pFAS) patients at different developmental stages. In mice, prenatal alcohol exposure induced a reduction of cortical vascular density, loss of the radial orientation of microvessels, and altered expression of VEGF receptors. Time-lapse experiments performed on brain slices revealed that ethanol inhibited glutamate-induced calcium mobilization in endothelial cells, affected plasticity, and promoted death of microvessels. These effects were prevented by VEGF. In humans, we evidenced a stage-dependent alteration of the vascular network in the cortices of fetuses with pFAS/FAS. Whereas no modification was observed from gestational week 20 (WG20) to WG22, the radial organization of cortical microvessels was clearly altered in pFAS/FAS patients from WG30 to WG38. Prenatal alcohol exposure affects cortical angiogenesis both in mice and in pFAS/FAS patients, suggesting that vascular defects contribute to alcohol-induced brain abnormalities. Copyright © 2012 American Neurological Association.

Long-term Renal Function in Living Kidney Donors Who Had Histological Abnormalities at Donation.

PubMed

Fahmy, Lara M; Massie, Allan B; Muzaale, Abimereki D; Bagnasco, Serena M; Orandi, Babak J; Alejo, Jennifer L; Boyarsky, Brian J; Anjum, Saad K; Montgomery, Robert A; Dagher, Nabil N; Segev, Dorry L

2016-06-01

Recent evidence suggests that living kidney donors are at an increased risk of end-stage renal disease. However, predicting which donors will have renal dysfunction remains challenging, particularly among those with no clinical evidence of disease at the time of donation. Although renal biopsies are not routinely performed as part of the donor evaluation process, they may yield valuable information that improves the ability to predict renal function in donors. We used implantation protocol biopsies to evaluate the association between histological abnormalities in the donated kidney and postdonation renal function (estimated glomerular filtration rate, eGFR) of the remaining kidney in living kidney donors. Longitudinal analysis using mixed-effects linear regression was used to account for multiple eGFR measures per donor. Among 310 donors between 1997 and 2012, median (IQR) follow-up was 6.2 (2.5-8.7; maximum 14.0) years. In this cohort, the overall prevalence of histological abnormalities was 65.8% (19.7% abnormal glomerulosclerosis, 23.9% abnormal interstitial fibrosis and tubular atrophy (IFTA), 4.8% abnormal mesangial matrix increase, 32.0% abnormal arteriolar hyalinosis, and 32.9% abnormal vascular intimal thickening). IFTA was associated with a 5-mL/min/1.73 m decrease of postdonation eGFR after adjusting for donor age at donation, sex, race, preoperative systolic blood pressure, preoperative eGFR, and time since donation (P < 0.01). In this single-center study, among healthy individuals cleared for living donation, IFTA was associated with decreased postdonation eGFR, whereas no other subclinical histological abnormalities provided additional information.

Long-Term Renal Function in Living Kidney Donors who had Histological Abnormalities at Donation

PubMed Central

Fahmy, Lara M.; Massie, Allan B.; Muzaale, Abimereki D.; Bagnasco, Serena M.; Orandi, Babak J.; Alejo, Jennifer L.; Boyarsky, Brian J.; Anjum, Saad K.; Montgomery, Robert A.; Dagher, Nabil N.; Segev, Dorry L.

2016-01-01

Background Recent evidence suggests that living kidney donors are at an increased risk of end-stage renal disease. However, predicting which donors will have renal dysfunction remains challenging, particularly among those with no clinical evidence of disease at the time of donation. Although renal biopsies are not routinely performed as part of the donor evaluation process, they may yield valuable information that improves the ability to predict renal function in donors. Methods We used implantation protocol biopsies to evaluate the association between histological abnormalities in the donated kidney and postdonation renal function (estimated glomerular filtration rate, eGFR) of the remaining kidney in living kidney donors. Longitudinal analysis using mixed-effects linear regression was used to account for multiple eGFR measures per donor. Results Among 310 donors between 1997 and 2012, median (IQR) follow-up was 6.2 (2.5–8.7; maximum 14.0) years. In this cohort, the overall prevalence of histological abnormalities was 65.8% (19.7% abnormal glomerulosclerosis, 23.9% abnormal interstitial fibrosis and tubular atrophy (IFTA), 4.8% abnormal mesangial matrix increase, 32.0% abnormal arteriolar hyalinosis, and 32.9% abnormal vascular intimal thickening). IFTA was associated with a 5-mL/min/1.73m2 decrease of postdonation eGFR after adjusting for donor age at donation, sex, race, preoperative systolic blood pressure, preoperative eGFR, and time since donation (p<0.01). Conclusions In this single-center study, among healthy individuals cleared for living donation, IFTA was associated with decreased postdonation eGFR, while no other subclinical histological abnormalities provided additional information. PMID:27152920

Antenatal Vitamin D Preserves Placental Vascular and Fetal Growth in Experimental Chorioamnionitis Due to Intra-amniotic Endotoxin Exposure.

PubMed

Cookson, Michael W; Ryan, Sharon L; Seedorf, Gregory J; Dodson, R Blair; Abman, Steve H; Mandell, Erica W

2018-05-01

 Chorioamnionitis (CA) is associated with a high risk for the development of bronchopulmonary dysplasia (BPD) after preterm birth, but mechanisms that increase susceptibility for BPD and strategies to prevent BPD are uncertain. As a model of CA, antenatal intra-amniotic (IA) endotoxin (ETX) exposure alters placental structure, causes fetal growth restriction, increases perinatal mortality, and causes sustained cardiorespiratory abnormalities throughout infancy. Vitamin D (Vit D) has been shown to have both anti-inflammatory and proangiogenic properties. Antenatal IA treatment with Vit D (1,25-(OH) 2 D 3 ) during IA ETX exposure improves survival and increases vascular and alveolar growth in infant rats. Whether IA ETX causes decreased placental vascular development and if the protective effects of prenatal Vit D treatment are due to direct effects on the fetus or to improved placental vascular development remain unknown.  The objective of this study was to determine if IA ETX impairs placental vascular development and Vit D metabolism, and whether 1,25-(OH) 2 D 3 treatment improves placental vascularity after IA ETX exposure during late gestation in pregnant rats.  Fetal rats were exposed to ETX (10 mg), ETX + 1,25-(OH) 2 D 3 (1 ng/mL), 1,25-(OH) 2 D 3 (1 ng/mL), or saline (control) via IA injection at E20 and delivered 2 days later. To assess placental vascular development, histologic sections from the placenta were stained for CD31 and vessel density per high power field (HPF) was determined and analyzed using Matlab software. To determine the effects of ETX on placental Vit D metabolism, Vit D receptor (VDR) and activity of the Vit D conversion enzyme, CYP27B1, were assayed from placental homogenates. Angiogenic mediators were measured by reverse transcription polymerase chain reaction by RNA extracted from placental tissue.  IA ETX reduced placenta and newborn birth weights by 22 and 20%, respectively, when compared with controls (placental weight: 0.60 vs. 0.47 g; p  < 0.0001; birth weight: 4.68 vs. 5.88 g; p  < 0.0001). IA 1,25-(OH) 2 D 3 treatment increased birth weight by 12% in ETX-exposed pups (5.25 vs. 4.68 g; p  < 0.001). IA ETX decreased placental vessel density by 24% in comparison with controls (1,114 vs. 848 vessels per HPF; p  < 0.05). Treatment with IA 1,25-(OH) 2 D 3 increased placenta vessel density twofold after ETX exposure (1,739 vs. 848); p  < 0.0001), and increased vessel density compared with saline controls by 56% (1,739 vs. 1,114; p  < 0.0001). IA ETX decreased both VDR and CYP27B1 expression by 83 and 35%, respectively ( p  < 0.01).  IA ETX decreases placental growth and vessel density and decreases placental VDR and CYP27B1 protein expression, and that antenatal 1,25-(OH) 2 D 3 restores placental weight and vessel density, as well as birth weight. We speculate that 1,25-(OH) 2 D 3 treatment preserves placental function in experimental CA and that these effects may be mediated by increased vascular growth. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects.

PubMed

Mathew, Manoj; Tay, Eric; Cusi, Kenneth

2010-02-16

CVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. We examined the contribution of FFA to these abnormalities following a 48-hour physiological increase in plasma FFA to levels of obesity and diabetes in a group of healthy subjects. 40 non-diabetic subjects (age = 38 +/- 3 yr, BMI = 28 +/- 1 kg/m2, FPG = 95 +/- 1 mg/dl, HbA1c = 5.3 +/- 0.1%) were admitted twice and received a 48-hour infusion of normal saline or low-dose lipid. Plasma was drawn for intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules-1, E-selectin (sE-S), myeloperoxidase (MPO) and total plasminogen inhibitor-1 (tPAI-1). Insulin sensitivity was measured by a hyperglycemic clamp (M/I). Lipid infusion increased plasma FFA to levels observed in obesity and T2DM and reduced insulin sensitivity by 27% (p = 0.01). Elevated plasma FFA increased plasma markers of endothelial activation ICAM-1 (138 +/- 10 vs. 186 +/- 25 ng/ml), VCAM-1 (1066 +/- 67 vs. 1204 +/- 65 ng/ml) and sE-S (20 +/- 1 vs. 24 +/- 1 ng/ml) between 13-35% and by > or = 2-fold plasma levels of myeloperoxidase (7.5 +/- 0.9 to 15 +/- 25 ng/ml), an inflammatory marker of future CVD, and tPAI-1 (9.7 +/- 0.6 to 22.5 +/- 1.5 ng/ml), an indicator of a prothrombotic state (all p < or = 0.01). The FFA-induced increase was independent from the degree of adiposity, being of similar magnitude in lean, overweight and obese subjects. An increase in plasma FFA within the physiological range observed in obesity and T2DM induces markers of endothelial activation, vascular inflammation and thrombosis in healthy subjects. This suggests that even transient (48-hour) and modest increases in plasma FFA may initiate early vascular abnormalities that promote atherosclerosis and CVD.

We Know More Than We Can Tell About Diabetes and Vascular Disease: The 2016 Edwin Bierman Award Lecture.

PubMed

Semenkovich, Clay F

2017-07-01

The Edwin Bierman Award Lecture is presented in honor of the memory of Edwin L. Bierman, MD, an exemplary scientist, mentor, and leader in the field of diabetes, obesity, hyperlipidemia, and atherosclerosis. The award and lecture recognizes a leading scientist in the field of macrovascular complications and contributing risk factors in diabetes. Clay F. Semenkovich, MD, the Irene E. and Michael M. Karl Professor and Chief of the Division of Endocrinology, Metabolism and Lipid Research at Washington University School of Medicine in St. Louis, St. Louis, MO, received the prestigious award at the American Diabetes Association's 76th Scientific Sessions, 10-14 June 2016, in New Orleans, LA. He presented the Edwin Bierman Award Lecture, "We Know More Than We Can Tell About Diabetes and Vascular Disease," on Sunday, 12 June 2016. Diabetes is a disorder of abnormal lipid metabolism, a notion strongly supported by the work of Edwin Bierman, for whom this eponymous lecture is named. This abnormal lipid environment continues to be associated with devastating vascular complications in diabetes despite current therapies, suggesting that our understanding of the pathophysiology of blood vessel disease in diabetes is limited. In this review, potential new insights into the nature of diabetic vasculopathy will be discussed. Recent observations suggest that while the concept of distinct macrovascular and microvascular complications of diabetes has been useful, vascular diseases in diabetes may be more interrelated than previously appreciated. Moreover, the intermediary metabolic pathway of de novo lipogenesis, which synthesizes lipids from simple precursors, is robustly sensitive to insulin and may contribute to these complications. De novo lipogenesis requires fatty acid synthase, and recent studies of this enzyme suggest that endogenously produced lipids are channeled to specific intracellular sites to affect physiology. These findings raise the possibility that novel approaches to treating diabetes and its complications could be based on altering the intracellular lipid milieu. © 2017 by the American Diabetes Association.

Pulmonary vascular dysfunction in ARDS

PubMed Central

2014-01-01

Acute respiratory distress syndrome (ARDS) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension (PH). Multiple factors may contribute to the development of PH in this setting. In this review, we report the results of a systematic search of the available peer-reviewed literature for papers that measured indices of pulmonary haemodynamics in patients with ARDS and reported on mortality in the period 1977 to 2010. There were marked differences between studies, with some reporting strong associations between elevated pulmonary arterial pressure or elevated pulmonary vascular resistance and mortality, whereas others found no such association. In order to discuss the potential reasons for these discrepancies, we review the physiological concepts underlying the measurement of pulmonary haemodynamics and highlight key differences between the concepts of resistance in the pulmonary and systemic circulations. We consider the factors that influence pulmonary arterial pressure, both in normal lungs and in the presence of ARDS, including the important effects of mechanical ventilation. Pulmonary arterial pressure, pulmonary vascular resistance and transpulmonary gradient (TPG) depend not alone on the intrinsic properties of the pulmonary vascular bed but are also strongly influenced by cardiac output, airway pressures and lung volumes. The great variability in management strategies within and between studies means that no unified analysis of these papers was possible. Uniquely, Bull et al. (Am J Respir Crit Care Med 182:1123–1128, 2010) have recently reported that elevated pulmonary vascular resistance (PVR) and TPG were independently associated with increased mortality in ARDS, in a large trial with protocol-defined management strategies and using lung-protective ventilation. We then considered the existing literature to determine whether the relationship between PVR/TPG and outcome might be causal. Although we could identify potential mechanisms for such a link, the existing evidence does not allow firm conclusions to be drawn. Nonetheless, abnormally elevated PVR/TPG may provide a useful index of disease severity and progression. Further studies are required to understand the role and importance of pulmonary vascular dysfunction in ARDS in the era of lung-protective ventilation. PMID:25593744

[A case of neurofibromatosis type I associated with basal meningocele and abnormal vessels].

PubMed

Yoshioka, H; Sakoda, K; Kohno, H; Hada, H; Hanaya, R; Arita, K; Kurisu, K

1998-03-01

A 21-year-old man with neurofibromatosis type 1 (NF 1) had many widespread cutaneous neurofibroma on his right face. Magnetic resonance imaging (MRI) revealed basal meningocele due to dysplasia of the skull base. Carotid and vertebral angiograms revealed occlusion of the right internal carotid artery, persistent primitive trigeminal artery. We have reviewed the clinical and radiographic features of this case of neurofibromatosis, meningocele and cerebral arterial abnormalities. NF associated with both intracranial vascular malformation and meningocele is very rare, and in our case both were thought to arise congenitally as a manifestation of mesodermal dysplasia. Careful follow up using MRI and MR angiography should be performed for such patients.

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

PubMed Central

Chen, Juanjuan; Khalil, Raouf A.

2017-01-01

Normal pregnancy is associated with marked hemodynamic and uterine changes that allow adequate uteroplacental blood flow and uterine expansion for the growing fetus. These pregnancy-associated changes involve significant uteroplacental and vascular remodeling. Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. Increases in MMP-2 and MMP-9 have been implicated in vasodilation, placentation and uterine expansion during normal pregnancy. The increases in MMPs could be induced by the increased production of estrogen and progesterone during pregnancy. MMP expression/activity may be altered during complications of pregnancy. Decreased vascular MMP-2 and MMP-9 may lead to decreased vasodilation, increased vasoconstriction, hypertensive pregnancy and preeclampsia. Abnormal expression of uteroplacental integrins, cytokines and MMPs may lead to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate remodeling of spiral arteries, and reduced uterine perfusion pressure (RUPP). RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic vascular endothelial growth factor and placental growth factor, or stimulate the release of inflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could target MMPs in the extracellular matrix as well as endothelial and vascular smooth muscle cells, causing generalized vascular dysfunction, increased vasoconstriction and hypertension in pregnancy. MMP activity can also be altered by endogenous tissue inhibitors of metalloproteinases (TIMPs) and changes in the MMP/TIMP ratio. In addition to their vascular effects, decreases in expression/activity of MMP-2 and MMP-9 in the uterus could impede uterine growth and expansion and lead to premature labor. Understanding the role of MMPs in uteroplacental and vascular remodeling and function could help design new approaches for prediction and management of preeclampsia and premature labor. PMID:28662830

Systemic vascular load in calcific degenerative aortic valve stenosis: insight from percutaneous valve replacement.

PubMed

Yotti, Raquel; Bermejo, Javier; Gutiérrez-Ibañes, Enrique; Pérez del Villar, Candelas; Mombiela, Teresa; Elízaga, Jaime; Benito, Yolanda; González-Mansilla, Ana; Barrio, Alicia; Rodríguez-Pérez, Daniel; Martínez-Legazpi, Pablo; Fernández-Avilés, Francisco

2015-02-10

Systemic arterial load impacts the symptomatic status and outcome of patients with calcific degenerative aortic stenosis (AS). However, assessing vascular properties is challenging because the arterial tree's behavior could be influenced by the valvular obstruction. This study sought to characterize the interaction between valvular and vascular functions in patients with AS by using transcatheter aortic valve replacement (TAVR) as a clinical model of isolated intervention. Aortic pressure and flow were measured simultaneously using high-fidelity sensors in 23 patients (mean 79 ± 7 years of age) before and after TAVR. Blood pressure and clinical response were registered at 6-month follow-up. Systolic and pulse arterial pressures, as well as indices of vascular function (vascular resistance, aortic input impedance, compliance, and arterial elastance), were significantly modified by TAVR, exhibiting stiffer vascular behavior post-intervention (all, p < 0.05). Peak left ventricular pressure decreased after TAVR (186 ± 36 mm Hg vs. 162 ± 23 mm Hg, respectively; p = 0.003) but remained at >140 mm Hg in 70% of patients. Wave intensity analysis showed abnormally low forward and backward compression waves at baseline, increasing significantly after TAVR. Stroke volume decreased (-21 ± 19%; p < 0.001) and correlated with continuous and pulsatile indices of arterial load. In the 48 h following TAVR, a hypertensive response was observed in 12 patients (52%), and after 6-month follow-up, 5 patients required further intensification of discharge antihypertensive therapy. Vascular function in calcific degenerative AS is conditioned by the upstream valvular obstruction that dampens forward and backward compression waves in the arterial tree. An increase in vascular load after TAVR limits the procedure's acute afterload relief. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

NLRP3 Inflammasome Mediates Aldosterone-Induced Vascular Damage.

PubMed

Bruder-Nascimento, Thiago; Ferreira, Nathanne S; Zanotto, Camila Z; Ramalho, Fernanda; Pequeno, Isabela O; Olivon, Vania C; Neves, Karla B; Alves-Lopes, Rheure; Campos, Eduardo; Silva, Carlos Alberto A; Fazan, Rubens; Carlos, Daniela; Mestriner, Fabiola L; Prado, Douglas; Pereira, Felipe V; Braga, Tarcio; Luiz, Joao Paulo M; Cau, Stefany B; Elias, Paula C; Moreira, Ayrton C; Câmara, Niels O; Zamboni, Dario S; Alves-Filho, Jose Carlos; Tostes, Rita C

2016-12-06

Inflammation is a key feature of aldosterone-induced vascular damage and dysfunction, but molecular mechanisms by which aldosterone triggers inflammation remain unclear. The NLRP3 inflammasome is a pivotal immune sensor that recognizes endogenous danger signals triggering sterile inflammation. We analyzed vascular function and inflammatory profile of wild-type (WT), NLRP3 knockout (NLRP3 -/- ), caspase-1 knockout (Casp-1 -/- ), and interleukin-1 receptor knockout (IL-1R -/- ) mice treated with vehicle or aldosterone (600 µg·kg -1 ·d -1 for 14 days through osmotic mini-pump) while receiving 1% saline to drink. Here, we show that NLRP3 inflammasome plays a central role in aldosterone-induced vascular dysfunction. Long-term infusion of aldosterone in mice resulted in elevation of plasma interleukin-1β levels and vascular abnormalities. Mice lacking the IL-1R or the inflammasome components NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In vitro, aldosterone stimulated NLRP3-dependent interleukin-1β secretion by bone marrow-derived macrophages by activating nuclear factor-κB signaling and reactive oxygen species generation. Moreover, chimeric mice reconstituted with NLRP3-deficient hematopoietic cells showed that NLRP3 in immune cells mediates aldosterone-induced vascular damage. In addition, aldosterone increased the expression of NLRP3, active caspase-1, and mature interleukin-1β in human peripheral blood mononuclear cells. Hypertensive patients with hyperaldosteronism or normal levels of aldosterone exhibited increased activity of NLRP3 inflammasome, suggesting that the effect of hyperaldosteronism on the inflammasome may be mediated through high blood pressure. Together, these data demonstrate that NLRP3 inflammasome, through activation of IL-1R, is critically involved in the deleterious vascular effects of aldosterone, placing NLRP3 as a potential target for therapeutic interventions in conditions with high aldosterone levels. © 2016 American Heart Association, Inc.

ALDOSTERONE DYSREGULATION WITH AGING PREDICTS RENAL-VASCULAR FUNCTION AND CARDIO-VASCULAR RISK

PubMed Central

Brown, Jenifer M.; Underwood, Patricia C.; Ferri, Claudio; Hopkins, Paul N.; Williams, Gordon H.; Adler, Gail K.; Vaidya, Anand

2014-01-01

Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal- and cardio-vascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1,124 visits) in a Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression-to-stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics, and the renal-vascular responses to dietary sodium manipulation and angiotensin II (AngII) infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (β= -4.60, p<0.0001) and higher SASSI (β= -58.63, p=0.001) predicted lower RPF and a blunted RPF response to sodium loading and AngII infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (p<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (p<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal-vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal-vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease. PMID:24664291

Reduced Cystathionine γ-Lyase and Increased miR-21 Expression Are Associated with Increased Vascular Resistance in Growth-Restricted Pregnancies

PubMed Central

Cindrova-Davies, Tereza; Herrera, Emilio A.; Niu, Youguo; Kingdom, John; Giussani, Dino A.; Burton, Graham J.

2013-01-01

Increased vascular impedance in the fetoplacental circulation is associated with fetal hypoxia and growth restriction. We sought to investigate the role of hydrogen sulfide (H2S) in regulating vasomotor tone in the fetoplacental vasculature. H2S is produced endogenously by catalytic activity of cystathionine β-synthase and cystathionine γ-lyase (CSE). Immunohistochemical analysis localized CSE to smooth muscle cells encircling arteries in stem villi. Immunoreactivity was reduced in placentas from pregnancies with severe early-onset growth-restriction and preeclampsia displaying abnormal umbilical artery Doppler waveforms compared with preeclamptic placentas with normal waveforms and controls. These findings were confirmed at the protein and mRNA levels. MicroRNA-21, which negatively regulates CSE expression, was increased in placentas with abnormal Doppler waveforms. Exposure of villus explants to hypoxia-reoxygenation significantly reduced CSE protein and mRNA and increased microRNA-21 expression. No changes were observed in cystathionine β-synthase expression, immunolocalized principally to the trophoblast, in pathologic placentas or in vitro. Finally, perfusion of normal placentas with an H2S donor, after preconstriction with a thromboxane mimetic, resulted in dose-dependent vasorelaxation. Glibenclamide and NG-nitro-l-arginine methyl ester partially blocked the effect, indicating that H2S acts through ATP-sensitive K+ channels and nitric oxide synthesis. These results demonstrate that H2S is a powerful vasodilator of the placental vasculature and that expression of CSE is reduced in placentas associated with increased vascular resistance. PMID:23410520

Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology

PubMed Central

Smith, Thomas G; Brooks, Jerome T; Balanos, George M; Lappin, Terence R; Layton, D. Mark; Leedham, Dawn L; Liu, Chun; Maxwell, Patrick H; McMullin, Mary F; McNamara, Christopher J; Percy, Melanie J; Pugh, Christopher W; Ratcliffe, Peter J; Talbot, Nick P; Treacy, Marilyn; Robbins, Peter A

2006-01-01

Background The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. Methods and Findings Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. Conclusions The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF. PMID:16768548

Profiling the role of mammalian target of rapamycin in the vascular smooth muscle metabolome in pulmonary arterial hypertension

PubMed Central

Kudryashova, Tatiana V.; Goncharov, Dmitry A.; Pena, Andressa; Ihida-Stansbury, Kaori; DeLisser, Horace; Kawut, Steven M.

2015-01-01

Abstract Increased proliferation and resistance to apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs), coupled with metabolic reprogramming, are key components of pulmonary vascular remodeling, a major and currently irreversible pathophysiological feature of pulmonary arterial hypertension (PAH). We recently reported that activation of mammalian target of rapamycin (mTOR) plays a key role in increased energy generation and maintenance of the proliferative, apoptosis-resistant PAVSMC phenotype in human PAH, but the downstream effects of mTOR activation on PAH PAVSMC metabolism are not clear. Using liquid and gas chromatography–based mass spectrometry, we performed pilot metabolomic profiling of human microvascular PAVSMCs from idiopathic-PAH subjects before and after treatment with the selective adenosine triphosphate–competitive mTOR inhibitor PP242 and from nondiseased lungs. We have shown that PAH PAVSMCs have a distinct metabolomic signature of altered metabolites—components of fatty acid synthesis, deficiency of sugars, amino sugars, and nucleotide sugars—intermediates of protein and lipid glycosylation, and downregulation of key biochemicals involved in glutathione and nicotinamide adenine dinucleotide (NAD) metabolism. We also report that mTOR inhibition attenuated or reversed the majority of the PAH-specific abnormalities in lipogenesis, glycosylation, glutathione, and NAD metabolism without affecting altered polyunsaturated fatty acid metabolism. Collectively, our data demonstrate a critical role of mTOR in major PAH PAVSMC metabolic abnormalities and suggest the existence of de novo lipid synthesis in PAVSMCs in human PAH that may represent a new, important component of disease pathogenesis worthy of future investigation. PMID:26697174

Galectin-1 expression imprints a neurovascular phenotype in proliferative retinopathies and delineates responses to anti-VEGF.

PubMed

Ridano, Magali E; Subirada, Paula V; Paz, María C; Lorenc, Valeria E; Stupirski, Juan C; Gramajo, Ana L; Luna, José D; Croci, Diego O; Rabinovich, Gabriel A; Sánchez, María C

2017-05-16

Neovascular retinopathies are leading causes of irreversible blindness. Although vascular endothelial growth factor (VEGF) inhibitors have been established as the mainstay of current treatment, clinical management of these diseases is still limited. As retinal impairment involves abnormal neovascularization and neuronal degeneration, we evaluated here the involvement of galectin-1 in vascular and non-vascular alterations associated with retinopathies, using the oxygen-induced retinopathy (OIR) model. Postnatal day 17 OIR mouse retinas showed the highest neovascular profile and exhibited neuro-glial injury as well as retinal functional loss, which persisted until P26 OIR. Concomitant to VEGF up-regulation, galectin-1 was highly expressed in P17 OIR retinas and it was mainly localized in neovascular tufts. In addition, OIR induced remodelling of cell surface glycophenotype leading to exposure of galectin-1-specific glycan epitopes. Whereas VEGF returned to baseline levels at P26, increased galectin-1 expression persisted until this time period. Remarkably, although anti-VEGF treatment in P17 OIR improved retinal vascularization, neither galectin-1 expression nor non-vascular and functional alterations were attenuated. However, this functional defect was partially prevented in galectin-1-deficient (Lgals1-/-) OIR mice, suggesting the importance of targeting both VEGF and galectin-1 as non-redundant independent pathways. Supporting the clinical relevance of these findings, we found increased levels of galectin-1 in aqueous humor from patients with proliferative diabetic retinopathy and neovascular glaucoma. Thus, using an OIR model and human samples, we identified a role for galectin-1 accompanying vascular and non-vascular retinal alterations in neovascular retinopathies.

Vascular Corrosion Casting: Review of Advantages and Limitations in the Application of Some Simple Quantitative Methods.

PubMed

Hossler, Fred E.; Douglas, John E.

2001-05-01

Vascular corrosion casting has been used for about 40 years to produce replicas of normal and abnormal vasculature and microvasculature of various tissues and organs that could be viewed at the ultrastructural level. In combination with scanning electron microscopy (SEM), the primary application of corrosion casting has been to describe the morphology and anatomical distribution of blood vessels in these tissues. However, such replicas should also contain quantitative information about that vasculature. This report summarizes some simple quantitative applications of vascular corrosion casting. Casts were prepared by infusing Mercox resin or diluted Mercox resin into the vasculature. Surrounding tissues were removed with KOH, hot water, and formic acid, and the resulting dried casts were observed with routine SEM. The orientation, size, and frequency of vascular endothelial cells were determined from endothelial nuclear imprints on various cast surfaces. Vascular volumes of heart, lung, and avian salt gland were calculated using tissue and resin densities, and weights. Changes in vascular volume and functional capillary density in an experimentally induced emphysema model were estimated from confocal images of casts. Clearly, corrosion casts lend themselves to quantitative analysis. However, because blood vessels differ in their compliances, in their responses to the toxicity of casting resins, and in their response to varying conditions of corrosion casting procedures, it is prudent to use care in interpreting this quantitative data. Some of the applications and limitations of quantitative methodology with corrosion casts are reviewed here.

Vascular uterine abnormalities: Comparison of imaging findings and clinical outcomes.

PubMed

Hugues, Clara; Le Bras, Yann; Coatleven, Frederic; Brun, Jean-Luc; Trillaud, Hervé; Grenier, Nicolas; Cornelis, François

2015-12-01

To retrospectively compare the imaging findings and the outcomes for patients with vascular uterine abnormalities (VUA) and to identify prognostic factors. Between 2007 and 2012, 38 patients with vaginal bleeding and abnormal ultrasonographic (US) findings consistent with acquired VUA were consecutively included (mean age 31.6 years, range 19-62). Follow-up was 32 months in mean (1-78 months). Seventeen women (44.7%) started bleeding immediately after curettage, spontaneous miscarriage, trophoblastic disease, or section scars, with the remainder starting bleeding after 8 days to 2 years. All US, CT (n=2), MR (n=5) and angiographic (n=26) images were reviewed and compared to medical reports in order to identify severe VUA requiring treatment, and predictive factors. No information about severity was provided by US, MRI or CT. Twelve patients were successfully managed conservatively. Angiography identified 6 non-severe VUA, corresponding to an isolated uterine hyperemia, and 20 severe VUA, corresponding to an association of a nidus and early venous drainage. Recurrences were more often observed for severe VUA (p=0.001). The hemoglobin level was significantly lower (below 11 g/L) in these cases (p=0.004). Recurrences were significantly more frequently observed for patients with history of dilatation and curettage (p=0.02). Hysterectomy was performed for three patients only (8%). Among the women who wished to have children, 14 (77.8%) were pregnant after 9 months in mean (range 2-23). Recurrence happens more frequently after curettage and in case of anemia or severe VUA findings on angiography, justifying adequate embolization for these patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Morphogenetic lability of reproductive structures in Ruppia maritima (Ruppiaceae, Alismatales): from two lateral flowers to a terminal flower].

PubMed

Lokk, I É; Sokolov, D D; Remizova, M V

2011-01-01

Flowers of Ruppia are normally arranged into an open two-flowered spike, but sometimes the two lateral flowers are congenitally united with each other and form a terminal flower-like structure. This developmental abnormality resembles those described in well-investigated mutants of model organisms of developmental genetics such as Arabidopsis Antirrhinum. A study of Ruppia allows investigating morphogenetic lability of this feature in natural populations. These data will be important for understanding evolutionary transitions between open and closed inflorescences. This paper presents first data on frequencies ofterminal flower-like structures in natural populations of Ruppia maritima and first observations of their development. Vascular supply of inflorescences with free and united flowers is compared for the first time. Strong differences in frequencies of occurrence of terminal flower-like structures among examined natural populations are revealed. Data on variation of organ numbers in flowers of plants from different populations allow hypothesizing that increased size of floral primordia is a factor that plays a role in their amalgamation into ajoint primordium of a terminal structure. Vascular system of inflorescences of R. maritima with united flowers is quite similar to the vascular system of a flower and nothing contradicts a hypothesis on terminal position ofthis structure. Transversally inserted stamens in inflorescences with united flowers are usually of inverted polarity. This appears to be the first documented example of an inversion of relative polarity of stamens and carpels in angiosperms.

[Polypoidal choroidal vasculopathy with spontaneous regression of subfoveal changes--case report].

PubMed

Lachowicz, Ewelina; Kubasik-Kładna, Katarzyna; Mozolewska-Piotrowska, Katarzyna; Karczewicz, Danuta

2012-01-01

To report a patient with polypoidal choroidal vasculopathy (PCV) with spontaneous regression of subfoveal changes during follow-up. The seventy six years old men was referred to the treatment of exudative type of age related macular degeneration (AMD) in the RE. The routine ophthalmological examination, the optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA) were performed. Decreasing of visual acuity of the RE and abnormal result of the Amsler test, hemorrhagic and exudative changes near inferior-temporalis vascular arcade were observed. Intraretinal fluid in the OCT was noted. FA revealed parapapillaris changes suggesting CNV. ICGA showed the presence of branching vascular network extending from choroidal vasculature (BVN) and polypoidal and aneurysmal vascular terminal lesion (PL) localized under retinal pigment epithelium (RPE). Based on the results PCV was diagnosed and the patient was referred to laserotherapy. Due to the regression of the eye fundus changes during the period of observation, confirmed by control OCT and FA the treatment was not implemented.

Digital image processing of vascular angiograms

NASA Technical Reports Server (NTRS)

Selzer, R. H.; Beckenbach, E. S.; Blankenhorn, D. H.; Crawford, D. W.; Brooks, S. H.

1975-01-01

The paper discusses the estimation of the degree of atherosclerosis in the human femoral artery through the use of a digital image processing system for vascular angiograms. The film digitizer uses an electronic image dissector camera to scan the angiogram and convert the recorded optical density information into a numerical format. Another processing step involves locating the vessel edges from the digital image. The computer has been programmed to estimate vessel abnormality through a series of measurements, some derived primarily from the vessel edge information and others from optical density variations within the lumen shadow. These measurements are combined into an atherosclerosis index, which is found in a post-mortem study to correlate well with both visual and chemical estimates of atherosclerotic disease.

Essential Thrombocythaemia and Peripheral Gangrene

PubMed Central

Preston, F. E.; Emmanuel, I. G.; Winfield, D. A.; Malia, R. G.

1974-01-01

Six patients are described in whom gangrene of one or more toes occurred as the presenting feature of essential thrombocythaemia. Spontaneous platelet aggregation was observed in platelet-rich plasma from four patients and platelet aggregation after the addition of adenosine diphosphate and collagen was highly abnormal in samples from all six. All of the patients described dramatic relief of pain within six hours of ingestion of aspirin and this coincided with disappearance of the spontaneous platelet aggregation and collagen-induced platelet aggregation. Treatment with phosphorus-32 corrected the platelet count and there were no further recurrences of peripheral vascular disease. Platelet function tests performed at the time all gave normal results. It is concluded that essential thrombocythaemia is an important and treatable cause of peripheral vascular disease. PMID:4472103

Technical Pitfall in 68Ga-Prostate Specific Membrane Antigen Imaging: Altered Biodistribution Caused by Free 68Ga-Citrate Due to Radiolysis Showing Increased Vascular Activity.

PubMed

Hod, Nir; Anconina, Reut; Levin, Daniel; Ezroh Kazap, Dina; Lantsberg, Sophie

2018-06-01

As with any new molecular imaging modality, accurate characterization of abnormalities on Ga-PSMA PET/CT imaging can be accomplished only if one is aware of the normal distribution pattern, physiological variants, and potential sources of false imaging findings. Altered biodistribution can have a significant impact on scan interpretation. Presented here is a rare case in which radiopharmaceutical radiolysis occurred causing excessive free Ga-citrate showing as an increased vascular activity. As Ga-PSMA PET/CT imaging is a relatively new imaging technique, it is important to be aware of such a potential technical pitfall in clinical practice in order to prevent scan misinterpretation.

Conditional Switching of Vascular Endothelial Growth Factor (VEGF) Expression in Tumors: Induction of Endothelial Cell Shedding and Regression of Hemangioblastoma-Like Vessels by VEGF Withdrawal

NASA Astrophysics Data System (ADS)

Benjamin, Laura E.; Keshet, Eli

1997-08-01

We have recently shown that VEGF functions as a survival factor for newly formed vessels during developmental neovascularization, but is not required for maintenance of mature vessels. Reasoning that expanding tumors contain a significant fraction of newly formed and remodeling vessels, we examined whether abrupt withdrawal of VEGF will result in regression of preformed tumor vessels. Using a tetracycline-regulated VEGF expression system in xenografted C6 glioma cells, we showed that shutting off VEGF production leads to detachment of endothelial cells from the walls of preformed vessels and their subsequent death by apoptosis. Vascular collapse then leads to hemorrhages and extensive tumor necrosis. These results suggest that enforced withdrawal of vascular survival factors can be applied to target preformed tumor vasculature in established tumors. The system was also used to examine phenotypes resulting from over-expression of VEGF. When expression of the transfected VEGF cDNA was continuously ``on,'' tumors became hyper-vascularized with abnormally large vessels, presumably arising from excessive fusions. Tumors were significantly less necrotic, suggesting that necrosis in these tumors is the result of insufficient angiogenesis.

Endothelial progenitor cells and rheumatic disease modifying therapy.

PubMed

Lo Gullo, Alberto; Aragona, Caterina Oriana; Michele, Scuruchi; Versace, Antonio Giovanni; Antonino, Saitta; Egidio, Imbalzano; Loddo, Saverio; Campo, Giuseppe Maurizio; Giuseppe, Mandraffino

2018-05-26

Rheumatic diseases are associated with accelerated atherosclerosis and with increased risk of cardiovascular morbidity and mortality. The mechanisms underlying the higher prevalence of cardiovascular disease are not completely clarified, but it is likely that a pivotal role is played by vascular inflammation and consequently to altered vascular endothelium homeostasis. Also, high prevalence of traditional risk factors, proatherogenic activation and endothelial dysfunction further contribute to vascular damage. Circulating endothelial progenitor cells (EPCs) can restore dysfunctional endothelium and protect against atherosclerotic vascular disease. However, abnormalities in number and function of these cells in patients with rheumatic condition have been extensively reported. During the last years, growing interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD has been shown; in addition, pioneering studies show that EPC dysfunction might be improved with pharmacological strategies. However, how to restore EPC function, and whether achieving this aim may be effective in preventing cardiovascular complications in rheumatic disease, remain to be established. In this review we report an overview on the current stand of knowledge on the effect of pharmaceutical and lifestyle intervention in improving EPCs number and function in rheumatic disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Changes in pulmonary circulation in severe bronchopulmonary dysplasia.

PubMed Central

Bush, A; Busst, C M; Knight, W B; Hislop, A A; Haworth, S G; Shinebourne, E A

1990-01-01

Eight patients with severe bronchopulmonary dysplasia underwent cardiac catheterisation. Seven had a pulmonary vascular resistance greater than 3 mm Hg.l-1 min.m2 (mean 8.9, range 2.2-13.8). All had raised intrapulmonary shunts (mean 25.6%, range 5.4-50%, normal less than 5%). Two had a high alveolar dead space, and two had unsuspected congenital heart disease. Epoprostenol (prostacyclin), but not 100% oxygen, caused a significant fall in pulmonary vascular resistance. Death was associated with a high pulmonary vascular resistance and a high shunt. Morphometric studies in three cases showed normal numbers of airways, but increased thickness of bronchial muscle. The numbers of alveoli were reduced and the walls thickened. There was increased medial thickness in small pulmonary arteries with distal extension of muscle. In the oldest child some vessels were obliterated by fibrosis. We speculate that measurements of pulmonary vascular resistance and shunt may have prognostic value; that a trial of pulmonary vasodilators other than oxygen might be worthwhile in patients with poor prognosis; and that abnormalities of the pulmonary circulation contribute to the difficulties of managing patients with bronchopulmonary dysplasia. Images Figure 7 PMID:2117421

Measurements of pulmonary vascular permeability with PET and gallium-68 transferrin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mintun, M.A.; Dennis, D.R.; Welch, M.J.

1987-11-01

We quantified pulmonary vascular permeability with positron emission tomography (PET) and gallium-68-(/sup 68/Ga) labeled transferrin. Six dogs with oleic acid-induced lung injury confined to the left lower lobe, two normal human volunteers, and two patients with the adult respiratory distress syndrome (ARDS) were evaluated. Lung tissue-activity measurements were obtained from sequential 1-5 min PET scans collected over 60 min, after in vivo labeling of transferrin through intravenous administration of (/sup 68/Ga)citrate. Blood-activity measurements were measured from simultaneously obtained peripheral blood samples. A forward rate constant describing the movement of transferrin from pulmonary vascular to extravascular compartments, the pulmonary transcapillary escapemore » rate (PTCER), was then calculated from these data using a two-compartment model. In dogs, PTCER was 49 +/- 18 in normal lung tissue and 485 +/- 114 10(-4) min-1 in injured lung. A repeat study in these dogs 4 hr later showed no significant change. Values in the human subjects showed similarly marked differences between normal and abnormal lung tissue. We conclude that PET will be a useful method of evaluating vascular permeability changes after acute lung injury.« less

Abnormal myocardial fluid retention as an early manifestation of ischemic injury.

PubMed Central

Willerson, J. T.; Scales, F.; Mukherjee, A.; Platt, M.; Templeton, G. H.; Fink, G. S.; Buja, L. M.

1977-01-01

Fifty-seven isolated, blood perfused, continuously weighed canine hearts have been utilized to study the development of abnormal myocardial fluid retention during early myocardial ischemic injury. Inflatable balloon catheters were positioned around the left anterior descending coronary arteries (LAD) of 54 hearts or the proximal left circumflex coronary arteries of three hearts for study of the following intervals of coronary occlusion: a) 10 minutes followed by 20 minutes of reflow, b) 40 minutes followed by either no reflow or by 20 minutes of reflow, and c) 60 minutes without reflow. After 60 minutes of fixed coronary occlusion, histologic and ultrastructural examination revealed mild swelling of many ischemic cardiac muscle cells in the absence of interstitial edema, cardiac weight gain, and obvious structural defects in cell membrane integrity. After 40 minutes of coronary occlusion and 20 minutes of reflow, significant cardiac weight gain occurred in association with characteristic alterations in the ischemic region, including widespread interstitial edema and focal vascular congestion and hemorrhage and swelling of cardiac muscle cells. Focal structural defects in cell membrane integrity were also noted. The development of abnormal myocardial fluid retention after 40 minutes of LAD occlusion occurred in association with a significant reduction in sodium-potassium-ATPase activity in the ischemic area, but with no significant alteration in either creatine phosphokinase or citrate synthase activity in the same region. Despite the abnormal myocardial fluid retention in these hearts, it was possible pharmacologically to vasodilate coronary vessels with adenosine and nitroglycerin infusion to maintain a consistently high coronary flow following release of the coronary occlusion after 40 minutes and to even exceed initial hyperemic flow values following release of the occlusion when adenosine and nitroglycerin infusion was delayed until 15 minutes after reflow. Thus, the data indicate that impaired cell volume regulation and interstitial fluid accumulation and focal structural defects in cell membrane integrity are early manifestations of ischemic injury followed by reflow, but fail to establish a major role for the abnormal fluid retention in altering coronary blood flow prior to the development of extensive myocardial necrosis. In contrast, fixed coronary occlusion for 60 minutes results in mild intracellular swelling but no significant interstitial edema and no obvious structural defects in cell membrane integrity. Images Figure 1 Figure 5 Figure 6 Figure 2 Figure 3 Figure 4 PMID:139829

A Predictive Framework to Elucidate Venous Stenosis: CFD & Shape Optimization.

PubMed

Javid Mahmoudzadeh Akherat, S M; Cassel, Kevin; Boghosian, Michael; Hammes, Mary; Coe, Fredric

2017-07-01

The surgical creation of vascular accesses for renal failure patients provides an abnormally high flow rate conduit in the patient's upper arm vasculature that facilitates the hemodialysis treatment. These vascular accesses, however, are very often associated with complications that lead to access failure and thrombotic incidents, mainly due to excessive neointimal hyperplasia (NH) and subsequently stenosis. Development of a framework to monitor and predict the evolution of the venous system post access creation can greatly contribute to maintaining access patency. Computational fluid dynamics (CFD) has been exploited to inspect the non-homeostatic wall shear stress (WSS) distribution that is speculated to trigger NH in the patient cohort under investigation. Thereafter, CFD in liaison with a gradient-free shape optimization method has been employed to analyze the deformation modes of the venous system enduring non-physiological hemodynamics. It is observed that the optimally evolved shapes and their corresponding hemodynamics strive to restore the homeostatic state of the venous system to a normal, pre-surgery condition. It is concluded that a CFD-shape optimization coupling that seeks to regulate the WSS back to a well-defined physiological WSS target range can accurately predict the mode of patient-specific access failure.

Analysis of homeobox gene action may reveal novel angiogenic pathways in normal placental vasculature and in clinical pregnancy disorders associated with abnormal placental angiogenesis.

PubMed Central

Murthi, Padma; Abumaree, Mohamed; Kalionis, Bill

2014-01-01

Homeobox genes are essential for both the development of the blood and lymphatic vascular systems, as well as for their maintenance in the adult. Homeobox genes comprise an important family of transcription factors, which are characterized by a well conserved DNA binding motif; the homeodomain. The specificity of the homeodomain allows the transcription factor to bind to the promoter regions of batteries of target genes and thereby regulates their expression. Target genes identified for homeodomain proteins have been shown to control fundamental cell processes such as proliferation, differentiation, and apoptosis. We and others have reported that homeobox genes are expressed in the placental vasculature, but our knowledge of their downstream target genes is limited. This review highlights the importance of studying the cellular and molecular mechanisms by which homeobox genes and their downstream targets may regulate important vascular cellular processes such as proliferation, migration, and endothelial tube formation, which are essential for placental vasculogenesis and angiogenesis. A better understanding of the molecular targets of homeobox genes may lead to new therapies for aberrant angiogenesis associated with clinically important pregnancy pathologies, including fetal growth restriction and preeclampsia. PMID:24926269

EETs reduces LPS-induced hyperpermeability by targeting GRP78 mediated Src activation and subsequent Rho/ROCK signaling pathway

PubMed Central

Dong, Ruolan; Hu, Danli; Yang, Yan; Chen, Zhihui; Fu, Menglu; Wang, Dao Wen; Xu, Xizhen; Tu, Ling

2017-01-01

Integrity of endothelial barrier is a determinant of the prognosis in the acute lung injury caused by sepsis. The epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, exhibit protective effects in various pathogenic states, however, whether EETs play a role in endothelial barrier enhancement and the involved mechanisms remain to be investigated. Here, we show that increased EETs level by endothelial specific cytochrome P450 epoxygenase 2J2 over-expression and soluble epoxide hydrolase (sEH) inhibitor TPPU reduced lipopolysaccharide-induced endothelial hyper-permeability in vivo, accompanied by improved survival of septic mice. In addition, sEH inhibitor AUDA and 11,12-EET also decreased endothelial hyper-permeability in the in-vitro study. Importantly, the relative mechanisms were associated with reduced GRP78-Src interaction and ROS production, and subsequently reduced RhoA/ROCK activation, and eventually decreased VE-cadherin and myosin light chain (MLC) phosphorylation. Thus CYP2J2-EETs is crucial for RhoA-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability, which may contribute to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability. PMID:28881620

Retrospective analysis of the incidence of epidural haematoma in patients with epidural catheters and abnormal coagulation parameters.

PubMed

Gulur, P; Tsui, B; Pathak, R; Koury, K M; Lee, H

2015-05-01

Epidural haematoma is a rare but potentially catastrophic complication associated with epidural catheterization. The times of insertion and removal of epidural catheters are high-risk periods for epidural haematoma formation, especially with abnormal coagulation parameters. There is a lack of data on the incidence of epidural haematoma in patients with abnormal coagulation parameters. A retrospective analysis was undertaken from 2002 to 2009 on patients with an epidural catheter. Queries were performed on the coagulation parameters for the dates of placement and removal of the catheters and on all documented epidural haematoma cases. During the study period, 11 600 epidural catheters were placed. In the setting of abnormal coagulation parameters, 278 (2.4%) epidural catheters were placed and 351 (3%) were removed. Two epidural haematomas occurred; both patients had epidural catheters and spinal drains placed for vascular procedures with abnormal coagulation parameters after operatation. The haematomas occurred after removal of the catheters. Based on our study, the incidence of epidural haematoma in patients with abnormal coagulation parameters is 1 in 315 patients, with the lower limit of the 95% confidence interval at 87 and the upper limit at 2597. The risk of epidural haematoma is clearly elevated with abnormal coagulation parameters. Our data suggest that as the incidence of epidural haematoma with neuraxial access in patients with abnormal coagulation is not 100%, individual risk-benefit evaluations are warranted. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Role of the podiatrist in diabetic limb salvage.

PubMed

Kim, Paul J; Attinger, Christopher E; Evans, Karen K; Steinberg, John S

2012-10-01

Podiatrists play an important role in the multidisciplinary team in diabetic limb salvage. Podiatry is a specialty that is licensed in the diagnoses and treatment of pathologies of the foot and ankle. The treatment includes both conservative and surgical modalities. Understanding the biomechanics of the lower extremity is principally emphasized in the education and training of a podiatrist. This is particularly important in the context of the diabetic foot where biomechanical abnormalities often precede ulcer development. Preventive ulcer development strategies employed by a podiatrist include regular monitoring, routine care of calluses, and insert/shoe recommendations. Further, clinic-based ulcer care as well as surgery that include prophylactic and acute intervention can translate to the preservation of a functional limb. Finally, continuous podiatric management can prevent ulcer recurrence through offloading strategies and diabetic foot education. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Disruption of the rice nitrate transporter OsNPF2.2 hinders root-to-shoot nitrate transport and vascular development

PubMed Central

Li, Yuge; Ouyang, Jie; Wang, Ya-Yun; Hu, Rui; Xia, Kuaifei; Duan, Jun; Wang, Yaqin; Tsay, Yi-Fang; Zhang, Mingyong

2015-01-01

Plants have evolved to express some members of the nitrate transporter 1/peptide transporter family (NPF) to uptake and transport nitrate. However, little is known of the physiological and functional roles of this family in rice (Oryza sativa L.). Here, we characterized the vascular specific transporter OsNPF2.2. Functional analysis using cDNA-injected Xenopus laevis oocytes revealed that OsNPF2.2 is a low-affinity, pH-dependent nitrate transporter. Use of a green fluorescent protein tagged OsNPF2.2 showed that the transporter is located in the plasma membrane in the rice protoplast. Expression analysis showed that OsNPF2.2 is nitrate inducible and is mainly expressed in parenchyma cells around the xylem. Disruption of OsNPF2.2 increased nitrate concentration in the shoot xylem exudate when nitrate was supplied after a deprivation period; this result suggests that OsNPF2.2 may participate in unloading nitrate from the xylem. Under steady-state nitrate supply, the osnpf2.2 mutants maintained high levels of nitrate in the roots and low shoot:root nitrate ratios; this observation suggests that OsNPF2.2 is involved in root-to-shoot nitrate transport. Mutation of OsNPF2.2 also caused abnormal vasculature and retarded plant growth and development. Our findings demonstrate that OsNPF2.2 can unload nitrate from the xylem to affect the root-to-shoot nitrate transport and plant development. PMID:25923512

Fetal programming of blood pressure in a transgenic mouse model of altered intrauterine environment.

PubMed

Chiossi, Giuseppe; Costantine, Maged M; Tamayo, Esther; Hankins, Gary D V; Saade, George R; Longo, Monica

2016-12-01

Nitric oxide is essential in the vascular adaptation to pregnancy, as knockout mice lacking nitric oxide synthase (NOS3) have abnormal utero-placental perfusion, hypertension and growth restriction. We previously showed with ex vivo studies on transgenic animals lacking NOS3 that adverse intrauterine environment alters fetal programming of vascular reactivity in adult offspring. The current research shows that altered vascular reactivity correlates with higher blood pressure in vivo. Our data suggest that higher blood pressure depends on both genetic background (NOS3 deficiency) and uterine environment, becomes more evident with age (> 7 postnatal weeks), activity and stress, is gender specific (preponderant among males), and can be affected by the sleep-awake cycle. In utero or early postnatal life (< 7 weeks), before onset of hypertension, may represent a potential window for intervention to prevent future cardiovascular disorders. Nitric oxide is involved in the vascular adaptation to pregnancy. Using transgenic animals, we previously showed that adverse intrauterine environment alters vascular reactivity in adult offspring. The aim of our study was to determine if altered vascular programming is associated with abnormal blood pressure (BP) profiles in vivo. Mice lacking a functional endothelial nitric oxide synthase (KO, NOS3 -/- ) and wild-type mice (WT, NOS3 +/+ ) were crossbred to generate homozygous NOS3 -/- (KO), maternally derived heterozygous NOS3 +/- (KOM: mother with adverse intrauterine environment from NOS3 deficiency), paternally derived heterozygous NOS3 +/- (KOP: mother with normal in utero milieu) and NOS3 +/+ (WT) litters. BP was measured in vivo at 7, 14 and 21 weeks of age. After univariate analysis, multivariate population-averaged linear regression models were used to identify factors affecting BP. When compared to WT offspring, systolic (SBP), diastolic (DBP) and mean (MAP) BP progressively increased from KOP, to KOM, and peaked among KO (P < 0.001), although significance was not reached for KOP. Higher BP was also associated with male gender, older age (> 7 postnatal weeks), higher locomotor activity, daytime recordings, and recent blood pressure transducer insertion (P < 0.001). Post hoc analysis showed that KOM had higher SBP than KOP (P < 0.05). Our study indicates that adverse intrauterine environment contributes, along with multiple other factors, to account for hypertension; moreover, in utero or early postnatal life may represent a possible therapeutic window for prevention of cardiovascular disease later in life. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Integrated Evaluation of Age-Related Changes in Structural and Functional Vascular Parameters Used to Assess Arterial Aging, Subclinical Atherosclerosis, and Cardiovascular Risk in Uruguayan Adults: CUiiDARTE Project

PubMed Central

Bia, Daniel; Zócalo, Yanina; Farro, Ignacio; Torrado, Juan; Farro, Federico; Florio, Lucía; Olascoaga, Alicia; Brum, Javier; Alallón, Walter; Negreira, Carlos; Lluberas, Ricardo; Armentano, Ricardo L.

2011-01-01

This work was carried out in a Uruguayan (South American) population to characterize aging-associated physiological arterial changes. Parameters markers of subclinical atherosclerosis and that associate age-related changes were evaluated in healthy people. A conservative approach was used and people with nonphysiological and pathological conditions were excluded. Then, we excluded subjects with (a) cardiovascular (CV) symptoms, (b) CV disease, (c) diabetes mellitus or renal failure, and (d) traditional CV risk factors (other than age and gender). Subjects (n = 388) were submitted to non-invasive vascular studies (gold-standard techniques), to evaluate (1) common (CCA), internal, and external carotid plaque prevalence, (2) CCA intima-media thickness and diameter, (3) CCA stiffness (percentual pulsatility, compliance, distensibility, and stiffness index), (4) aortic stiffness (carotid-femoral pulse wave velocity), and (5) peripheral and central pressure wave-derived parameters. Age groups: ≤20, 21–30, 31–40, 41–50, 51–60, 61–70, and 71–80 years old. Age-related structural and functional vascular parameters profiles were obtained and analyzed considering data from other populations. The work has the strength of being the first, in Latin America, that uses an integrative approach to characterize vascular aging-related changes. Data could be used to define vascular aging and abnormal or disease-related changes. PMID:22187622

Transactivation of ErbB receptors by leptin in the cardiovascular system: mechanisms, consequences and target for therapy.

PubMed

Bełtowski, Jerzy; Jazmroz-Wiśniewska, Anna

2014-01-01

Many experimental and clinical studies have demonstrated that elevated leptin concentration in patients with obesity/metabolic syndrome contributes to the pathogenesis of cardiovascular disorders including arterial hypertension, atherosclerosis, restenosis after coronary angioplasty and myocardial hypertrophy. Receptor tyrosine kinases belonging to the ErbB family, especially ErbB1 (epidermal growth factor receptor) and ErbB2 are abundantly expressed in the blood vessels and the heart. EGFR is activated not only by its multiple peptide ligands but also by many other factors including angiotensin II, endothelin-1, norepinephrine, thrombin and prorenin; the phenomenon referred to as "transactivation". Augmented EGFR signaling contributes to abnormalities of vascular tone and renal sodium handling as well as vascular remodeling and myocardial hypertrophy through various intracellular mechanisms, in particular extracellular signal-regulated kinases (ERK) and phosphoinositide 3-kinase (PI3K). Recent experimental studies indicate that chronically elevated leptin transactivates the EGFR through the mechanisms requiring reactive oxygen species and cytosolic tyrosine kinase, c-Src. In addition, hyperleptinemia increases ErbB2 activity in the arterial wall. Stimulation of EGFR and ErbB2 downstream signaling pathways such as ERK and PI3K in the vascular wall and the kidney may contribute to the increase in vascular tone, enhanced tubular sodium reabsorption as well as vascular and renal lesions in hyperleptinemic obese subjects.

Integrated Evaluation of Age-Related Changes in Structural and Functional Vascular Parameters Used to Assess Arterial Aging, Subclinical Atherosclerosis, and Cardiovascular Risk in Uruguayan Adults: CUiiDARTE Project.

PubMed

Bia, Daniel; Zócalo, Yanina; Farro, Ignacio; Torrado, Juan; Farro, Federico; Florio, Lucía; Olascoaga, Alicia; Brum, Javier; Alallón, Walter; Negreira, Carlos; Lluberas, Ricardo; Armentano, Ricardo L

2011-01-01

This work was carried out in a Uruguayan (South American) population to characterize aging-associated physiological arterial changes. Parameters markers of subclinical atherosclerosis and that associate age-related changes were evaluated in healthy people. A conservative approach was used and people with nonphysiological and pathological conditions were excluded. Then, we excluded subjects with (a) cardiovascular (CV) symptoms, (b) CV disease, (c) diabetes mellitus or renal failure, and (d) traditional CV risk factors (other than age and gender). Subjects (n = 388) were submitted to non-invasive vascular studies (gold-standard techniques), to evaluate (1) common (CCA), internal, and external carotid plaque prevalence, (2) CCA intima-media thickness and diameter, (3) CCA stiffness (percentual pulsatility, compliance, distensibility, and stiffness index), (4) aortic stiffness (carotid-femoral pulse wave velocity), and (5) peripheral and central pressure wave-derived parameters. Age groups: ≤20, 21-30, 31-40, 41-50, 51-60, 61-70, and 71-80 years old. Age-related structural and functional vascular parameters profiles were obtained and analyzed considering data from other populations. The work has the strength of being the first, in Latin America, that uses an integrative approach to characterize vascular aging-related changes. Data could be used to define vascular aging and abnormal or disease-related changes.

Effect of hypoxia mimetic cobalt chloride on the expression of extracellular-superoxide dismutase in retinal pericytes.

PubMed

Adachi, Tetsuo; Aida, Kazunari; Nishihara, Hiroko; Kamiya, Tetsuro; Hara, Hirokazu

2011-01-01

The initial clinical stage of diabetic retinopathy (DR) is characterized by the development of intraretinal microvascular abnormalities. The increased formation of reactive oxygen species (ROS) is thought to be a key event in the pathogenesis of DR. Extracellular-superoxide dismutase (EC-SOD) is an anti-inflammatory enzyme that is distributed mainly in vascular cells and protects cells from ROS by scavenging superoxide anion. Treatment with cobalt chloride (CoCl(2)) decreased the expression of EC-SOD but not other SOD isozymes in pericytes accompanied with an increase of intracellular ROS production. Pre-treatment with N-acetylcysteine (NAC) significantly suppressed the ROS production and down-regulation of EC-SOD. We observed the activation of caspase-3 and DNA fragmentation as signs of apoptotic process by CoCl(2) treatment. In addition, these phenomena were significantly inhibited by pre-treatment with NAC. EC-SOD enhancer 4-phenyl butyric acid also suppressed the caspase-3 activation. It is known that the presence of a high level of EC-SOD throughout the vessel walls might have an important protective role against superoxide in the vascular system. The decrease in EC-SOD expression accompanied with elevation of ROS level in pericytes under hypoxia might induce and/or promote the ROS-triggered apoptosis of pericytes and the development of pathogenesis in DR.

[Morphological alterations in nailfold capillaroscopy and the clinical picture of vascular involvement in autoimmune diseases: systemic lupus erythematosus and type 1 diabetes].

PubMed

Kuryliszyn-Moskal, Anna; Ciołkiewicz, Mariusz; Dubicki, Artur

2010-01-01

Systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (DM) belong to the group of autoimmune diseases presenting with a wide range of organ manifestations. Microvascular abnormalities seem to play a crucial role in the development of persistent multi-organ complications in both diseases. The aim of this study was to determine the relationship between microvascular changes examined with nailfold capillaroscopy and organ involvement. We eurolled 76 SLE patients, 106 patients with type 1 diabetes, and 40 healthy controls. Morphological changes were observed with nailfold capillaroscopy in 86 (81%) diabetics and in 70 (92.1%) SLE patients. Severe capillaroscopic changes were disclosed in 32 out of 54 (59%) diabetic patients with microangiopathy and in only 7 out of 52 (13%) patients without microangiopathy. In the SLE group, severe capillaroscopic abnormalities were found in 18 out of 34 (52.9%) patients with organ involvement and in 9 out of 42 (21.4%) patients without organ involvement. The capillaroscopic score was significantly higher in diabetic patients with microangiopathic complications in comparison to patients without microangiopathy (p < 0.001). Moreover, diabetic patients with advanced microvascular changes had longer disease durations than patients with mild abnormalities. A similar comparison between SLE patients with and without systemic manifestations showed significantly higher capillaroscopic scores in the group with organ involvement (p < 0.001). Furthermore, a positive correlation between capillaroscopic score and disease activity was observed in SLE patients (p < 0.01). Our findings suggest that abnormalities in nailfold capillaroscopy reflect the extent of microvascular involvement and are associated with organ involvement in SLE and diabetes.

MRI or not to MRI! Should brain MRI be a routine investigation in children with autistic spectrum disorders?

PubMed

Zeglam, Adel M; Al-Ogab, Marwa F; Al-Shaftery, Thouraya

2015-09-01

To evaluate the routine usage of Magnetic Resonance Imaging (MRI) of brain and estimate the prevalence of brain abnormalities in children presenting to the Neurodevelopment Clinic of Al-Khadra Hospital (NDC-KH), Tripoli, Libya with autistic spectrum disorders (ASD). The records of all children with ASD presented to NDC-KH over 4-year period (from January 2009 to December 2012) were reviewed. All MRIs were acquired with a 1.5-T Philips (3-D T1, T2, FLAIR coronal and axial sequences). MRIs were reported to be normal, abnormal or no significant abnormalities by a consultant neuroradiologist. One thousand and seventy-five children were included in the study. Seven hundred and eighty-two children (72.7 %) had an MRI brain of whom 555 (71 %) were boys. 26 children (24 males and 2 females) (3.3 %) demonstrated MRI abnormalities (8 leukodystrophic changes, 4 periventricular leukomalacia, 3 brain atrophy, 2 tuberous sclerosis, 2 vascular changes, 1 pineoblastoma, 1 cerebellar angioma, 1 cerebellar hypoplasia, 3 agenesis of corpus callosum, 1 neuro-epithelial cyst). An unexpectedly high rate of MRI abnormalities was found in the first large series of clinical MRI investigations in children with autism. These results could contribute to further research into the pathogenesis of autistic spectrum disorder.

Penile blood flow by xenon-133 washout

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haden, H.T.; Katz, P.G.; Mulligan, T.

1989-06-01

Penile erectile failure is often attributed to abnormalities of vascular supply or drainage, but few direct measurements of penile blood flow have been made. We describe the xenon washout method for measurement of penile blood flow, and present the results obtained in a group of normal and impotent subjects. The procedure was performed with standard nuclear imaging equipment. Flaccid-state penile blood flow in the impotent patients studied was not significantly different from the normal group, suggesting that flaccid-state measurements may not be helpful in evaluation of erectile failure. However, this method can be used to measure penile venous outflow withmore » stimulated or induced erection, and may provide a method for detecting abnormal venous leakage.« less

Fibulin-4 E57K Knock-in Mice Recapitulate Cutaneous, Vascular and Skeletal Defects of Recessive Cutis Laxa 1B with both Elastic Fiber and Collagen Fibril Abnormalities.

PubMed

Igoucheva, Olga; Alexeev, Vitali; Halabi, Carmen M; Adams, Sheila M; Stoilov, Ivan; Sasaki, Takako; Arita, Machiko; Donahue, Adele; Mecham, Robert P; Birk, David E; Chu, Mon-Li

2015-08-28

Fibulin-4 is an extracellular matrix protein essential for elastic fiber formation. Frameshift and missense mutations in the fibulin-4 gene (EFEMP2/FBLN4) cause autosomal recessive cutis laxa (ARCL) 1B, characterized by loose skin, aortic aneurysm, arterial tortuosity, lung emphysema, and skeletal abnormalities. Homozygous missense mutations in FBLN4 are a prevalent cause of ARCL 1B. Here we generated a knock-in mouse strain bearing a recurrent fibulin-4 E57K homozygous missense mutation. The mutant mice survived into adulthood and displayed abnormalities in multiple organ systems, including loose skin, bent forelimb, aortic aneurysm, tortuous artery, and pulmonary emphysema. Biochemical studies of dermal fibroblasts showed that fibulin-4 E57K mutant protein was produced but was prone to dimer formation and inefficiently secreted, thereby triggering an endoplasmic reticulum stress response. Immunohistochemistry detected a low level of fibulin-4 E57K protein in the knock-in skin along with altered expression of selected elastic fiber components. Processing of a precursor to mature lysyl oxidase, an enzyme involved in cross-linking of elastin and collagen, was compromised. The knock-in skin had a reduced level of desmosine, an elastin-specific cross-link compound, and ultrastructurally abnormal elastic fibers. Surprisingly, structurally aberrant collagen fibrils and altered organization into fibers were characteristics of the knock-in dermis and forelimb tendons. Type I collagen extracted from the knock-in skin had decreased amounts of covalent intermolecular cross-links, which could contribute to the collagen fibril abnormalities. Our studies provide the first evidence that fibulin-4 plays a role in regulating collagen fibril assembly and offer a preclinical platform for developing treatments for ARCL 1B. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Vinpocetine suppresses pathological vascular remodeling by inhibiting vascular smooth muscle cell proliferation and migration.

PubMed

Cai, Yujun; Knight, Walter E; Guo, Shujie; Li, Jian-Dong; Knight, Peter A; Yan, Chen

2012-11-01

Abnormal vascular smooth muscle cell (SMC) activation is associated with various vascular disorders such as atherosclerosis, in-stent restenosis, vein graft disease, and transplantation-associated vasculopathy. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. However, its role in pathological vascular remodeling remains unexplored. Herein, we show that systemic administration of vinpocetine significantly reduced neointimal formation in carotid arteries after ligation injury. Vinpocetine also markedly decreased spontaneous remodeling of human saphenous vein explants in ex vivo culture. In cultured SMCs, vinpocetine dose-dependently suppressed cell proliferation and caused G1-phase cell cycle arrest, which is associated with a decrease in cyclin D1 and an increase in p27Kip1 levels. In addition, vinpocetine dose-dependently inhibited platelet-derived growth factor (PDGF)-stimulated SMC migration as determined by the two-dimensional migration assays and three-dimensional aortic medial explant invasive assay. Moreover, vinpocetine significantly reduced PDGF-induced type I collagen and fibronectin expression. It is noteworthy that PDGF-stimulated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), but not protein kinase B, was specifically inhibited by vinpocetine. Vinpocetine powerfully attenuated intracellular reactive oxidative species (ROS) production, which largely mediates the inhibitory effects of vinpocetine on ERK1/2 activation and SMC growth. Taken together, our results reveal a novel function of vinpocetine in attenuating neointimal hyperplasia and pathological vascular remodeling, at least partially through suppressing ROS production and ERK1/2 activation in SMCs. Given the safety profile of vinpocetine, this study provides insight into the therapeutic potential of vinpocetine in proliferative vascular disorders.

Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

PubMed Central

Cai, Yujun; Knight, Walter E.; Guo, Shujie; Li, Jian-Dong; Knight, Peter A.

2012-01-01

Abnormal vascular smooth muscle cell (SMC) activation is associated with various vascular disorders such as atherosclerosis, in-stent restenosis, vein graft disease, and transplantation-associated vasculopathy. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. However, its role in pathological vascular remodeling remains unexplored. Herein, we show that systemic administration of vinpocetine significantly reduced neointimal formation in carotid arteries after ligation injury. Vinpocetine also markedly decreased spontaneous remodeling of human saphenous vein explants in ex vivo culture. In cultured SMCs, vinpocetine dose-dependently suppressed cell proliferation and caused G1-phase cell cycle arrest, which is associated with a decrease in cyclin D1 and an increase in p27Kip1 levels. In addition, vinpocetine dose-dependently inhibited platelet-derived growth factor (PDGF)-stimulated SMC migration as determined by the two-dimensional migration assays and three-dimensional aortic medial explant invasive assay. Moreover, vinpocetine significantly reduced PDGF-induced type I collagen and fibronectin expression. It is noteworthy that PDGF-stimulated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), but not protein kinase B, was specifically inhibited by vinpocetine. Vinpocetine powerfully attenuated intracellular reactive oxidative species (ROS) production, which largely mediates the inhibitory effects of vinpocetine on ERK1/2 activation and SMC growth. Taken together, our results reveal a novel function of vinpocetine in attenuating neointimal hyperplasia and pathological vascular remodeling, at least partially through suppressing ROS production and ERK1/2 activation in SMCs. Given the safety profile of vinpocetine, this study provides insight into the therapeutic potential of vinpocetine in proliferative vascular disorders. PMID:22915768

Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk.

PubMed

Brown, Jenifer M; Underwood, Patricia C; Ferri, Claudio; Hopkins, Paul N; Williams, Gordon H; Adler, Gail K; Vaidya, Anand

2014-06-01

Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal vascular and cardiovascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1124 visits) in the General Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression to stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics and the renal vascular responses to dietary sodium manipulation and angiotensin II infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (β=-4.60; P<0.0001) and higher SASSI (β=-58.63; P=0.001) predicted lower RPF and a blunted RPF response to sodium loading and angiotensin II infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (P<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (P<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease.

Why is it necessary to examine retina when the patient suffers from aplastic anemia?

PubMed

Tomcikova, D; Gerinec, A; Busanyova, B; Gresikova, M; Biskup, S; Hortnagel, K

2018-01-01

To inform about a case of Revesz syndrome (RS) with initial ophthalmological symptomatology of severe proliferative vitreoretinopathy of the left eye (LE). After the aplastic anemia had developed, RS was established. The exudative retinopathy was successfully treated with photocoagulation on the right eye (RE). RS is characterized by fatal bone marrow failure, exudative retinopathy, neuroradiographic abnormalities, neurodevelopmental delay and skin abnormalities. Non-treated exudative retinopathy leads to blindness. We report ophthalmological findings as follows: fundus photography and fluorescein angiography (FA) acquired by examinations under general anesthesia in patient with RS. Results of genetic tests helped to establish the diagnosis. Two‑year old Caucasian male was examined due to total retinal detachment on LE and signs of chorioretinal scarring on RE. In preoperative screening, thrombocytopenia was detected; later, severe pancytopenia developed. Considering the hematological findings and clinical appearance, we suspected RS, which was confirmed by genetic tests. We found a pathogenic mutation in gene TINF2 (variant c.865C>T;p.Pro289Ser) in a mosaic state with autosomal dominant mode of inheritance. This mutation has not been described in RS yet. Blind LE was enucleated because of dolorous neovascular glaucoma. FA of RE shows excessive areas of capillary nonperfusion with vascular abnormalities and exudation. After the photocoagulation, the visual acuity (VA) on RE remains 0.9 at the age of 7 years. RS is an extremely rare condition.  The initial symptomatology could be ophthalmological or hematological. The positive finding of TINF2 gene mutation helped in establishing the correct diagnosis. The ischemic retinopathy was successfully treated by photocoagulation (Fig. 6, Ref. 6). Text in PDF www.elis.sk.

[Systemic lupus erythematosus and pregnancy].

PubMed

Basheva, S; Nikolov, A; Stoilov, R; Stoilov, N

2012-01-01

Connective-tissue disorders, also referred to as collagen-vascular disorders, are characterized by autoantibody-mediated connective-tissue abnormalities. These are also called immune-complex diseases because many involve deposition of immune complexes in specific organ or tissue sites. Some of these disorders are characterized by sterile inflammation, especially of the skin, joints, blood vessels, and kidneys, and are referred to as rheumatic diseases. For inexplicable reasons, many rheumatic diseases primarily affect women. Another major category of connective-tissue diseases includes inherited disorders of bone, skin, cartilage, blood vessels. Examples include Marfan syndrome, osteogenesis imperfecta, and Ehlers-Danlos syndrome. Lupus erythematosus (LE) is the main and most important disease in the group of systemic connective tissue diseases. It is heterogeneous, multiple organs autoimmune inflammatory disease with complex pathogenesis, which is the result of interaction between the susceptible genes and environmental factors that lead to abnormal immune response. In this review will consider: its incidence, pathogenesis, clinical forms and clinical features and diagnosis set based on generally accepted clinical criteria developed by the American College of Rheumatology (ACR), the course of pregnancy in patients suffering from LE, the most common complications of LE during pregnancy and antiphospholipid syndrome as part of LE.

Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering.

PubMed

Dachet, Fabien; Bagla, Shruti; Keren-Aviram, Gal; Morton, Andrew; Balan, Karina; Saadat, Laleh; Valyi-Nagy, Tibor; Kupsky, William; Song, Fei; Dratz, Edward; Loeb, Jeffrey A

2015-02-01

Although epilepsy is associated with a variety of abnormalities, exactly why some brain regions produce seizures and others do not is not known. We developed a method to identify cellular changes in human epileptic neocortex using transcriptional clustering. A paired analysis of high and low spiking tissues recorded in vivo from 15 patients predicted 11 cell-specific changes together with their 'cellular interactome'. These predictions were validated histologically revealing millimetre-sized 'microlesions' together with a global increase in vascularity and microglia. Microlesions were easily identified in deeper cortical layers using the neuronal marker NeuN, showed a marked reduction in neuronal processes, and were associated with nearby activation of MAPK/CREB signalling, a marker of epileptic activity, in superficial layers. Microlesions constitute a common, undiscovered layer-specific abnormality of neuronal connectivity in human neocortex that may be responsible for many 'non-lesional' forms of epilepsy. The transcriptional clustering approach used here could be applied more broadly to predict cellular differences in other brain and complex tissue disorders. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Why are tumour blood vessels abnormal and why is it important to know?

PubMed Central

Nagy, J A; Chang, S-H; Dvorak, A M; Dvorak, H F

2009-01-01

Tumour blood vessels differ from their normal counterparts for reasons that have received little attention. We report here that they are of at least six distinct types, we describe how each forms, and, looking forward, encourage the targeting of tumour vessel subsets that have lost their vascular endothelial growth factor-A (VEGF-A) dependency and so are likely unresponsive to anti-VEGF-A therapies. PMID:19240721

Transcatheter correction of Scimitar syndrome: occlusion of abnormal pulmonary venous drainage and vascular supply in an infant.

PubMed

Saltik, Levent; Ugan Atik, Sezen; Bornaun, Helen

2017-10-01

Treatment of Scimitar syndrome is usually surgical; however, if there is "dual drainage" - that is, one to the inferior caval vein and the other to the left atrium - it is possible to successfully treat this anomaly via a less-invasive transcatheter approach. We report a case of Scimitar syndrome in a 21-month-old, male infant successfully treated with transcatheter embolisation.

Absent circle of Willis with vascular pollarding in an adult with colpocephaly: A developmental perspective

PubMed Central

Verghese, Renjan; Paul, Divyan

2015-01-01

Absent circle of Willis (COW) has been described in cases of severe forms of cerebral developmental anomalies such as alobar prosencephaly. However, there are no reports of absent COW in patients with a milder form of cerebral abnormality such as colpocephaly. We report a unique case of an adult with colpocephaly and absent COW and discuss their association from a developmental perspective. PMID:26443299

Basilar artery hypoplasia associated with changes of brainstem potential, transcranial Doppler and perfusion-weighted imaging.

PubMed

Zhang, Dao Pei; Yin, Suo; Zhang, Shu Ling; Zhang, Jie Wen; Ma, Qian Kun; Lu, Gui Feng

2017-07-01

The aim of this study was to observe brainstem hemodynamic alterations associated with basilar artery hypoplasia (BAH). Nine hundred and fifty-two consecutive patients received emergency multimodal computed tomography; magnetic resonance imaging and magnetic resonance angiogram during the period of January 2011 to December 2014 were included. The vascular risk factors, brainstem auditory evoked potential (BAEP), blink reflex (BR), transcranial Doppler (TCD) and dynamic susceptibility contrast-enhanced perfusion-weighted imaging were completed. There was significant difference in the abnormal rates of TCD and BAEP between BAH and non-BAH patients. A positive correlation between basilar artery diameter and systolic velocity among BAH patients was suggested. V-wave value was used to predict posterior circulation infarction (PCI) with the sensitivity of 0.933 and specificity of 0.50 with the cutoff value of 5.97 s. Abnormal BR rate was also significantly different in BAH and non-BAH patients. The latency of R2 was used to predict PCI with the sensitivity of 0.933 and specificity of 0.50 with the cutoff value of 46.4 ms. The incidence of hypoperfusion was higher in BAH than non-BAH group and it was significant difference. BAH is closely associated with hemodynamic alterations within the pons, which might contribute to vascular vertigo due to regional hypoperfusion.

Symmetricity analysis of time to peak parameter of indocyanine green dynamics

NASA Astrophysics Data System (ADS)

An, Yuri; Lee, Jungsul; Choi, Chulhee

2013-03-01

We have previously discovered that near-infrared optical imaging of indocyanine green (ICG) signal and analyzing its dynamics can be applied for measurement of blood perfusion rate and detection of Raynaud's phenomenon (RP). Especially, RP is closely associated with abnormal vasomotor responses and can progress to tissue necrosis due to excessively sustained vasoconstriction. Therefore, early detecting of RP is one of important implication to prevent tissue damage from peripheral vascular disorders. In the present study, we propose new analysis and scoring method of symmetricity of Tmax value of left and right extremities. Moreover, this symmetricity analysis can give further information about microvascular insufficiency. For validation of the proposed method, we tested whether the segmental and paired analysis of Tmax value (time-to-peak) of ICG dynamics can be used for sensitive diagnosis of microvascular abnormalities which cannot be detected by conventional methods. From the near-infrared images of diabetes mellitus patients with vascular complications, the trend of asymmetry in Tmax value was observed. We assumed that decreasing local blood perfusion by autonomic nerve dysfunction causes the asymmetric Tmax value of right and left feet. These results collectively indicate that the proposed method can be used as a useful diagnostic tool for RP or other microvascular disorders.

Placental Growth Factor Contributes to Micro-Vascular Abnormalization and Blood-Retinal Barrier Breakdown in Diabetic Retinopathy

PubMed Central

Kowalczuk, Laura; Touchard, Elodie; Omri, Samy; Jonet, Laurent; Klein, Christophe; Valamanes, Fatemeh; Berdugo, Marianne; Bigey, Pascal; Massin, Pascale; Jeanny, Jean-Claude; Behar-Cohen, Francine

2011-01-01

Objective There are controversies regarding the pro-angiogenic activity of placental growth factor (PGF) in diabetic retinopathy (DR). For a better understanding of its role on the retina, we have evaluated the effect of a sustained PGF over-expression in rat ocular media, using ciliary muscle electrotransfer (ET) of a plasmid encoding rat PGF-1 (pVAX2-rPGF-1). Materials and Methods pVAX2-rPGF-1 ET in the ciliary muscle (200 V/cm) was achieved in non diabetic and diabetic rat eyes. Control eyes received saline or naked plasmid ET. Clinical follow up was carried out over three months using slit lamp examination and fluorescein angiography. After the control of rPGF-1 expression, PGF-induced effects on retinal vasculature and on the blood-external barrier were evaluated respectively by lectin and occludin staining on flat-mounts. Ocular structures were visualized through histological analysis. Results After fifteen days of rPGF-1 over-expression in normal eyes, tortuous and dilated capillaries were observed. At one month, microaneurysms and moderate vascular sprouts were detected in mid retinal periphery in vivo and on retinal flat-mounts. At later stages, retinal pigmented epithelial cells demonstrated morphological abnormalities and junction ruptures. In diabetic retinas, PGF expression rose between 2 and 5 months, and, one month after ET, rPGF-1 over-expression induced glial activation and proliferation. Conclusion This is the first demonstration that sustained intraocular PGF production induces vascular and retinal changes similar to those observed in the early stages of diabetic retinopathy. PGF and its receptor Flt-1 may therefore be looked upon as a potential regulatory target at this stage of the disease. PMID:21408222

Autonomic nervous system profile in fibromyalgia patients and its modulation by exercise: a mini review.

PubMed

Kulshreshtha, Poorvi; Deepak, Kishore K

2013-03-01

This review imparts an impressionistic tone to our current understanding of autonomic nervous system abnormalities in fibromyalgia. In the wake of symptoms present in patients with fibromyalgia (FM), autonomic dysfunction seems plausible in fibromyalgia. A popular notion is that of a relentless sympathetic hyperactivity and hyporeactivity based on heart rate variability (HRV) analyses and responses to various physiological stimuli. However, some exactly opposite findings suggesting normal/hypersympathetic reactivity in patients with fibromyalgia do exist. This heterogeneous picture along with multiple comorbidities accounts for the quantitative and qualitative differences in the degree of dysautonomia present in patients with FM. We contend that HRV changes in fibromyalgia may not actually represent increased cardiac sympathetic tone. Normal muscle sympathetic nerve activity (MSNA) and normal autonomic reactivity tests in patients with fibromyalgia suggest defective vascular end organ in fibromyalgia. Previously, we proposed a model linking deconditioning with physical inactivity resulting from widespread pain in patients with fibromyalgia. Deconditioning also modulates the autonomic nervous system (high sympathetic tone and a low parasympathetic tone). A high peripheral sympathetic tone causes regional ischaemia, which in turn results in widespread pain. Thus, vascular dysregulation and hypoperfusion in patients with FM give rise to ischaemic pain leading to physical inactivity. Microvascular abnormalities are also found in patients with FM. Therapeutic interventions (e.g. exercise) that result in vasodilatation and favourable autonomic alterations have proven to be effective. In this review, we focus on the vascular end organ in patients with fibromyalgia in particular and its modulation by exercise in general. © 2012 The Authors Clinical Physiology and Functional Imaging © 2012 Scandinavian Society of Clinical Physiology and Nuclear Medicine.

BIANCA (Brain Intensity AbNormality Classification Algorithm): A new tool for automated segmentation of white matter hyperintensities.

PubMed

Griffanti, Ludovica; Zamboni, Giovanna; Khan, Aamira; Li, Linxin; Bonifacio, Guendalina; Sundaresan, Vaanathi; Schulz, Ursula G; Kuker, Wilhelm; Battaglini, Marco; Rothwell, Peter M; Jenkinson, Mark

2016-11-01

Reliable quantification of white matter hyperintensities of presumed vascular origin (WMHs) is increasingly needed, given the presence of these MRI findings in patients with several neurological and vascular disorders, as well as in elderly healthy subjects. We present BIANCA (Brain Intensity AbNormality Classification Algorithm), a fully automated, supervised method for WMH detection, based on the k-nearest neighbour (k-NN) algorithm. Relative to previous k-NN based segmentation methods, BIANCA offers different options for weighting the spatial information, local spatial intensity averaging, and different options for the choice of the number and location of the training points. BIANCA is multimodal and highly flexible so that the user can adapt the tool to their protocol and specific needs. We optimised and validated BIANCA on two datasets with different MRI protocols and patient populations (a "predominantly neurodegenerative" and a "predominantly vascular" cohort). BIANCA was first optimised on a subset of images for each dataset in terms of overlap and volumetric agreement with a manually segmented WMH mask. The correlation between the volumes extracted with BIANCA (using the optimised set of options), the volumes extracted from the manual masks and visual ratings showed that BIANCA is a valid alternative to manual segmentation. The optimised set of options was then applied to the whole cohorts and the resulting WMH volume estimates showed good correlations with visual ratings and with age. Finally, we performed a reproducibility test, to evaluate the robustness of BIANCA, and compared BIANCA performance against existing methods. Our findings suggest that BIANCA, which will be freely available as part of the FSL package, is a reliable method for automated WMH segmentation in large cross-sectional cohort studies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Post-mortem computed tomography angiography using left ventricle cardiac puncture: A whole-body, angiographic approach

PubMed Central

Li, Zhengdong; Liu, Ningguo; Huang, Ping; Zou, Donghua

2017-01-01

Post-mortem computed tomography (PMCT) and PMCT angiography (PMCTA) are rapidly becoming effective and practical methods in forensic medicine. In this article, the authors introduce a whole-body PMCTA approach involving left ventricle cardiac puncture. This procedure was performed in 9 males and 3 females. PMCT was performed first. Then a biopsy core needle was used for a percutaneous puncture into the left ventricle through the intercostal area under CT guidance. 1000 mL of contrast media (diatrizoate meglumine and normal saline [0.9%] at 1:2 ratio) was injected at a rate of 50 mL/8 s, followed by CT scan. Visualization of systemic arteries was achieved in 11 cases, while only partial visualization was achieved in 1 case, which may have been related to incomplete thawing of the cadaver. PMCTA results revealed no vascular diseases and abnormalities in 10 victims. Among the 10 victims, 4 post-scan autopsies were performed and found no vascular abnormalities, consistent with the PMCTA results. Autopsy of the other 6 victims were refused by the relatives. PMCTA revealed signs of internal carotid artery aneurysm inside the sphenoid sinus in one victim, which was confirmed by autopsy. PMCTA results of another victim showed signs of stenosis and blockage of the distal part of the right vertebral artery and basilar artery. Thromboembolism of those arteries was found during autopsy. Compared with other existing PMCTA methods for examination of vascular injuries and diseases, this technique involves simple procedures, is less time consuming, has lower associated costs, does not require specialized equipment, provides adequate imaging quality, and is suitable for centres not equipped with cardiopulmonary bypass machines or other specialized equipment. PMID:28827844

Adams-Oliver Syndrome with Unusual Central Nervous System Findings and an Extrahepatic Portosystemic Shunt

PubMed Central

Pérez-García, Carlos; Martín, Yolanda Ruíz; del Hoyo, Alejandra Aguado; Rodríguez, Carlos Marín; Domínguez, Minia Campos

2017-01-01

We report a case of a premature neonate girl with scalp and skull defects and brachydactyly of the feet consistent with an Adams-Oliver syndrome (AOS). The patient had central nervous system abnormalities, such as periventricular calcifications, hypoplastic corpus callosum, and bilateral hemispheric corticosubcortical hemorrhagic lesions. A muscular ventricular septal defect and a portosystemic shunt were diagnosed. To our knowledge, this is the first report of congenital supratentorial grey-white matter junction lesions without dural sinus thrombosis in association with AOS. Some of these lesions may be secondary to birth trauma (given the skull defect) whilst others have a watershed location, perhaps as further evidence of vascular disruption and decreased perfusion during critical periods of fetal brain development as the previously proposed pathogenesis of this syndrome. PMID:28706620

Cerebral vasculopathy after 4-bromo-2,5-dimethoxyphenethylamine ingestion.

PubMed

Ambrose, Josiah B; Bennett, Heather D; Lee, Han S; Josephson, S Andrew

2010-05-01

4-bromo-2,5-dimethoxyphenethylamine (2C-B) is a designer-drug variant of 3,4-methylenedioxymethamphetamine (ecstasy) whose recreational use has increased significantly over the last 10 years. Neurologic consequences of 2C-B usage are currently unknown. A 43-year-old woman experienced severe headaches within 48 hours of taking liquid 2C-B, after which time she developed progressive encephalopathy and quadraparesis, which did not improve over several months. MRA and cerebral angiogram imaging demonstrated profound vascular abnormalities of large, medium, and small-caliber vessels with subsequent watershed infarction. Brain biopsy and cerebrospinal fluid studies ruled out an inflammatory process. This case demonstrates an idiosyncratic and devastating neurologic response to 2C-B, a recreational drug whose popularity has increased with widespread availability of online guides for its synthesis.

Comprehensive vascular imaging using optical coherence tomography-based angiography and photoacoustic tomography

NASA Astrophysics Data System (ADS)

Zabihian, Behrooz; Chen, Zhe; Rank, Elisabet; Sinz, Christoph; Bonesi, Marco; Sattmann, Harald; Ensher, Jason; Minneman, Michael P.; Hoover, Erich; Weingast, Jessika; Ginner, Laurin; Leitgeb, Rainer; Kittler, Harald; Zhang, Edward; Beard, Paul; Drexler, Wolfgang; Liu, Mengyang

2016-09-01

Studies have proven the relationship between cutaneous vasculature abnormalities and dermatological disorders, but to image vasculature noninvasively in vivo, advanced optical imaging techniques are required. In this study, we imaged a palm of a healthy volunteer and three subjects with cutaneous abnormalities with photoacoustic tomography (PAT) and optical coherence tomography with angiography extension (OCTA). Capillaries in the papillary dermis that are too small to be discerned with PAT are visualized with OCTA. From our results, we speculate that the PA signal from the palm is mostly from hemoglobin in capillaries rather than melanin, knowing that melanin concentration in volar skin is significantly smaller than that in other areas of the skin. We present for the first time OCTA images of capillaries along with the PAT images of the deeper vessels, demonstrating the complementary effective imaging depth range and the visualization capabilities of PAT and OCTA for imaging human skin in vivo. The proposed imaging system in this study could significantly improve treatment monitoring of dermatological diseases associated with cutaneous vasculature abnormalities.

VEGF and VEGFB Play Balancing Roles in Adipose Differentiation, Gene Expression, and Function.

PubMed

Jin, Honghong; Li, Dan; Wang, Xutong; Jia, Jia; Chen, Yang; Yao, Yapeng; Zhao, Chunlan; Lu, Xiaodan; Zhang, Shujie; Togo, Jacques; Ji, Yan; Zhang, Luqing; Feng, Xuechao; Zheng, Yaowu

2018-05-01

Obesity is the result of abnormal adipose development and energy metabolism. Using vascular endothelial growth factor (VEGF) B-knockout and inducible VEGF downregulation mouse models, we have shown that VEGFB inactivation caused expansion of white adipose, whitening of brown adipose, an increase in fat accumulation, and a reduction in energy consumption. At the same time, expression of the white adipose-associated genes was increased and brown adipose-associated genes decreased. VEGF repression, in contrast, induced brown adipose expansion and brown adipocyte development in white adipose, increased energy expenditure, upregulated brown adipose-associated genes, and downregulated white adipose-associated genes. When VEGFB-knockout and VEGF-repressed mice are crossed together, VEGF and VEGFB can counteractively regulate large numbers of genes and efficiently reverse each other's roles. These genes, under counteractive VEGF and VEGFB regulations, include transcription factors, adhesion molecules, and metabolic enzymes. This balancing role is confirmed by morphologic and functional changes. This study reports that VEGF and VEGFB counteractively regulate adipose development and function in energy metabolism.

Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain

PubMed Central

Lumniczky, Katalin; Szatmári, Tünde; Sáfrány, Géza

2017-01-01

Radiation-induced late brain injury consisting of vascular abnormalities, demyelination, white matter necrosis, and cognitive impairment has been described in patients subjected to cranial radiotherapy for brain tumors. Accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well. The pathophysiological mechanisms underlying these alterations are not elucidated so far. A permanent deficit in neurogenesis, chronic microvascular alterations, and blood–brain barrier dysfunctionality are considered among the main causative factors. Chronic neuroinflammation and altered immune reactions in the brain, which are inherent complications of brain irradiation, have also been directly implicated in the development of cognitive decline after radiation. This review aims to give a comprehensive overview on radiation-induced immune alterations and inflammatory reactions in the brain and summarizes how these processes can influence cognitive performance. The available data on the risk of low-dose radiation exposure in the development of cognitive impairment and the underlying mechanisms are also discussed. PMID:28529513

Melatonin prevents retinal oxidative stress and vascular changes in diabetic rats

PubMed Central

Özdemir, G; Ergün, Y; Bakariş, S; Kılınç, M; Durdu, H; Ganiyusufoğlu, E

2014-01-01

Purpose To evaluate the role of melatonin, an antioxidant agent, in diabetic oxidative stress and vascular damage. Methods Diabetes was induced in 21 male Wistar rats by intraperitoneal (IP) administration of streptozotocin and then the rats were equally and randomly allocated to diabetic, melatonin, and vehicle groups. Seven healthy normal rats with similar features comprised the control group as the fourth group. All animals were followed for 12 weeks. The melatonin group received IP melatonin daily and the vehicle group received 2.5% ethanol IP at the last month. At the end of 12 weeks, the rats were killed and retinas were harvested. The retinas were investigated for the existence of hypoxia-inducible factor 1-α (HIF-1α), vascular endothelial growth factor A (VEGF-A), and pigment epithelium-derived factor (PEDF) by ELISA. Retinal oxidative stress is quantitated by measuring nitrotyrosine and malondialdehyde levels. Retinal immunohistochemistry with antibody against CD31 antigen was carried out on retinal cross-sections. For statistics, ANOVA test was used for multiple comparisons. Results Hyperglycemia increased retinal oxidation as measured through levels of nitrotyrosine and malondialdehyde. Diabetic retinas are also associated with abnormal vascular changes such as dilatation and deformation. HIF-1α, VEGF-A, and PEDF were all increased because of diabetic injury. Melatonin showed a potential beneficial effect on retinopathy in diabetic rats. It decreased retinal nitrotyrosine and malondialdehyde levels, showing an antioxidative support. The vasculomodulator cytokines are decreased accordingly by melatonin therapy. Melatonin normalized retinal vascular changes as well. Conclusion Melatonin may show some advantage on diabetic vascular changes through decreasing oxidative stress and vessel-related cytokines. PMID:24924441

Myocardial infarction with Moyamoya disease and pituitary gigantism in a young female patient.

PubMed

Ahn, Y K; Jeong, M H; Bom, H S; Park, J C; Kim, J K; Chung, D J; Chung, M Y; Cho, J G; Kang, J C

1999-08-01

Myocardial infarction is very rare in young female patients with systemic vascular disorders. Moyamoya disease is a cerebrovascular disease associated with an abnormal vascular network. This report presents a 19-year-old female patient who suffered from chest pain and exertional dyspnea for 2 months prior to admission. She had a history of Moyamoya disease and pituitary gigantism since childhood. Her ejection fraction on echocardiogram was 20% and a perfusion defect with partial reversibility in the anterior wall was demonstrated on stress single photon emission computed tomography (SPECT). Diagnostic coronary angiogram revealed critical stenosis in the middle left anterior descending artery, which was treated by coronary stenting. Her subjective symptoms were relieved and the perfusion defect seen on SPECT decreased after coronary intervention.

Vascular normalization as an emerging strategy to enhance cancer immunotherapy.

PubMed

Huang, Yuhui; Goel, Shom; Duda, Dan G; Fukumura, Dai; Jain, Rakesh K

2013-05-15

The recent approval of Provenge has brought new hope for anticancer vaccine therapies. However, the immunosuppressive tumor microenvironment seems to impair the efficacy of vaccine therapies. The abnormal tumor vasculature creates a hypoxic microenvironment that polarizes inflammatory cells toward immune suppression. Moreover, tumors systemically alter immune cells' proliferation, differentiation, and function via secretion of growth factors and cytokines. For example, VEGF, a major proangiogenic cytokine induced by hypoxia, plays a critical role in immunosuppression via these mechanisms. Hence, antiangiogenic treatment may be an effective modality to potentiate immunotherapy. Here, we discuss the local and systemic effects of VEGF on tumor immunity and propose a potentially translatable strategy to re-engineer the tumor-immune microenvironment and improve cancer immunotherapy by using lower "vascular normalizing" doses of antiangiogenic agents. ©2013 AACR.

The role of contrast-enhanced ultrasound in imaging carotid arterial diseases.

PubMed

Clevert, Dirk A; Paprottka, Philipp; Sommer, Wieland H; Helck, Andreas; Reiser, Maximilian F; Zengel, Pamela

2013-06-01

The standard of care for the initial diagnosis of carotid artery bifurcation diseases is carotid duplex ultrasound. Carotid abnormalities or difficult examinations may represent a diagnostic challenge in patients with clinical symptoms as well as in the follow-up after carotid endarterectomy, carotid artery stenting or other interventions. A promising new method in the diagnosis and follow-up of pathologic carotid diseases is contrast-enhanced ultrasound (CEUS). In comparison with magnetic resonance imaging or computed tomography, the contrast agents used for CEUS remain within the vascular space and hence can be used to study vascular disease and could provide additional information on carotid arterial diseases. This review describes the current carotid duplex ultrasound examination and compares the pathologic findings with CEUS. Copyright © 2013 Elsevier Inc. All rights reserved.

The 7q11.23 Microduplication Syndrome: A Clinical Report with Review of Literature

PubMed Central

Abbas, Elham; Cox, Devin M.; Smith, Teri; Butler, Merlin G.

2016-01-01

We report a 14-year-old adolescent girl with selective mutism (SM) and a 7q11.23 microduplication detected by chromosomal microarray (CMA) analysis and reviewed the literature from 18 published clinical reports. Our patient had specific phobias, SM, extreme anxiety, obesity, cutis marmorata, and a round appearing face with a short neck and over folded ears. We reviewed the published clinical, cognitive, behavioral, and cytogenetic findings grouped by speech and language delay, growth and development, craniofacial, clinical, and behavior and cognitive features due to the 7q11.23 microduplication. This microduplication syndrome is characterized by speech delay (91%), social anxiety (42%), attention deficit hyperactivity disorder (ADHD, 37%), autism spectrum disorder (29%), and separation anxiety (13%). Other findings include abnormal brain imaging (80%), congenital heart and vascular defects (54%), and mild intellectual disability (38%). We then compared the phenotype with Williams–Beuren syndrome (WBS) which is due to a deletion of the same chromosome region. Both syndromes have abnormal brain imaging, hypotonia, delayed motor development, joint laxity, mild intellectual disability, ADHD, autism, and poor visuospatial skills but opposite or dissimilar findings regarding speech and behavioral patterns, cardiovascular problems, and social interaction. Those with WBS are prone to have hyperverbal speech, lack of stranger anxiety, and supravalvular aortic stenosis while those with the 7q11.23 microduplication have speech delay, SM, social anxiety, and are prone to aortic dilatation. PMID:27617154

Video-rate resonant scanning multiphoton microscopy

PubMed Central

Kirkpatrick, Nathaniel D.; Chung, Euiheon; Cook, Daniel C.; Han, Xiaoxing; Gruionu, Gabriel; Liao, Shan; Munn, Lance L.; Padera, Timothy P.; Fukumura, Dai; Jain, Rakesh K.

2013-01-01

The abnormal tumor microenvironment fuels tumor progression, metastasis, immune suppression, and treatment resistance. Over last several decades, developments in and applications of intravital microscopy have provided unprecedented insights into the dynamics of the tumor microenvironment. In particular, intravital multiphoton microscopy has revealed the abnormal structure and function of tumor-associated blood and lymphatic vessels, the role of aberrant tumor matrix in drug delivery, invasion and metastasis of tumor cells, the dynamics of immune cell trafficking to and within tumors, and gene expression in tumors. However, traditional multiphoton microscopy suffers from inherently slow imaging rates—only a few frames per second, thus unable to capture more rapid events such as blood flow, lymphatic flow, and cell movement within vessels. Here, we report the development and implementation of a video-rate multiphoton microscope (VR-MPLSM) based on resonant galvanometer mirror scanning that is capable of recording at 30 frames per second and acquiring intravital multispectral images. We show that the design of the system can be readily implemented and is adaptable to various experimental models. As examples, we demonstrate the utility of the system to directly measure flow within tumors, capture metastatic cancer cells moving within the brain vasculature and cells in lymphatic vessels, and image acute responses to changes in a vascular network. VR-MPLSM thus has the potential to further advance intravital imaging and provide new insight into the biology of the tumor microenvironment. PMID:24353926

The 7q11.23 Microduplication Syndrome: A Clinical Report with Review of Literature.

PubMed

Abbas, Elham; Cox, Devin M; Smith, Teri; Butler, Merlin G

2016-09-01

We report a 14-year-old adolescent girl with selective mutism (SM) and a 7q11.23 microduplication detected by chromosomal microarray (CMA) analysis and reviewed the literature from 18 published clinical reports. Our patient had specific phobias, SM, extreme anxiety, obesity, cutis marmorata, and a round appearing face with a short neck and over folded ears. We reviewed the published clinical, cognitive, behavioral, and cytogenetic findings grouped by speech and language delay, growth and development, craniofacial, clinical, and behavior and cognitive features due to the 7q11.23 microduplication. This microduplication syndrome is characterized by speech delay (91%), social anxiety (42%), attention deficit hyperactivity disorder (ADHD, 37%), autism spectrum disorder (29%), and separation anxiety (13%). Other findings include abnormal brain imaging (80%), congenital heart and vascular defects (54%), and mild intellectual disability (38%). We then compared the phenotype with Williams-Beuren syndrome (WBS) which is due to a deletion of the same chromosome region. Both syndromes have abnormal brain imaging, hypotonia, delayed motor development, joint laxity, mild intellectual disability, ADHD, autism, and poor visuospatial skills but opposite or dissimilar findings regarding speech and behavioral patterns, cardiovascular problems, and social interaction. Those with WBS are prone to have hyperverbal speech, lack of stranger anxiety, and supravalvular aortic stenosis while those with the 7q11.23 microduplication have speech delay, SM, social anxiety, and are prone to aortic dilatation.

The cardiovascular system in growth hormone excess and growth hormone deficiency.

PubMed

Lombardi, G; Di Somma, C; Grasso, L F S; Savanelli, M C; Colao, A; Pivonello, R

2012-12-01

The clinical conditions associated with GH excess and GH deficiency (GHD) are known to be associated with an increased risk for the cardiovascular morbidity and mortality, suggesting that either an excess or a deficiency in GH and/or IGF-I is deleterious for cardiovascular system. In patients with acromegaly, chronic GH and IGF-I excess commonly causes a specific cardiomyopathy characterized by a concentric cardiac hypertrophy associated with diastolic dysfunction and, in later stages, with systolic dysfunction ending in heart failure if GH/IGF-I excess is not controlled. Abnormalities of cardiac rhythm and anomalies of cardiac valves can also occur. Moreover, the increased prevalence of cardiovascular risk factors, such as hypertension, diabetes mellitus, and insulin resistance, as well as dyslipidemia, confer an increased risk for vascular atherosclerosis. Successful control of the disease is accompanied by a decrease of the cardiac mass and improvement of cardiac function and an improvement in cardiovascular risk factors. In patients with hypopituitarism, GHD has been considered the under- lying factor of the increased mortality when appropriate standard replacement of the pituitary hormones deficiencies is given. Either childhood-onset or adulthood-onset GHD are characterized by a cluster of abnormalities associated with an increased cardiovascular risk, including altered body composition, unfavorable lipid profile, insulin resistance, endothelial dysfunction and vascular atherosclerosis, a decrease in cardiac mass together with an impairment of systolic function mainly after exercise. Treatment with recombinant GH in patients with GHD is followed by an improvement of the cardiovascular risk factors and an increase in cardiac mass together with an improvement in cardiac performance. In conclusion, acromegaly and GHD are associated with an increased risk for cardiovascular morbidity and mortality, but the control of GH/IGF-I secretion reverses cardiovascular abnormalities and restores the normal life expectancy.

Arterial Wall Imaging in Pediatric Stroke.

PubMed

Dlamini, Nomazulu; Yau, Ivanna; Muthusami, Prakash; Mikulis, David J; Elbers, Jorina; Slim, Mahmoud; Askalan, Rand; MacGregor, Daune; deVeber, Gabrielle; Shroff, Manohar; Moharir, Mahendranath

2018-04-01

Arteriopathy is common in childhood arterial ischemic stroke (AIS) and predicts stroke recurrence. Currently available vascular imaging techniques mainly image the arterial lumen rather than the vessel wall and have a limited ability to differentiate among common arteriopathies. We aimed to investigate the value of a magnetic resonance imaging-based technique, namely noninvasive arterial wall imaging (AWI), for distinguishing among arteriopathy subtypes in a consecutive cohort of children presenting with AIS. Children with confirmed AIS and magnetic resonance angiography underwent 3-Tesla AWI including T1-weighted 2-dimensional fluid-attenuated inversion recovery fast spin echo sequences pre- and post-gadolinium contrast. AWI characteristics, including wall enhancement, wall thickening, and luminal stenosis, were documented for all. Twenty-six children with AIS had AWI. Of these, 9 (35%) had AWI enhancement. AWI enhancement was associated with anterior circulation magnetic resonance angiography abnormality and cortical infarction in 8 of 9 (89%) children and normal magnetic resonance angiography with posterior circulation subcortical infarction in 1 (1 of 9; 11%) child. AWI enhancement was not seen in 17 (65%), 10 (59%) of whom had an abnormal magnetic resonance angiography. Distinct patterns of pre- and postcontrast signal abnormality were demonstrated in the vessel wall in the region of interest in children with transient cerebral arteriopathy, arterial dissection, primary central nervous system angiitis, dissecting aneurysm, and cardioembolic stroke. AWI is a noninvasive, high-resolution magnetic resonance AWI technique, which can be successfully used in children presenting with AIS. Patterns of AWI enhancement are recognizable and associated with specific AIS pathogeneses. Further studies are required to assess the additional diagnostic utility of AWI over routine vascular imaging techniques, in childhood AIS. © 2018 American Heart Association, Inc.

Alterations of the tunica vasculosa lentis in the rat model of retinopathy of prematurity.

PubMed

Favazza, Tara L; Tanimoto, Naoyuki; Munro, Robert J; Beck, Susanne C; Garcia Garrido, Marina; Seide, Christina; Sothilingam, Vithiyanjali; Hansen, Ronald M; Fulton, Anne B; Seeliger, Mathias W; Akula, James D

2013-08-01

To study the relationship between retinal and tunica vasculosa lentis (TVL) disease in retinopathy of prematurity (ROP). Although the clinical hallmark of ROP is abnormal retinal blood vessels, the vessels of the anterior segment, including the TVL, are also altered. ROP was induced in Long-Evans pigmented and Sprague Dawley albino rats; room-air-reared (RAR) rats served as controls. Then, fluorescein angiographic images of the TVL and retinal vessels were serially obtained with a scanning laser ophthalmoscope near the height of retinal vascular disease, ~20 days of age, and again at 30 and 64 days of age. Additionally, electroretinograms (ERGs) were obtained prior to the first imaging session. The TVL images were analyzed for percent coverage of the posterior lens. The tortuosity of the retinal arterioles was determined using Retinal Image multiScale Analysis (Gelman et al. in Invest Ophthalmol Vis Sci 46:4734-4738, 2005). In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30 days, the TVL in RAR rats had almost fully regressed, while in ROP rats, it was still pronounced. By the final test age, the TVL had completely regressed in both ROP and RAR rats. In parallel, the tortuous retinal arterioles in ROP rats resolved with increasing age. ERG components indicating postreceptoral dysfunction, the b-wave, and oscillatory potentials were attenuated in ROP rats. These findings underscore the retinal vascular abnormalities and, for the first time, show abnormal anterior segment vasculature in the rat model of ROP. There is delayed regression of the TVL in the rat model of ROP. This demonstrates that ROP is a disease of the whole eye.

Alterations of the Tunica Vasculosa Lentis in the Rat Model of Retinopathy of Prematurity

PubMed Central

Favazza, Tara L; Tanimoto, Naoyuki; Munro, Robert J.; Beck, Susanne C.; Garrido, Marina G.; Seide, Christina; Sothilingam, Vithiyanjali; Hansen, Ronald M.; Fulton, Anne B.; Seeliger, Mathias W.; Akula, James D

2013-01-01

Purpose To study the relation between retinal and tunica vasculosa lentis (TVL) disease in ROP. Although the clinical hallmark of retinopathy of prematurity (ROP) is abnormal retinal blood vessels, the vessels of the anterior segment, including the TVL, are also altered. Methods ROP was induced in Long Evans pigmented and Sprague-Dawley albino rats; room-air-reared (RAR) rats served as controls. Then, fluorescein angiographic images of the TVL and retinal vessels were serially obtained with a scanning laser ophthalmoscope (SLO) near the height of retinal vascular disease, ∼20 days-of-age, and again at 30 and 64 days-of-age. Additionally, electroretinograms (ERGs) were obtained prior to the first imaging session. The TVL images were analyzed for percent coverage of the posterior lens. The tortuosity of the retinal arterioles was determined using Retinal Image multiScale Analysis (RISA; Gelman et al., 2005). Results In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30 days, the TVL in RAR rats had almost fully regressed, while in ROP rats it was still pronounced. By the final test age, the TVL had completely regressed in both ROP and RAR rats. In parallel, the tortuous retinal arterioles in ROP rats resolved with increasing age. ERG components indicating postreceptoral dysfunction, the b-wave and oscillatory potentials (OPs), were attenuated in ROP rats. Conclusions These findings underscore the retinal vascular abnormalities and, for the first time, show abnormal anterior segment vasculature in the rat model of ROP. There is delayed regression of the TVL in the rat model of ROP. This demonstrates that ROP is a disease of the whole eye. PMID:23748796

Benign paroxysmal vertigo of childhood: diagnostic value of vestibular test and high stimulus rate auditory brainstem response test.

PubMed

Zhang, Daogong; Fan, Zhaomin; Han, Yuechen; Wang, Mingming; Xu, Lei; Luo, Jianfen; Ai, Yu; Wang, Haibo

2012-01-01

To investigate the diagnostic value of vestibular test and high stimulus rate auditory brainstem response (ABR) test and the possible mechanism responsible for benign paroxysmal vertigo of childhood (BPVC). Data of 56 patients with BPVC in vertigo clinic of our hospital from May 2007 to September 2008 were retrospectively analyzed in this study. Patients with BPVC were tested with pure tone audiometry, high stimulus rate auditory brainstem response test (ABR), transcranial Doppler sonography (TCD), bithermal caloric test, and VEMP. The results of the hearing and vestibular function test were compared and analyzed. There were 56 patients with BPVC, including 32 men, 24 women, aged 3-12 years old, with an average of 6.5 years. Among 56 cases of BPVC patients, the results of pure tone audiometry were all normal. High stimulus rate ABR was abnormal in 66.1% (37/56) of cases. TCD showed 57.1% abnormality in 56 cases, including faster flow rate in 28 cases and slower flow rate in 4 cases. High stimulus rate ABR and TCD were both abnormal in 48.2% (27/56) of cases. Bithermal caloric test was abnormal in 14.3% (8/56) of cases. VEMP showed 32.1% abnormality, including amplitude abnormality in 16 cases and latency abnormality in 2 cases. The abnormal rate of VEMP was much higher than that of caloric test. Vascular mechanisms might be involved in the pathogenesis of BPVC and there is strong evidence for close relationship between BPVC and migraine. High stimulus rate ABR is helpful in the diagnosis of BPVC. The inferior vestibular pathway is much more impaired than the superior vestibular pathway in BPVC. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Right ventricular pressure response to exercise in adults with isolated ventricular septal defect closed in early childhood.

PubMed

Moller, Thomas; Lindberg, Harald; Lund, May Brit; Holmstrom, Henrik; Dohlen, Gaute; Thaulow, Erik

2018-06-01

We previously demonstrated an abnormally high right ventricular systolic pressure response to exercise in 50% of adolescents operated on for isolated ventricular septal defect. The present study investigated the prevalence of abnormal right ventricular systolic pressure response in 20 adult (age 30-45 years) patients who underwent surgery for early ventricular septal defect closure and its association with impaired ventricular function, pulmonary function, or exercise capacity. The patients underwent cardiopulmonary tests, including exercise stress echocardiography. Five of 19 patients (26%) presented an abnormal right ventricular systolic pressure response to exercise ⩾ 52 mmHg. Right ventricular systolic function was mixed, with normal tricuspid annular plane systolic excursion and fractional area change, but abnormal tricuspid annular systolic motion velocity (median 6.7 cm/second) and isovolumetric acceleration (median 0.8 m/second2). Left ventricular systolic and diastolic function was normal at rest as measured by the peak systolic velocity of the lateral wall and isovolumic acceleration, early diastolic velocity, and ratio of early diastolic flow to tissue velocity, except for ejection fraction (median 53%). The myocardial performance index was abnormal for both the left and right ventricle. Peak oxygen uptake was normal (mean z score -0.4, 95% CI -2.8-0.3). There was no association between an abnormal right ventricular systolic pressure response during exercise and right or left ventricular function, pulmonary function, or exercise capacity. Abnormal right ventricular pressure response is not more frequent in adult patients compared with adolescents. This does not support the theory of progressive pulmonary vascular disease following closure of left-to-right shunts.

[Effects of different oxygen inhalation modes on retinal vessels development in neonatal mice].

PubMed

Wang, Yu-Huan; Chen, Chao; Shi, Wen-Jing; Xiao, Hong-Lei; Tong, Bei-Yan; Zhou, Guo-Min

2006-04-01

This study was designed to investigate the effects of different oxygen inhalation modes on retinal vessels development in neonatal mice in order to provide experimental data for proper oxygen therapy for premature infants. A total of 144 postnatal day (P) 7 C57BL/6J mice were randomly assigned into 6 groups according to different oxygen inhalation modes (n=24). Experimental group 1 was exposed to 30%, 40%, 50%, 60% and 75% oxygen in turn for one day respectively, followed by room air exposure for 5 days. Experimental group 2 was exposed to 75%, 60%, 50%, 40% and 30% oxygen in turn for one day respectively, followed by room air exposure for 5 days. Experimental group 3 was exposed to 75% oxygen for 5 days, followed by room air exposure for 5 days. Experimental group 4 was exposed to 75% oxygen for 5 days, 50% oxygen for 2 days and 30% oxygen for 2 days, then room air exposure for 6 days. The supplemental 75% oxygen and room air recovering was performed alternately for the mice in Experimental group 5 for 3 times and then room air exposure for 5 days. The Control group was exposed to room air for consecutive 10 days. The retinal vascular development and proliferation were evaluated by the retinal flat-mounts (ADPase stained retina) and cross-section. The peripheral vascular pattern was clear, and a few avascular areas were seen in the Control group at P12. At P14 the avascular area disappeared. At P17, the entire vascular pattern became completely normal. In the Experimental groups 1, 3 and 5, the central vessels became tortuous and constricted and the central avascular area increased at P12. At P14, neovascularization was seen peaking at P17 in the Experimental groups 1, 3 and 5. In the Experimental group 4, the central avascular area increased and neovascularization was seen at P14, but the central avascular area was reduced and abnormal neovascularization disappeared, with slight constriction of the deep vessels, at P17. Five days later the vascular pattern became almost normal in the Experimental group 4. The retinal vascular form of the Experimental group 2 was similar to that of the Control group. The average number of neovascular nuclei extending into the vitreous per cross-section in the Experimental groups 1, 2, 3, 4, and 5 and the Control group was 49.50 +/- 1.36, 5.17 +/- 0.67, 47.68 +/- 4.70, 5.74 +/- 2.37, 29.15 +/- 2.48, and 1.22 +/- 0.20 respectively. There were significant differences between the Experimental groups 1, 3, 5 and the Control group (P < 0.05). The effects of different oxygen inhalation modes on the retinal vessels development in neonatal mice were different. The obvious fluctuation of inhaled oxygen concentration and abrupt stop of supplemental oxygen after high levels of supplemental oxygen may severely affect the development of retina vascular, leading to the pathologic changes similar to retinopathy of prematurity.

Inhibitory Effects of Hydrogen on Proliferation and Migration of Vascular Smooth Muscle Cells via Down-Regulation of Mitogen/Activated Protein Kinase and Ezrin-Radixin-Moesin Signaling Pathways.

PubMed

Zhang, Ya-Xing; Xu, Jing-Ting; You, Xin-Chao; Wang, Chen; Zhou, Ke-Wen; Li, Ping; Sun, Peng; Wang, Ling; Wang, Ting-Huai

2016-02-29

Molecular hydrogen (H₂) has recently attracted considerable attention for the prevention of oxidative stress-related vascular diseases. The purpose of this study is to evaluate the effects of hydrogen on proliferation and migration of vascular smooth muscle cells (VSMCs) stimulated by angiotensin II (Ang II) in vitro, and on vascular hypertrophy induced by abdominal aortic coarctation (AAC) in vivo. Hydrogen-rich medium (0.6~0.9 ppm) was added 30 min before 10⁻⁷ M Ang II administration, then the proliferation and migration index were determined 24 h after Ang II stimulation. Hydrogen gas (99.999%) was given by intraperitoneal injection at the dose of 1 ml/100 g/day consecutively for one week before AAC and lasted for 6 weeks in vivo. Hydrogen inhibited proliferation and migration of VSMCs with Ang II stimulation in vitro, and improved the vascular hypertrophy induced by AAC in vivo. Treatment with hydrogen reduced Ang II- or AAC-induced oxidative stress, which was reflected by diminishing the induction of reactive oxygen species (ROS) in Ang II-stimulated VSMCs, inhibiting the levels of 3-nitrotyrosine (3-NT) in vascular and serum malondialdehyde (MDA). Hydrogen treatment also blocked Ang II-induced phosphorylation of the extracellular signal-regulated kinase1/2 (ERK1/2), p38 MAPK, c-Jun NH₂-terminal kinase (JNK) and the ezrin/radixin/moesin (ERM) in vitro. Taken together, our studies indicate that hydrogen prevents AAC-induced vascular hypertrophy in vivo, and inhibits Ang II-induced proliferation and migration of VSMCs in vitro possibly by targeting ROS-dependent ERK1/2, p38 MAPK, JNK and ERM signaling. It provides the molecular basis of hydrogen on inhibiting the abnormal proliferation and migration of VSMCs and improving vascular remodeling diseases.

Flow effects of blood constitutive equations in 3D models of vascular anomalies

NASA Astrophysics Data System (ADS)

Neofytou, Panagiotis; Tsangaris, Sokrates

2006-06-01

The effects of different blood rheological models are investigated numerically utilizing two three- dimensional (3D) models of vascular anomalies, namely a stenosis and an abdominal aortic aneurysm model. The employed CFD code incorporates the SIMPLE scheme in conjunction with the finite-volume method with collocated arrangement of variables. The approximation of the convection terms is carried out using the QUICK differencing scheme, whereas the code enables also multi-block computations, which are useful in order to cope with the two-block grid structure of the current computational domain. Three non-Newtonian models are employed, namely the Casson, Power-Law and Quemada models, which have been introduced in the past for modelling the rheological behaviour of blood and cover both the viscous as well as the two-phase character of blood. In view of the haemodynamical mechanisms related to abnormalities in the vascular network and the role of the wall shear stress in initiating and further developing of arterial diseases, the present study focuses on the 3D flow field and in particular on the distribution as well as on both low and high values of the wall shear stress in the vicinity of the anomaly. Finally, a comparison is made between the effects of each rheological model on the aforementioned parameters. Results show marked differences between simulating blood as Newtonian and non-Newtonian fluid and furthermore the Power-Law model exhibits different behaviour in all cases compared to the other models whereas Quemada and Casson models exhibit similar behaviour in the case of the stenosis but different behaviour in the case of the aneurysm.

Tumoral micro-blood vessels and vascular microenvironment in human astrocytic tumors. A transmission electron microscopy study.

PubMed

Arismendi-Morillo, Gabriel; Castellano, Alan

2005-07-01

The development of peritumoral edema is thought to be due to extravasation of plasma water and macromolecules through a defective blood-brain barrier (BBB), but the exact mechanism by which occurs is poorly understood. The aim of this study was analyze at submicroscopic level the morphological changes in both micro-blood vessels and vascular microenvironment of astrocytic tumors in an attempt of understanding the pathological aspects that may help in the future researches for the design of future therapeutic strategies. Biopsies of 25 patients with pathological diagnosis of astrocytic tumors were examined with the transmission electron microscope. Both open and close tight junctions were observed in the micro-blood vessels, inclusive in a same tumor. Cytoskeletal disorganization associated with disintegrated perijunctional actin filaments were seen. The paracellular space showed enlargement and commonly occupied by fluid proteinaceous, endothelial cells display oncotic and ischemic changes, basal lamina reveals enlargement, edema, vacuolization and collagen fibers disposed in irregular array. Pericytes exhibited edema and phagocytoced material, astrocytic perivascular-feet showed signs of oncosis and necrosis, co-option vessels totally surrounding by neoplastic cells also were seen. The ultrastructural abnormalities observed in both junctional complexes and vascular microenvironment suggest a multi-factorial pathobiology process, probably hypoxia intratumoral, calcium overload in endothelial cells, and degradative effects of metalloproteinases over the basal membrane appear as determinant factors that leading to structural modifications of junctional complexes, therefore, treatment with both HIF-1alpha and metalloproteinases inhibitors possibly can contribute with the pharmacological handling of the peritumoral edema associated with astrocytic tumors.

Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep

PubMed Central

Seedorf, Gregory J.; Brown, Alicia; Roe, Gates; O'Meara, Meghan C.; Gien, Jason; Tang, Jen-Ruey; Abman, Steven H.

2011-01-01

Intrauterine growth restriction (IUGR) increases the risk for bronchopulmonary dysplasia (BPD). Abnormal lung structure has been noted in animal models of IUGR, but whether IUGR adversely impacts fetal pulmonary vascular development and pulmonary artery endothelial cell (PAEC) function is unknown. We hypothesized that IUGR would decrease fetal pulmonary alveolarization, vascular growth, and in vitro PAEC function. Studies were performed in an established model of severe placental insufficiency and IUGR induced by exposing pregnant sheep to elevated temperatures. Alveolarization, quantified by radial alveolar counts, was decreased 20% (P < 0.005) in IUGR fetuses. Pulmonary vessel density was decreased 44% (P < 0.01) in IUGR fetuses. In vitro, insulin increased control PAEC migration, tube formation, and nitric oxide (NO) production. This response was absent in IUGR PAECs. VEGFA stimulated tube formation, and NO production also was absent. In control PAECs, insulin increased cell growth by 68% (P < 0.0001). Cell growth was reduced in IUGR PAECs by 29% at baseline (P < 0.01), and the response to insulin was attenuated (P < 0.005). Despite increased basal and insulin-stimulated Akt phosphorylation in IUGR PAECs, endothelial NO synthase (eNOS) protein expression as well as basal and insulin-stimulated eNOS phosphorylation were decreased in IUGR PAECs. Both VEGFA and VEGFR2 also were decreased in IUGR PAECs. We conclude that fetuses with IUGR are characterized by decreased alveolar and vascular growth and PAEC dysfunction in vitro. This may contribute to the increased risk for adverse respiratory outcomes and BPD in infants with IUGR. PMID:21873446

Rapid prototyping to create vascular replicas from CT scan data: making tools to teach, rehearse, and choose treatment strategies.

PubMed

Knox, K; Kerber, Charles W; Singel, S A; Bailey, M J; Imbesi, S G

2005-05-01

Our goal was to develop and prove the accuracy of a system that would allow us to re-create live patient arterial pathology. Anatomically accurate replicas of blood vessels could allow physicians to teach and practice dangerous interventional techniques and might also be used to gather basic physiologic information. The preparation of replicas has, until now, depended on acquisition of fresh cadaver material. Using rapid prototyping, it should be able to replicate vascular pathology in a live patient. We obtained CT angiographic scan data from two patients with known arterial abnormalities. We took such data and, using proprietary software, created a 3D replica using a commercially available rapid prototyping machine. From the prototypes, using a lost wax technique, we created vessel replicas, placed those replicas in the CT scanner, then compared those images with the original scans. Comparison of the images made directly from the patient and from the replica showed that with each step, the relationships were maintained, remaining within 3% of the original, but some smoothing occurred in the final computer manipulation. From routinely obtainable CT angiographic data, it is possible to create accurate replicas of human vascular pathology with the aid of commercially available stereolithography equipment. Visual analysis of the images appeared to be as important as the measurements. With 64 and 128 slice detector scanners becoming available, acquisition times fall enough that we should be able to model rapidly moving structures such as the aortic root. (c) 2005 Wiley-Liss, Inc.

Levels of Nonphosphorylated and Phosphorylated Tau in Cerebrospinal Fluid of Alzheimer’s Disease Patients

PubMed Central

Hu, Yuan Yuan; He, Shan Shu; Wang, Xiaochuan; Duan, Qiu Hong; Grundke-Iqbal, Inge; Iqbal, Khalid; Wang, Jianzhi

2002-01-01

We have developed an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay for the measurement of Alzheimer’s disease (AD) abnormally hyperphosphorylated tau in cerebrospinal fluid (CSF). The assay, which recognizes attomolar amounts of tau, is ∼400 and ∼1300 times more sensitive than conventional enzyme-linked immunosorbent assay in determining the hyperphosphorylated tau and total tau, respectively. With this method, we measured both total tau and tau phosphorylated at Ser-396/Ser-404 in lumbar CSFs from AD and control patients. We found that the total tau was 215 ± 77 pg/ml in cognitively normal control (n = 56), 234 ± 92 pg/ml in non-AD neurological (n = 37), 304 ± 126 pg/ml in vascular dementia (n = 46), and 486 ± 168 pg/ml (n = 52) in AD patients, respectively. However, a remarkably elevated level in phosphorylated tau was only found in AD (187 ± 84 pg/ml), as compared with normal controls (54 ± 33 pg/ml), non-AD (63 ± 34 pg/ml), and vascular dementia (72 ± 33 pg/ml) groups. If we used the ratio of hyperphosphorylated tau to total tau of ≥0.33 as cutoff for AD diagnosis, we could confirm the diagnosis in 96% of the clinically diagnosed patients with a specificity of 95%, 86%, 100%, and 94% against nonneurological, non-AD neurological, vascular dementia, and all of the three control groups combined, respectively. It is suggested that the CSF level of tau phosphorylated at Ser-396/Ser-404 is a promising diagnostic marker of AD. PMID:11943712

Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention.

PubMed

Jeanne, Marion; Jorgensen, Jeff; Gould, Douglas B

2015-05-05

Collagen type IV alpha1 (COL4A1) and alpha2 (COL4A2) form heterotrimers critical for vascular basement membrane stability and function. Patients with COL4A1 or COL4A2 mutations suffer from diverse cerebrovascular diseases, including cerebral microbleeds, porencephaly, and fatal intracerebral hemorrhage (ICH). However, the pathogenic mechanisms remain unknown, and there is a lack of effective treatment. Using Col4a1 and Col4a2 mutant mouse models, we investigated the genetic complexity and cellular mechanisms underlying the disease. We found that Col4a1 mutations cause abnormal vascular development, which triggers small-vessel disease, recurrent hemorrhagic strokes, and age-related macroangiopathy. We showed that allelic heterogeneity, genetic context, and environmental factors such as intense exercise or anticoagulant medication modulated disease severity and contributed to phenotypic heterogeneity. We found that intracellular accumulation of mutant collagen in vascular endothelial cells and pericytes was a key triggering factor of ICH. Finally, we showed that treatment of mutant mice with a US Food and Drug Administration-approved chemical chaperone resulted in a decreased collagen intracellular accumulation and a significant reduction in ICH severity. Our data are the first to show therapeutic prevention in vivo of ICH resulting from Col4a1 mutation and imply that a mechanism-based therapy promoting protein folding might also prevent ICH in patients with COL4A1 and COL4A2 mutations. © 2015 American Heart Association, Inc.

Is Doppler ultrasound useful for evaluating gestational trophoblastic disease?

PubMed

Lin, Lawrence H; Bernardes, Lisandra S; Hase, Eliane A; Fushida, Koji; Francisco, Rossana P V

2015-12-01

Doppler ultrasound is a non-invasive method for evaluating vascularization and is widely used in clinical practice. Gestational trophoblastic neoplasia includes a group of highly vascularized malignancies derived from placental cells. This review summarizes data found in the literature regarding the applications of Doppler ultrasound in managing patients with gestational trophoblastic neoplasia. The PubMed/Medline, Web of Science, Cochrane and LILACS databases were searched for articles published in English until 2014 using the following keywords: "Gestational trophoblastic disease AND Ultrasonography, Doppler." Twenty-eight articles met the inclusion criteria and were separated into the 4 following groups according to the aim of the study. (1) Doppler ultrasound does not seem to be capable of differentiating partial from complete moles, but it might be useful when evaluating pregnancies in which a complete mole coexists with a normal fetus. (2) There is controversy in the role of uterine artery Doppler velocimetry in the prediction of development of gestational trophoblastic neoplasia. (3) Doppler ultrasound is a useful tool in the diagnosis of gestational trophoblastic neoplasia because abnormal myometrial vascularization and lower uterine artery Doppler indices seem to be correlated with invasive disease. (4) Lower uterine artery Doppler indices in the diagnosis of gestational trophoblastic neoplasia are associated with methotrexate resistance and might play a role in prognosis. Several studies support the importance of Doppler ultrasound in the management of patients with gestational trophoblastic neoplasia, particularly the role of Doppler velocimetry in the prediction of trophoblastic neoplasia and the chemoresistance of trophoblastic tumors. Doppler findings should be used as ancillary tools, along with human chorionic gonadotropin assessment, in the diagnosis of gestational trophoblastic neoplasia.

Silencing Of Circular RNA-ZNF609 Ameliorates Vascular Endothelial Dysfunction.

PubMed

Liu, Chang; Yao, Mu-Di; Li, Chao-Peng; Shan, Kun; Yang, Hong; Wang, Jia-Jian; Liu, Ban; Li, Xiu-Miao; Yao, Jin; Jiang, Qin; Yan, Biao

2017-01-01

Vascular dysfunction is a hallmark of ischemic, cancer, and inflammatory diseases, contributing to disease progression. Circular RNAs (circRNAs) are endogenous non-coding RNAs, which have been reported to be abnormally expressed in many human diseases. In this study, we used retinal vasculature to determine the role of circular RNA in vascular dysfunction. We revealed that cZNF609 was significantly up-regulated upon high glucose and hypoxia stress in vivo and in vitro . cZNF609 silencing decreased retinal vessel loss and suppressed pathological angiogenesis in vivo . cZNF609 silencing increased endothelial cell migration and tube formation, and protected endothelial cell against oxidative stress and hypoxia stress in vitro . By contrast, transgenic overexpression of cZNF609 showed an opposite effects. cZNF609 acted as an endogenous miR-615-5p sponge to sequester and inhibit miR-615-5p activity, which led to increased MEF2A expression. MEF2A overexpression could rescue cZNF609 silencing-mediated effects on endothelial cell migration, tube formation, and apoptosis. Moreover, dysregulated cZNF609 expression was detected in the clinical samples of the patients with diabetes, hypertension, and coronary artery disease. Intervention of cZNF609 expression is promising therapy for vascular dysfunction.

Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice.

PubMed

Fu, Zhongjie; Wang, Zhongxiao; Liu, Chi-Hsiu; Gong, Yan; Cakir, Bertan; Liegl, Raffael; Sun, Ye; Meng, Steven S; Burnim, Samuel B; Arellano, Ivana; Moran, Elizabeth; Duran, Rubi; Poblete, Alexander; Cho, Steve S; Talukdar, Saswata; Akula, James D; Hellström, Ann; Smith, Lois E H

2018-05-01

Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes. © 2018 by the American Diabetes Association.

The forkhead box m1 transcription factor is essential for embryonic development of pulmonary vasculature.

PubMed

Kim, Il-Man; Ramakrishna, Sneha; Gusarova, Galina A; Yoder, Helena M; Costa, Robert H; Kalinichenko, Vladimir V

2005-06-10

Transgenic and gene knock-out studies demonstrated that the mouse Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) is essential for hepatocyte entry into mitosis during liver development, regeneration, and liver cancer. Targeted deletion of Foxm1 gene in mice produces an embryonic lethal phenotype due to severe abnormalities in the development of liver and heart. In this study, we show for the first time that Foxm1(-/-) lungs exhibit severe hypertrophy of arteriolar smooth muscle cells and defects in the formation of peripheral pulmonary capillaries as evidenced by significant reduction in platelet endothelial cell adhesion molecule 1 staining of the distal lung. Consistent with these findings, significant reduction in proliferation of the embryonic Foxm1(-/-) lung mesenchyme was found, yet proliferation levels were normal in the Foxm1-deficient epithelial cells. Severe abnormalities of the lung vasculature in Foxm1(-/-) embryos were associated with diminished expression of the transforming growth factor beta receptor II, a disintegrin and metalloprotease domain 17 (ADAM-17), vascular endothelial growth factor receptors, Polo-like kinase 1, Aurora B kinase, laminin alpha4 (Lama4), and the Forkhead Box f1 transcription factor. Cotransfection studies demonstrated that Foxm1 stimulates transcription of the Lama4 promoter, and this stimulation requires the Foxm1 binding sites located between -1174 and -1145 bp of the mouse Lama4 promoter. In summary, development of mouse lungs depends on the Foxm1 transcription factor, which regulates expression of genes essential for mesenchyme proliferation, extracellular matrix remodeling, and vasculogenesis.

[Potential role of the angiogenic factor "EG-VEGF" in gestational trophoblastic diseases].

PubMed

Boufettal, H; Feige, J-J; Benharouga, M; Aboussaouira, T; Nadifi, S; Mahdaoui, S; Samouh, N; Alfaidy, N

2013-10-01

Gestational trophoblastic disease (MGT) includes a wide spectrum of pathologies of the placenta, ranging from benign precancerous lesions, with gestational trophoblastic tumors. Metastases are the leading causes of death as a result of this tumor. They represent a major problem for obstetrics and for the public health system. To date, there is no predictor of the progression of molar pregnancies to gestational trophoblastic tumor (GTT). Only an unfavorable plasma hCG monitoring after evacuation of hydatidiform mole is used to diagnose a TTG. The causes of the development of this cancer are still poorly understood. Increasing data in the literature suggests a close association between the development of this tumor and poor placental vascularization during the first trimester of pregnancy. The development of the human placenta depends on a coordination between the trophoblast and endothelial cells. A disruption in the expression of angiogenic factors could contribute to uterine or extra-uterine tissue invasion by extravillous trophoblast, contributing to the development of TTG. This review sheds lights on the phenomenon of angiogenesis during normal and abnormal placentation, especially during the MGT and reports preliminary finding concerning, the variability of expression of "Endocrine Gland-Derived Vascular Endothelial Growth Factor" (EG-VEGF), a specific placental angiogenic factor, in normal and molar placentas, and the potential role of differentiated expressions of the main placental angiogenic factors in the scalability of hydatidiform moles towards a recovery or towards the development of gestational trophoblastic tumor. Deciphering the mechanisms by which the angiogenic factor influences these processes will help understand the pathophysiology of MGT and to create opportunities for early diagnosis and treatment of the latter. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Neonatal systemic inflammation in rats alters retinal vessel development and simulates pathologic features of retinopathy of prematurity.

PubMed

Hong, Hye Kyoung; Lee, Hyun Ju; Ko, Jung Hwa; Park, Ji Hyun; Park, Ji Yeon; Choi, Chang Won; Yoon, Chang-Hwan; Ahn, Seong Joon; Park, Kyu Hyung; Woo, Se Joon; Oh, Joo Youn

2014-05-15

Alteration of retinal angiogenesis during development leads to retinopathy of prematurity (ROP) in preterm infants, which is a leading cause of visual impairment in children. A number of clinical studies have reported higher rates of ROP in infants who had perinatal infections or inflammation, suggesting that exposure of the developing retina to inflammation may disturb retinal vessel development. Thus, we investigated the effects of systemic inflammation on retinal vessel development and retinal inflammation in neonatal rats. To induce systemic inflammation, we intraperitoneally injected 100 μl lipopolysaccharide (LPS, 0.25 mg/ml) or the same volume of normal saline in rat pups on postnatal days 1, 3, and 5. The retinas were extracted on postnatal days 7 and 14, and subjected to assays for retinal vessels, inflammatory cells and molecules, and apoptosis. We found that intraperitoneal injection of LPS impaired retinal vessel development by decreasing vessel extension, reducing capillary density, and inducing localized overgrowth of abnormal retinal vessels and dilated peripheral vascular ridge, all of which are characteristic findings of ROP. Also, a large number of CD11c+ inflammatory cells and astrocytes were localized in the lesion of abnormal vessels. Further analysis revealed that the number of major histocompatibility complex (MHC) class IIloCD68loCD11bloCD11chi cells in the retina was higher in LPS-treated rats compared to controls. Similarly, the levels of TNF-α, IL-1β, and IL-12a were increased in LPS-treated retina. Also, apoptosis was increased in the inner retinal layer where retinal vessels are located. Our data demonstrate that systemic LPS-induced inflammation elicits retinal inflammation and impairs retinal angiogenesis in neonatal rats, implicating perinatal inflammation in the pathogenesis of ROP.

Chronic hyperglicemia and nitric oxide bioavailability play a pivotal role in pro-atherogenic vascular modifications

PubMed Central

De Filippis, Elena Anna

2007-01-01

Diabetes is associated with accelerated atherosclerosis and macrovascular complications are a major cause of morbidity and mortality in this disease. Although our understanding of vascular pathology has lately greatly improved, the mechanism(s) underlying enhanced atherosclerosis in diabetes remain unclear. Endothelial cell dysfunction is emerging as a key component in the pathophysiology of cardiovascular abnormalities associated with diabetes. Although it has been established that endothelium plays a critical role in overall homeostasis of the vessels, vascular smooth muscle cells (vSMC) in the arterial intima have a relevant part in the development of atherosclerosis in diabetes. However, high glucose induced alterations in vSMC behaviour are not fully characterized. Several studies have reported that impaired nitric oxide (NO) synthesis and/or actions are often present in diabetes and endothelial dysfunction. Furthermore, although endothelial cells are by far the main site of vascular NO synthesis, vSMC do express nitric oxyde synthases (NOSs) and NO synthesis in vSMC might be important in vessel’s function. Although it is known that vSMC contribute to vascular pathology in diabetes by their change from a quiescent state to an activated proliferative and migratory phenotype (termed phenotypic modulation), whether this altered phenotypic modulation might also involve alterations in the nitrergic systems is still controversial. Our recent data indicate that, in vivo, chronic hyperglycemia might induce an increased number of vSMC proliferative clones which persist in culture and are associated with increased eNOS expression and activity. However, upregulation of eNOS and increased NO synthesis occur in the presence of a marked concomitant increase of O2− production. Since NO bioavailabilty might not be increased in high glucose stimulated vSMC, it is tempting to hypothesize that the proliferative phenotype observed in cells from diabetic rats is associated with a redox imbalance responsible quenching and/or trapping of NO, with the consequent loss of its biological activity. This might provide new insight on the mechanisms responsible for accelerated atherosclerosis in diabetes. PMID:18850175

Trichotillomania in a dementia case

PubMed Central

Caixeta, Leonardo; Lopes, Danielly Bandeira

2011-01-01

We report an 87-year-old male case of hair pulling associated with a white-matter vascular dementia (Binswanger’s disease). Trichotillomania in our case did not resolve using mirtazapine or anticholinesterasic medication. Trichotillomania seems to be related to a form of perseveration associated with dementia. The findings in this case suggest the abnormality involving white matter in the pathogenesis of trichotillomania, may constitute a defect in connectivity in the right frontal-subcortical circuit. PMID:29213722

Vascular and Skeletal Muscle Function in Gulf War Veterans Illness

DTIC Science & Technology

2016-07-01

Approximately 40% of Gulf War Veterans (over ¼ million Veterans) have GWI by the Center for Disease Control criteria for GWI (a recommended method for defining...for Disease Control and Prevention (CDC)’s clinical diagnostic criteria for GWI is one of two recommended by an Expert Committee, and is based on...other illnesses with muscle fatigue, pain, and abnormal muscle metabolism, such as peripheral artery disease and chronic heart failure, and advance

Increased plasma lipid levels exacerbate muscle pathology in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Milad, Nadia; White, Zoe; Tehrani, Arash Y; Sellers, Stephanie; Rossi, Fabio M V; Bernatchez, Pascal

2017-09-12

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin expression and leads to severe ambulatory and cardiac function decline. However, the dystrophin-deficient mdx murine model of DMD only develops a very mild form of the disease. Our group and others have shown vascular abnormalities in animal models of MD, a likely consequence of the fact that blood vessels express the same dystrophin-associated glycoprotein complex (DGC) proteins as skeletal muscles. To test the blood vessel contribution to muscle damage in DMD, mdx 4cv mice were given elevated lipid levels via apolipoprotein E (ApoE) gene knockout combined with normal chow or lipid-rich Western diets. Ambulatory function and heart function (via echocardiogram) were assessed at 4 and 7 months of age. After sacrifice, muscle histology and aortic staining were used to assess muscle pathology and atherosclerosis development, respectively. Plasma levels of total cholesterol, high-density lipoprotein (HDL), triglycerides, and creatine kinase (CK) were also measured. Although there was an increase in left ventricular heart volume in mdx-ApoE mice compared to that in mdx mice, parameters of heart function were not affected. Compared with wild-type and ApoE-null, only mdx-ApoE KO mice showed significant ambulatory dysfunction. Despite no significant difference in plasma CK, histological analyses revealed that elevated plasma lipids in chow- and Western diet-fed mdx-ApoE mice was associated with severe exacerbation of muscle pathology compared to mdx mice: significant increase in myofiber damage and fibrofatty replacement in the gastrocnemius and triceps brachii muscles, more reminiscent of human DMD pathology. Finally, although both ApoE and mdx-ApoE groups displayed increased plasma lipids, mdx-ApoE exhibited atherosclerotic plaque deposition equal to or less than that of ApoE mice. Since others have shown that lipid abnormalities correlate with DMD severity, our data suggest that plasma lipids could be primary contributors to human DMD severity and that the notoriously mild phenotype of mdx mice might be attributable in part to their endogenously low plasma lipid profiles. Hence, DMD patients may benefit from lipid-lowering and vascular-targeted therapies.

Emotional withdrawal, CT abnormalities and drug response in late life depression.

PubMed

Altamura, A Carlo; Bassetti, Roberta; Santini, Annalisa; Frisoni, G B; Mundo, Emanuela

2004-03-01

In this study, the authors investigated if CNS degenerative abnormalities could correlate with depressive symptoms in elderly patients, if the presence of mild/moderate cognitive impairment could be related to the response to treatment and the role of peculiar clinical features in influencing the response to treatment. Fifty-three patients (60-75 years) diagnosed as affected by late onset (after 60 years) Major Depressive Episodes according to DSM-IV criteria were studied. Brain vascular and degenerative markers were assessed by computed tomography (CT) through measurements of a lateralized version of the bifrontal index and a rating scale addressing subcortical disease. The presence of mild/moderate cognitive impairment [(24-28 total score at the Mini-Mental State Examination (MMSE)], and of specific symptoms were assessed at baseline and evaluated with respect to the antidepressant response. Patients with CT abnormalities showed higher baseline scores on Hamilton Rating Scale for Depression (HAM-D) items "late insomnia" (t=-2.674, P=.002), "somatic symptoms" (t=-3.355 P=.002), and Brief Psychiatric Rating Scale (BPRS) item "emotional withdrawal" (t=-3.355, P=.002). No significant correlation was found between the vascular index and baseline clinical symptoms, while the HAM-D "depressed mood" item was negatively correlated to the right frontal index (R=-0.692, P=.006). Patients with CT abnormalities showed a lower reduction of HAM-D total scores than patients with normal CT (time effect: F=29.277, P<.0001; group effect: F=5.154, P<.03), while a significant reduction of symptoms in time (time effect: F=33.33, P<.0001) but no differences between groups were found on Hamilton Rating Scale for Anxiety (HAM-A). Both patients with and without mild cognitive impairment improved on the HAM-D (time effect: F=19.668, P<.0001), BPRS (time effect: F=18.345, P<.0001), and HAM-A (time effect: F=17.959, P<.0001) total scores. Patients with emotional withdrawal showed lower improvement on BPRS total scores (time effect: F=26.946, P<.0001; group effect: F=5.121, P<.03). The results from this study showed that patients with baseline emotional withdrawal and CT abnormalities have poorer outcome. Further investigations on larger samples are needed to confirm these findings.