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Sample records for abnormal vascular remodeling

  1. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models.

    PubMed

    Funahashi, Yasuhiro; Okamoto, Kiyoshi; Adachi, Yusuke; Semba, Taro; Uesugi, Mai; Ozawa, Yoichi; Tohyama, Osamu; Uehara, Taisuke; Kimura, Takayuki; Watanabe, Hideki; Asano, Makoto; Kawano, Satoshi; Tizon, Xavier; McCracken, Paul J; Matsui, Junji; Aoshima, Ken; Nomoto, Kenichi; Oda, Yoshiya

    2014-10-01

    Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell-pericyte interactions, and in the epithelial-mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits. PMID:25060424

  2. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models

    PubMed Central

    Funahashi, Yasuhiro; Okamoto, Kiyoshi; Adachi, Yusuke; Semba, Taro; Uesugi, Mai; Ozawa, Yoichi; Tohyama, Osamu; Uehara, Taisuke; Kimura, Takayuki; Watanabe, Hideki; Asano, Makoto; Kawano, Satoshi; Tizon, Xavier; McCracken, Paul J; Matsui, Junji; Aoshima, Ken; Nomoto, Kenichi; Oda, Yoshiya

    2014-01-01

    Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell–pericyte interactions, and in the epithelial–mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits. PMID:25060424

  3. Decreased MicroRNA Is Involved in the Vascular Remodeling Abnormalities in Chronic Kidney Disease (CKD)

    PubMed Central

    O'Neill, Kalisha D.; Chen, Xianming; Moorthi, Ranjani N.; Gattone, Vincent H.; Allen, Matthew R.; Moe, Sharon M.

    2013-01-01

    Patients with CKD have abnormal vascular remodeling that is a risk factor for cardiovascular disease. MicroRNAs (miRNAs) control mRNA expression intracellularly and are secreted into the circulation; three miRNAs (miR-125b, miR-145 and miR-155) are known to alter vascular smooth muscle cell (VSMC) proliferation and differentiation. We measured these vascular miRNAs in blood from 90 patients with CKD and found decreased circulating levels with progressive loss of eGFR by multivariate analyses. Expression of these vascular miRNAs miR-125b, miR-145, and miR-155 was decreased in the thoracic aorta in CKD rats compared to normal rats, with concordant changes in target genes of RUNX2, angiotensin II type I receptor (AT1R), and myocardin. Furthermore, the expression of miR-155 was negatively correlated with the quantity of calcification in the aorta, a process known to be preceded by vascular de-differentiation in these animals. We then examined the mechanisms of miRNA regulation in primary VSMC and found decreased expression of miR-125b, 145, and 155 in VSMC from rats with CKD compared to normal littermates but no alteration in DROSHA or DICER, indicating that the low levels of expression is not due to altered intracellular processing. Finally, overexpression of miR-155 in VSMC from CKD rats inhibited AT1R expression and decreased cellular proliferation supporting a direct effect of miR-155 on VSMC. In conclusion, we have found ex vivo and in vitro evidence for decreased expression of these vascular miRNA in CKD, suggesting that alterations in miRNAs may lead to the synthetic state of VSMC found in CKD. The decreased levels in the circulation may reflect decreased vascular release but more studies are needed to confirm this relationship. PMID:23717629

  4. Redox regulation of vascular remodeling.

    PubMed

    Karimi Galougahi, Keyvan; Ashley, Euan A; Ali, Ziad A

    2016-01-01

    Vascular remodeling is a dynamic process of structural and functional changes in response to biochemical and biomechanical signals in a complex in vivo milieu. While inherently adaptive, dysregulation leads to maladaptive remodeling. Reactive oxygen species participate in homeostatic cell signaling in tightly regulated- and compartmentalized cellular circuits. It is well established that perturbations in oxidation-reduction (redox) homeostasis can lead to a state of oxidative-, and more recently, reductive stress. We provide an overview of the redox signaling in the vasculature and review the role of oxidative- and reductive stress in maladaptive vascular remodeling. Particular emphasis has been placed on essential processes that determine phenotype modulation, migration and fate of the main cell types in the vessel wall. Recent advances in systems biology and the translational opportunities they may provide to specifically target the redox pathways driving pathological vascular remodeling are discussed. PMID:26483132

  5. Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation.

    PubMed

    Choi, Seung Hee; Park, Sungmi; Oh, Chang Joo; Leem, Jaechan; Park, Keun-Gyu; Lee, In-Kyu

    2015-10-01

    Dipeptidyl peptidase-4 (DPP-4) inhibitors exert a potent anti-hyperglycemic effect and reduce cardiovascular risk in type 2 diabetic patients. Several studies have shown that DPP-4 inhibitors including sitagliptin have beneficial effects in atherosclerosis and cardiac infarction involving reactive oxygen species. Here, we show that gemigliptin can directly attenuate the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) via enhanced NF-E2-related factor 2 (Nrf2) activity. Gemigliptin dramatically prevented ligation injury-induced neointimal hyperplasia in mouse carotid arteries. Likewise, the proliferation of primary VSMCs was significantly attenuated by gemigliptin in a dose-dependent manner consistent with a decrease in phospho-Rb, resulting in G1 cell cycle arrest. We found that gemigliptin enhanced Nrf2 activity not only by mRNA expression, but also by increasing Keap1 proteosomal degradation by p62, leading to the induction of Nrf2 target genes such as HO-1 and NQO1. The anti-proliferative role of gemigliptin disappeared with DPP-4 siRNA knockdown, indicating that the endogenous DPP-4 in VSMCs contributed to the effect of gemigliptin. In addition, gemigliptin diminished TNF-α-mediated cell adhesion molecules such as MCP-1 and VCAM-1 and reduced MMP2 activity in VSMCs. Taken together, our data indicate that gemigliptin exerts a preventative effect on the proliferation and migration of VSMCs via Nrf2. PMID:26187356

  6. Thyroid Hormone and Vascular Remodeling.

    PubMed

    Ichiki, Toshihiro

    2016-01-01

    Both hyperthyroidism and hypothyroidism affect the cardiovascular system. Hypothyroidism is known to be associated with enhanced atherosclerosis and ischemic heart diseases. The accelerated atherosclerosis in the hypothyroid state has been traditionally ascribed to atherogenic lipid profile, diastolic hypertension, and impaired endothelial function. However, recent studies indicate that thyroid hormone has direct anti-atherosclerotic effects, such as production of nitric oxide and suppression of smooth muscle cell proliferation. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modification of risk factors for atherosclerosis. This review summarizes the basic and clinical studies on the role of thyroid hormone in vascular remodeling. The possible application of thyroid hormone mimetics to the therapy of hypercholesterolemia and atherosclerosis is also discussed. PMID:26558400

  7. MicroRNA and vascular remodelling in acute vascular injury and pulmonary vascular remodelling

    PubMed Central

    McDonald, Robert A.; Hata, Akiko; MacLean, Margaret R.; Morrell, Nicholas W.; Baker, Andrew H.

    2012-01-01

    Vascular remodelling is an integral pathological process central to a number of cardiovascular diseases. The complex interplay between distinct cell populations in the vessel wall following vascular injury leads to inflammation, cellular dysfunction, pro-growth signals in the smooth muscle cell (SMC) compartment, and the acquisition of a synthetic phenotype. Although the signals for vascular remodelling are diverse in different pathological contexts, SMC proliferation and migration are consistently observed. It is therefore critical to elucidate key mechanisms central to these processes. MicroRNAs (miRNAs) are small non-coding sequences of RNA that have the capacity to regulate many genes, pathways, and complex biological networks within cells, acting either alone or in concert with one another. In diseases such as cancer and cardiac disease, the role of miRNA in disease pathogenesis has been documented in detail. In contrast, despite a great deal of interest in miRNA, relatively few studies have directly assessed the role of miRNA in vascular remodelling. The potential for modulation of miRNA to achieve therapeutic benefits in this setting is attractive. Here, we focus on the role of miRNA in vascular inflammation and remodelling associated with acute vascular injury (vein graft disease, angioplasty restenosis, and in-stent restenosis) as well as in vascular remodelling associated with the development of pulmonary arterial hypertension. PMID:22065733

  8. Bioresorbable vascular scaffolds: Biodegradation, drug delivery and vascular remodeling.

    PubMed

    Tesfamariam, Belay

    2016-05-01

    The metallic stents with durable polymers have been effective in reducing the need for revascularization, but the permanent presence of the metal and polymer have been associated with persistent inflammation, hypersensitivity reactions and incidence of thrombosis. Recent innovations of bioresorbable polymers are in development which could serve as temporary scaffolds that degrade into molecules and eventually resorb overtime, and leave the artery free of any permanent prosthetic constraints. The transient scaffolding has the advantages of restoring blood vessel to natural state, improve vasomotor tone and increase lumen enlargement because of expansive remodeling following completion of polymer resorption. The success of bioresorbable vascular scaffolds will depend on the degradation timeline, such that the elastic recoil of the blood vessel and negative remodeling which could potentially lead to restenosis are prevented. Bioresorbable scaffolds with bulky backbone and thick struts could lead to prolonged biodegradation, alter blood flow dynamics and increase thrombogenicity. The development of bioresorbable scaffolds is challenging because of the complexity of finding an ideal balance of polymer biodegradation and controlled drug release over time, such that the fractional drug released achieves optimal inhibitory concentration until the blood vessel remodels to a stable set point. This review discusses the various types of biodegradable materials, factors affecting biodegradation, drug release kinetics, vascular biocompatibility, adaptive vascular remodeling, and challenges in the development of bioresorbable scaffolds to treat vascular restenosis. PMID:27001225

  9. Abnormal bone remodelling in inflammatory arthritis

    PubMed Central

    Bogoch, Earl R.; Moran, Erica

    1998-01-01

    Osteopenia is responsible for substantial comorbidity in patients suffering from rheumatoid arthritis and is an important factor in the surgical management of joint disease. In animal models of bone loss stimulated by inflammatory arthritis, increased bone remodelling and altered microstructure of bone have been documented. The subchondral bone plate near the joint surface is narrow and perforated by vascular inflammatory invasion, and in the shaft the thin cortices are weakened by giant resorption defects. Biomechanical tests and a mathematical model of bone strength suggest that cortical defects, much larger than those found in normal osteonal remodelling, are principally responsible for the experimentally observed loss of strength. Similarly, these defects may explain the increased femoral fracture risk in rheumatoid arthritis. The osteoclast, the cell resorbing bone, is demonstrated in increased number and activity in rheumatoid arthritis and in animal models. Bisphosphonates, drugs that inhibit osteoclast function, have been shown experimentally to reduce both focal and generalized osteopenia and to prevent loss of bone strength. Bisphosphonates also protect articular cartilage from damage characteristic of inflammatory arthritis. The mechanism of chondroprotection may be prevention of subchondral bone resorption by the osteoclast and also an altered distribution of bone marrow cells. Thus, bisphosphonates, currently in clinical use for other bone metabolic diseases, appear to have potential as prophylaxis and treatment for osteopenia and joint damage in inflammatory arthritis. PMID:9711159

  10. REACTIVE OXYGEN SPECIES IN PULMONARY VASCULAR REMODELING

    PubMed Central

    Aggarwal, Saurabh; Gross, Christine M.; Sharma, Shruti; Fineman, Jeffrey R.; Black, Stephen M.

    2014-01-01

    The pathogenesis of pulmonary hypertension is a complex multifactorial process that involves the remodeling of pulmonary arteries. This remodeling process encompasses concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by vascular smooth muscle cell (SMC) hyperplasia and hypertrophy. In addition, in uncontrolled pulmonary hypertension, the clonal expansion of apoptosis-resistant endothelial cells leads to the formation of plexiform lesions. Based upon a large number of studies in animal models, the three major stimuli that drive the vascular remodeling process are inflammation, shear stress and hypoxia. Although, the precise mechanisms by which these stimuli impair pulmonary vascular function and structure are unknown, reactive oxygen species (ROS)-mediated oxidative damage appears to play an important role. ROS are highly reactive due to their unpaired valence shell electron. Oxidative damage occurs when the production of ROS exceeds the quenching capacity of the anti-oxidant mechanisms of the cell. ROS can be produced from complexes in the cell membrane (nicotinamide adenine dinucleotide phosphate-oxidase), cellular organelles (peroxisomes and mitochondria), and in the cytoplasm (xanthine oxidase). Furthermore, low levels of tetrahydrobiopterin (BH4) and L-arginine the rate limiting co-factor and substrate for endothelial nitric oxide synthase (eNOS), can cause the uncoupling of eNOS, resulting in decreased NO production and increased ROS production. This review will focus on the ROS generation systems, scavenger antioxidants, and oxidative stress associated alterations in vascular remodeling in pulmonary hypertension. PMID:23897679

  11. Molecular Imaging of Angiogenesis and Vascular Remodeling in Cardiovascular Pathology

    PubMed Central

    Golestani, Reza; Jung, Jae-Joon; Sadeghi, Mehran M.

    2016-01-01

    Angiogenesis and vascular remodeling are involved in a wide array of cardiovascular diseases, from myocardial ischemia and peripheral arterial disease, to atherosclerosis and aortic aneurysm. Molecular imaging techniques to detect and quantify key molecular and cellular players in angiogenesis and vascular remodeling (e.g., vascular endothelial growth factor and its receptors, αvβ3 integrin, and matrix metalloproteinases) can advance vascular biology research and serve as clinical tools for early diagnosis, risk stratification, and selection of patients who would benefit most from therapeutic interventions. To target these key mediators, a number of molecular imaging techniques have been developed and evaluated in animal models of angiogenesis and vascular remodeling. This review of the state of the art molecular imaging of angiogenesis and vascular (and valvular) remodeling, will focus mostly on nuclear imaging techniques (positron emission tomography and single photon emission tomography) that offer high potential for clinical translation. PMID:27275836

  12. Aberrant Pulmonary Vascular Growth and Remodeling in Bronchopulmonary Dysplasia

    PubMed Central

    Alvira, Cristina M.

    2016-01-01

    In contrast to many other organs, a significant portion of lung development occurs after birth during alveolarization, thus rendering the lung highly susceptible to injuries that may disrupt this developmental process. Premature birth heightens this susceptibility, with many premature infants developing the chronic lung disease, bronchopulmonary dysplasia (BPD), a disease characterized by arrested alveolarization. Over the past decade, tremendous progress has been made in the elucidation of mechanisms that promote postnatal lung development, including extensive data suggesting that impaired pulmonary angiogenesis contributes to the pathogenesis of BPD. Moreover, in addition to impaired vascular growth, patients with BPD also frequently demonstrate alterations in pulmonary vascular remodeling and tone, increasing the risk for persistent hypoxemia and the development of pulmonary hypertension. In this review, an overview of normal lung development will be presented, and the pathologic features of arrested development observed in BPD will be described, with a specific emphasis on the pulmonary vascular abnormalities. Key pathways that promote normal pulmonary vascular development will be reviewed, and the experimental and clinical evidence demonstrating alterations of these essential pathways in BPD summarized. PMID:27243014

  13. The multifactorial nature of microRNAs in vascular remodelling.

    PubMed

    Welten, S M J; Goossens, E A C; Quax, P H A; Nossent, A Y

    2016-05-01

    Vascular remodelling is a multifactorial process that involves both adaptive and maladaptive changes of the vessel wall through, among others, cell proliferation and migration, but also apoptosis and necrosis of the various cell types in the vessel wall. Vascular remodelling can be beneficial, e.g. during neovascularization after ischaemia, as well as pathological, e.g. during atherosclerosis and aneurysm formation. In recent years, it has become clear that microRNAs are able to target many genes that are involved in vascular remodelling processes and either can promote or inhibit structural changes of the vessel wall. Since many different processes of vascular remodelling are regulated by similar mechanisms and factors, both positive and negative vascular remodelling can be affected by the same microRNAs. A large number of microRNAs has been linked to various aspects of vascular remodelling and indeed, several of these microRNAs regulate multiple vascular remodelling processes, including both the adaptive processes angiogenesis and arteriogenesis as well as maladaptive processes of atherosclerosis, restenosis and aneurysm formation. Here, we discuss the multifactorial role of microRNAs and microRNA clusters that were reported to play a role in multiple forms of vascular remodelling and are clearly linked to cardiovascular disease (CVD). The microRNAs reviewed are miR-126, miR-155 and the microRNA gene clusters 17-92, 23/24/27, 143/145 and 14q32. Understanding the contribution of these microRNAs to the entire spectrum of vascular remodelling processes is important, especially as these microRNAs may have great potential as therapeutic targets for treatment of various CVDs. PMID:26912672

  14. 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. PMID:22915768

  15. 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

  16. Obstruction-induced pulmonary vascular remodeling.

    PubMed

    Chow, Ming-Jay; Zou, Yu; He, Huamei; McGowan, Francis X; Zurakowski, David; Zhang, Yanhang

    2011-11-01

    Pulmonary obstruction occurs in many common forms of congenital heart disease. In this study, pulmonary artery (PA) banding is used as a model for pulmonary stenosis. Significant remodeling of the vascular bed occurs as a result of a prolonged narrowing of the PAs, and here we quantify the biophysical and molecular changes proximal and distal to the obstruction. Main and branch PAs are harvested from banded and sham rabbits and their mechanical properties are assessed using a biaxial tensile tester. Measurements defined as initial and stiff slopes are taken, assuming a linear region at the start and end of the J-shaped stress-strain curves, along with a transitional knee point. Collagen, elastin assays, Movat's pentachrome staining, and Doppler protocols are used to quantify biochemical, structural, and physiological differences. The banded main PAs have significantly greater initial slopes while banded branch PAs have lower initial slopes; however, this change in mechanical behavior cannot be explained by the assay results as the elastin content in both main and branch PAs is not significantly different. The stiff slopes of the banded main PAs are higher, which is attributed to the significantly greater amounts of insoluble collagen. Shifting of the knee points reveals a decreased toe region in the main PAs but an opposite trend in the branch PAs. The histology results show a loss of integrity of the media, increase in ground substance, and dispersion of collagen in the banded tissue samples. This indicates other structural changes could have led to the mechanical differences in banded and normal tissue. PMID:22168741

  17. Assessment of bone vascularization and its role in bone remodeling

    PubMed Central

    Lafage-Proust, Marie-Hélène; Roche, Bernard; Langer, Max; Cleret, Damien; Vanden Bossche, Arnaud; Olivier, Thomas; Vico, Laurence

    2015-01-01

    Bone is a composite organ that fulfils several interconnected functions, which may conflict with each other in pathological conditions. Bone vascularization is at the interface between these functions. The roles of bone vascularization are better documented in bone development, growth and modeling than in bone remodeling. However, every bone remodeling unit is associated with a capillary in both cortical and trabecular envelopes. Here we summarize the most recent data on vessel involvement in bone remodeling, and we present the characteristics of bone vascularization. Finally, we describe the various techniques used for bone vessel imaging and quantitative assessment, including histology, immunohistochemistry, microtomography and intravital microscopy. Studying the role of vascularization in adult bone should provide benefits for the understanding and treatment of metabolic bone diseases. PMID:25861447

  18. Biomechanics of vascular mechanosensation and remodeling

    PubMed Central

    Baeyens, Nicolas; Schwartz, Martin A.

    2016-01-01

    Flowing blood exerts a frictional force, fluid shear stress (FSS), on the endothelial cells that line the blood and lymphatic vessels. The magnitude, pulsatility, and directional characteristics of FSS are constantly sensed by the endothelium. Sustained increases or decreases in FSS induce vessel remodeling to maintain proper perfusion of tissue. In this review, we discuss these mechanisms and their relevance to physiology and disease, and propose a model for how information from different mechanosensors might be integrated to govern remodeling. PMID:26715421

  19. βA3/A1-crystallin in astroglial cells regulates retinal vascular remodeling during development

    PubMed Central

    Sinha, Debasish; Klise, Andrew; Sergeev, Yuri; Hose, Stacey; Bhutto, Imran A.; Hackler, Laszlo; Malpic-llanos, Tanya; Samtani, Sonia; Grebe, Rhonda; Goldberg, Morton F.; Hejtmancik, J. Fielding; Nath, Avindra; Zack, Donald J.; Fariss, Robert N.; McLeod, D. Scott; Sundin, Olof; Broman, Karl W.; Lutty, Gerard A.; Zigler, J. Samuel

    2016-01-01

    Vascular remodeling is a complex process critical to development of the mature vascular system. Astrocytes are known to be indispensable for initial formation of the retinal vasculature; our studies with the Nuc1 rat provide novel evidence that these cells are also essential in the retinal vascular remodeling process. Nuc1 is a spontaneous mutation in the Sprague–Dawley rat originally characterized by nuclear cataracts in the heterozygote and microphthalmia in the homozygote. We report here that the Nuc1 allele results from mutation of the βA3/A1-crystallin gene, which in the neural retina is expressed only in astrocytes. We demonstrate striking structural abnormalities in Nuc1 astrocytes with profound effects on the organization of intermediate filaments. While vessels form in the Nuc1 retina, the subsequent remodeling process required to provide a mature vascular network is deficient. Our data implicate βA3/A1-crystallin as an important regulatory factor mediating vascular patterning and remodeling in the retina. PMID:17931883

  20. Iron chelation inhibits the development of pulmonary vascular remodeling.

    PubMed

    Wong, Chi-Ming; Preston, Ioana R; Hill, Nicholas S; Suzuki, Yuichiro J

    2012-11-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Because iron is an important regulator of ROS biology, this study examined the effects of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited the growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension. PMID:22974762

  1. Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

    PubMed Central

    Leopold, Jane A.; Maron, Bradley A.

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype. PMID:27213345

  2. Role of microRNAs in Vascular Remodeling.

    PubMed

    Fang, Y-C; Yeh, C-H

    2015-01-01

    Besides being involved in the gradual formation of blood vessels during embryonic development, vascular remodeling also contributes to the progression of various cardiovascular diseases, such as; myocardial infarction, heart failure, atherosclerosis, pulmonary artery hypertension, restenosis, aneurysm, etc. The integrated mechanisms; proliferation of medial smooth muscle cell, dysregulation of intimal endothelial cell, activation of adventitial fibroblast, inflammation of macrophage, and the participation of extracellular matrix proteins are important factors in vascular remodeling. In the recent studies, microRNAs (miRs) have been shown to be expressed in all of these cell-types and play important roles in the mechanisms of vascular remodeling. Therefore, some miRs may be involved in prevention and others in the aggravation of the vascular lesions. miRs are small, endogenous, conserved, single-stranded, non-coding RNAs; which degrade target RNAs or inhibit translation post-transcriptionally. In this paper, we reviewed the function and mechanisms of miRs, which are highly expressed in various cells types, especially endothelial and smooth muscle cells, which are closely involved in the process of vascular remodeling. We also assess the functions of these miRs in the hope that they may provide new possibilities of diagnosis and treatment choices for the related diseases. PMID:26391551

  3. Para-cresyl sulfate acutely impairs vascular reactivity and induces vascular remodeling.

    PubMed

    Gross, Priscilla; Massy, Ziad A; Henaut, Lucie; Boudot, Cédric; Cagnard, Joanna; March, Cécilia; Kamel, Saïd; Drueke, Tilman B; Six, Isabelle

    2015-12-01

    Chronic kidney disease (CKD) is characterized by vascular remodeling and the retention of uremic toxins, several of which are independently associated with the high cardiovascular mortality rate in CKD patients. Whether the association between these uremic toxins and cardiovascular mortality is due to induction of vascular dysfunction and resulting vascular remodeling remains to be determined. This study evaluates the effects of para-cresyl sulfate (PCS), a newly identified uremic toxin, on vascular function and remodeling. PCS acutely induced oxidative stress in both endothelial and vascular smooth muscle cells, with a maximal effect at 0.15 mM, corresponding to the mean "uremic" concentration found in dialysis patients. PCS significantly increased within 30 min phenylephrine-induced contraction of mouse thoracic aorta, through direct activation of rho-kinase, independently of oxidative stress induction, as demonstrated by the capacity of rho-kinase inhibitor Y-27632 to abolish this effect. After exposure of the aorta to PCS for 48 h, we observed inward eutrophic remodeling, a hallmark of uremic vasculopathy characterized by a reduction of the area of both lumen and media, with unchanged media/lumen ratio. In conclusion, elevated PCS concentrations such as those observed in CKD patients, by promoting both vascular dysfunction and vascular remodeling, may contribute to the development of hypertension and to cardiovascular mortality in CKD. PMID:25899466

  4. Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis

    PubMed Central

    Nicolosi, Pier Andrea; Tombetti, Enrico; Maugeri, Norma; Rovere-Querini, Patrizia; Brunelli, Silvia; Manfredi, Angelo A.

    2016-01-01

    Fibrosis of the skin and of internal organs, autoimmunity, and vascular inflammation are hallmarks of Systemic Sclerosis (SSc). The injury and activation of endothelial cells, with hyperplasia of the intima and eventual obliteration of the vascular lumen, are early features of SSc. Reduced capillary blood flow coupled with deficient angiogenesis leads to chronic hypoxia and tissue ischemia, enforcing a positive feed-forward loop sustaining vascular remodelling, further exacerbated by extracellular matrix accumulation due to fibrosis. Despite numerous developments and a growing number of controlled clinical trials no treatment has been shown so far to alter SSc natural history, outlining the need of further investigation in the molecular pathways involved in the pathogenesis of the disease. We review some processes potentially involved in SSc vasculopathy, with attention to the possible effect of sustained vascular inflammation on the plasticity of vascular cells. Specifically we focus on mesenchymal transition, a key phenomenon in the cardiac and vascular development as well as in the remodelling of injured vessels. Recent work supports the role of transforming growth factor-beta, Wnt, and Notch signaling in these processes. Importantly, endothelial-mesenchymal transition may be reversible, possibly offering novel cues for treatment. PMID:27069480

  5. Hyperhomocysteinemia promotes vascular remodeling in vein graph in mice.

    PubMed

    Tan, Hongmei; Shi, Chengwei; Jiang, Xiaohua; Lavelle, Muriel; Yu, Caijia; Yang, Xiaofeng; Wang, Hong

    2014-01-01

    This study investigated the role and mechanism of Hyperhomocysteinemia (HHcy) on vascular remodeling in mice. We assessed the effect of HHcy on vascular remodeling using a carotid arterial vein patch model in mice with the gene deletion of cystathionine-beta-synthase (Cbs). Vein grafts were harvested 4 weeks after surgery. Cross sections were analyzed using Verhoeff-van Gieson staining, Masson`s Trichrome staining, and immunostaining for morphological analysis and protein level assessment. The effect of Hcy on collagen secretion was examined in cultured rat aortic smooth muscle cells (RASMC). We found that Cbs-/- mice with severe HHcy exhibited thicker neointima and a higher percentage of luminal narrowing in vein grafts. In addition, severe HHcy increased elastin and collagen deposition in the neointima. Further, severe HHcy increases CD45 positive cells and proliferative cells in vein grafts. Finally, Hcy increases collagen secretion in RASMC. These results demonstrate that HHcy increases neointima formation, elastin and collagen deposition following a carotid arterial vein patch. The capacity of Hcy to promote vascular fibrosis and inflammation may contribute to the development of vascular remodeling. PMID:24896329

  6. Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

    PubMed Central

    Papamatheakis, Demosthenes G.; Blood, Arlin B.; Kim, Joon H.; Wilson, Sean M.

    2015-01-01

    This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression. PMID:24063380

  7. Phosphodiesterase 10A Upregulation Contributes to Pulmonary Vascular Remodeling

    PubMed Central

    Tian, Xia; Vroom, Christina; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Bieniek, Ewa; Grimminger, Friedrich; Seeger, Werner; Schermuly, Ralph Theo; Pullamsetti, Soni Savai

    2011-01-01

    Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%–50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH. PMID:21494592

  8. Phosphodiesterase 10A upregulation contributes to pulmonary vascular remodeling.

    PubMed

    Tian, Xia; Vroom, Christina; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Bieniek, Ewa; Grimminger, Friedrich; Seeger, Werner; Schermuly, Ralph Theo; Pullamsetti, Soni Savai

    2011-01-01

    Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%-50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH. PMID:21494592

  9. Pulmonary vascular remodelling in a high-altitude Aymara Indian

    NASA Astrophysics Data System (ADS)

    Heath, Donald; Williams, David

    1991-12-01

    A histological study of the pulmonary vasculature in a young male high-altitude Aymara Indian revealed four aspects of interest. There was muscularization of the terminal portion of the pulmonary arterial tree to involve pulmonary arterioles as small as 15 μm in diameter, thus forming a basis for the slightly increased pulmonary vascular resistance of native highlanders. Intimal longitudinal muscle was found in pulmonary arteries and arterioles and thought to be due to chronic alveolar hypoxia. Inner muscular tubes similar to those found in chronic obstructive lung disease were present. Pulmonary veins and venules also showed intimal muscularization suggesting that alveolar hypoxia affects vascular smooth muscle cells per se irrespective of their situation. The nature of the remodelling in a pulmonary blood vessel depends on a combination of hypoxia and haemodynamics.

  10. Tie1 controls angiopoietin function in vascular remodeling and inflammation.

    PubMed

    Korhonen, Emilia A; Lampinen, Anita; Giri, Hemant; Anisimov, Andrey; Kim, Minah; Allen, Breanna; Fang, Shentong; D'Amico, Gabriela; Sipilä, Tuomas J; Lohela, Marja; Strandin, Tomas; Vaheri, Antti; Ylä-Herttuala, Seppo; Koh, Gou Young; McDonald, Donald M; Alitalo, Kari; Saharinen, Pipsa

    2016-09-01

    The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1- and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability. PMID:27548530

  11. Integrative models of vascular remodeling during tumor growth

    PubMed Central

    Rieger, Heiko; Welter, Michael

    2015-01-01

    Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551

  12. Luteolin Ameliorates Hypertensive Vascular Remodeling through Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells

    PubMed Central

    Su, Jie; Xu, Han-Ting; Yu, Jing-Jing; Gao, Jian-Li; Lei, Jing; Yin, Qiao-Shan; Li, Bo; Pang, Min-Xia; Su, Min-Xia; Mi, Wen-Jia; Chen, Su-Hong; Lv, Gui-Yuan

    2015-01-01

    Objectives. Preliminary researches showed that luteolin was used to treat hypertension. However, it is still unclear whether luteolin has effect on the hypertensive complication such as vascular remodeling. The present study was designed to investigate the effect of luteolin on the hypertensive vascular remodeling and its molecular mechanism. Method and Results. We evaluated the effect of luteolin on aorta thickening of hypertension in spontaneous hypertensive rats (SHRs) and found that luteolin could significantly decrease the blood pressure and media thickness of aorta in vivo. Luteolin could inhibit angiotensin II- (Ang II-) induced proliferation and migration of vascular smooth muscle cells (VSMCs). Dichlorofluorescein diacetate (DCFH-DA) staining result showed that luteolin reduced Ang II-stimulated ROS production in VSMCs. Furthermore, western blot and gelatin zymography results showed that luteolin treatment leaded to a decrease in ERK1/2, p-ERK1/2, p-p38, MMP2, and proliferating cell nuclear antigen (PCNA) protein level. Conclusion. These data support that luteolin can ameliorate hypertensive vascular remodeling by inhibiting the proliferation and migration of Ang II-induced VSMCs. Its mechanism is mediated by the regulation of MAPK signaling pathway and the production of ROS. PMID:26495010

  13. Systemic and Pulmonary Vascular Remodelling in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Muñoz-Esquerre, Mariana; López-Sánchez, Marta; Escobar, Ignacio; Huertas, Daniel; Penín, Rosa; Molina-Molina, María; Manresa, Frederic; Dorca, Jordi; Santos, Salud

    2016-01-01

    Background Chronic Obstructive Pulmonary Disease (COPD) is associated with subclinical systemic atherosclerosis and pulmonary vascular remodelling characterized by intimal hyperplasia and luminal narrowing. We aimed to determine differences in the intimal thickening of systemic and pulmonary arteries in COPD subjects and smokers. Secondary aims include comparisons with a non-smokers group; determining the clinical variables associated with systemic and pulmonary intimal thickening, and the correlations between systemic and pulmonary remodelling changes. Methods All consecutive subjects undergoing lung resection were included and divided into 3 groups: 1) COPD, 2) smokers, and 3) non-smokers. Sections of the 5th intercostal artery and muscular pulmonary arteries were measured by histo-morphometry. Four parameters of intimal thickening were evaluated: 1) percentage of intimal area (%IA), 2) percentage of luminal narrowing, 3) intimal thickness index, and 4) intima-to-media ratio. Results In the adjusted analysis, the systemic arteries of COPD subjects showed greater intimal thickening (%IA) than those of smokers (15.6±1.5% vs. 14.2±1.6%, p = 0.038). In the pulmonary arteries, significant differences were observed for %IA between the 2 groups (37.3±2.2% vs. 29.3±2.3%, p = 0.016). Among clinical factors, metabolic syndrome, gender and COPD status were associated with the systemic intimal thickening, while only COPD status was associated with pulmonary intimal thickening. A correlation between the %IA of the systemic and pulmonary arteries was observed (Spearman’s rho = 0.46, p = 0.008). Conclusions Greater intimal thickening in systemic and pulmonary arteries is observed in COPD patients than in smokers. There is a correlation between systemic and pulmonary vascular remodelling in the overall population. PMID:27046203

  14. Thymoquinone inhibits inflammation, neoangiogenesis and vascular remodeling in asthma mice.

    PubMed

    Su, Xinming; Ren, Yuan; Yu, Na; Kong, Lingfei; Kang, Jian

    2016-09-01

    Asthma is a chronic obstructive disease which is characterized by recurring airway inflammation, reversible airway obstruction, airway hyper responsiveness and vascular remodeling. Thymoquinone (TQ), an active ingredient isolated from Nigella sativa, was reported to exhibit anti-inflammation and anti-proliferation of in various cancer cells as well as epithelial cells. The aim of this study was to evaluate the effect of TQ on the inflammation, neoangiogenesis and vascular remodeling induced by Ovalbumin (OVA) in asthma mice in vivo and the anti-angiogenesis effects of TQ in VEGF-induced human umbilical vein endothelial cells (HUVECs) in vitro. Our results revealed that TQ inhibited the production of inflammatory factors interleukin-4/-5 (IL-4/-5) by enzyme-linked immunesorbent assay (ELISA). Immunohistochemistry analysis showed that the increase of platelet endothelial cell adhesion molecule-1, which is also known as CD31 and α-smooth muscle actinalpha (α-SMA) expression in asthma mice challenged by OVA was suppressed by TQ. Moreover, TQ suppressed the activation of VEGFR2-PI3K-Akt pathway and up-regulated the expression of Slit glycoprotein-2 (Slit-2) both in vivo and in vitro with the inhibition of tube information in HUVEC cells. Meanwhile immunofluorescence analysis showed that Slit-2 and Roundabout-4 (Robo-4) were co-expressing after TQ treatment in OVA-challenged asthma mice. Our study demonstrates that TQ attenuated the inflammatory reaction by antagonizing IL-4/-5 while the anti-neoangiogenesis effect of TQ is mediated by inhibition of vascular endothelial growth factor (VEGF) expression through VEGFR2/PI3K/Akt signaling pathway, which supports a potential role for TQ in ameliorating asthma. PMID:27240137

  15. Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

    PubMed Central

    Chen, Yu-cai; Yuan, Tian-yi; Zhang, Hui-fang; Wang, Dan-shu; Yan, Yu; Niu, Zi-ran; Lin, Yi-huang; Fang, Lian-hua; Du, Guan-hua

    2016-01-01

    Aim: The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling, which is characteristic of pulmonary arterial hypertension (PAH). In this study we examined whether salvianolic acid A (SAA) extracted from the traditional Chinese medicine 'Dan Shen' attenuated vascular remodeling in a PAH rat model, and elucidated the underlying mechanisms. Methods: PAH was induced in rats by injecting a single dose of monocrotaline (MCT 60 mg/kg, sc). The rats were orally treated with either SAA (0.3, 1, 3 mg·kg−1·d−1) or a positive control bosentan (30 mg·kg−1·d−1) for 4 weeks. Echocardiography and hemodynamic measurements were performed on d 28. Then the hearts and lungs were harvested, the organ indices and pulmonary artery wall thickness were calculated, and biochemical and histochemical analysis were conducted. The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting. Results: Treatment with SAA or bosentan effectively ameliorated MCT-induced pulmonary artery remodeling, pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure (RVSP). Furthermore, the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium, parenchymal injury and collagen deposition in the lungs. Moreover, the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs. The treatments partially restored MCT-induced reductions of bone morphogenetic protein type II receptor (BMPRII) and phosphorylated Smad1/5 in the lungs. Conclusion: SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRII-Smad pathway and inhibiting apoptosis. Thus, SAA may have therapeutic potential for the patients at high risk of PAH. PMID:27180980

  16. Mutually Supportive Mechanisms of Inflammation and Vascular Remodeling.

    PubMed

    Whiteford, J R; De Rossi, G; Woodfin, A

    2016-01-01

    Chronic inflammation is often accompanied by angiogenesis, the development of new blood vessels from existing ones. This vascular response is a response to chronic hypoxia and/or ischemia, but is also contributory to the progression of disorders including atherosclerosis, arthritis, and tumor growth. Proinflammatory and proangiogenic mediators and signaling pathways form a complex and interrelated network in these conditions, and many factors exert multiple effects. Inflammation drives angiogenesis by direct and indirect mechanisms, promoting endothelial proliferation, migration, and vessel sprouting, but also by mediating extracellular matrix remodeling and release of sequestered growth factors, and recruitment of proangiogenic leukocyte subsets. The role of inflammation in promoting angiogenesis is well documented, but by facilitating greater infiltration of leukocytes and plasma proteins into inflamed tissues, angiogenesis can also propagate chronic inflammation. This review examines the mutually supportive relationship between angiogenesis and inflammation, and considers how these interactions might be exploited to promote resolution of chronic inflammatory or angiogenic disorders. PMID:27572130

  17. In vivo bioluminescence imaging of vascular remodeling after stroke

    PubMed Central

    Adamczak, Joanna M.; Schneider, Gabriele; Nelles, Melanie; Que, Ivo; Suidgeest, Ernst; van der Weerd, Louise; Löwik, Clemens; Hoehn, Mathias

    2014-01-01

    Thrombolysis remains the only beneficial therapy for ischemic stroke, but is restricted to a short therapeutic window following the infarct. Currently research is focusing on spontaneous regenerative processes during the sub-acute and chronic phase. Angiogenesis, the formation of new blood vessels from pre-existing ones, was observed in stroke patients, correlates with longer survival and positively affects the formation of new neurons. Angiogenesis takes place in the border zones of the infarct, but further insight into the temporal profile is needed to fully apprehend its therapeutic potential and its relevance for neurogenesis and functional recovery. Angiogenesis is a multistep process, involving extracellular matrix degradation, endothelial cell proliferation, and, finally, new vessel formation. Interaction between vascular endothelial growth factor and its receptor 2 (VEGFR2) plays a central role in these angiogenic signaling cascades. In the present study we investigated non-invasively the dynamics of VEGFR2 expression following cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO). We used a transgenic mouse expressing firefly luciferase under the control of the VEGFR2 promotor to non-invasively elucidate the temporal profile of VEGFR2 expression after stroke as a biomarker for VEGF/VEGFR2 signaling. We measured each animal repetitively up to 2 weeks after stroke and found increased VEGFR2 expression starting 3 days after the insult with peak values at 7 days. These were paralleled by increased VEGFR2 protein levels and increased vascular volume in peri-infarct areas at 14 days after the infarct, indicating that signaling via VEGFR2 leads to successful vascular remodeling. This study describes VEGFR2-related signaling is active at least up to 2 weeks after the infarct and results in increased vascular volume. Further, this study presents a novel strategy for the non-invasive evaluation of angiogenesis-based therapies. PMID:25249937

  18. Neutrophil Dependence of Vascular Remodeling after Mycoplasma Infection of Mouse Airways

    PubMed Central

    Baluk, Peter; Phillips, Keeley; Yao, Li-Chin; Adams, Alicia; Nitschké, Maximilian; McDonald, Donald M.

    2015-01-01

    Vascular remodeling is a feature of sustained inflammation in which capillaries enlarge and acquire the phenotype of venules specialized for plasma leakage and leukocyte recruitment. We sought to determine whether neutrophils are required for vascular remodeling in the respiratory tract by using Mycoplasma pulmonis infection as a model of sustained inflammation in mice. The time course of vascular remodeling coincided with the influx of neutrophils during the first few days after infection and peaked at day 5. Depletion of neutrophils with antibody RB6-8C5 or 1A8 reduced neutrophil influx and vascular remodeling after infection by about 90%. Similarly, vascular remodeling after infection was suppressed in Cxcr2−/− mice, in which neutrophils adhered to the endothelium of venules but did not extravasate into the tissue. Expression of the venular adhesion molecule P-selectin increased in endothelial cells from day 1 to day 3 after infection, as did expression of the Cxcr2-receptor ligands Cxcl1 and Cxcl2. Tumor necrosis factor α (TNFα) expression increased more than sixfold in the trachea of wild-type and Cxcr2−/− mice, but intratracheal administration of TNFα did not induce vascular remodeling similar to that seen in infection. We conclude that neutrophil influx is required for remodeling of capillaries into venules in the airways of mice with Mycoplasma infection and that TNFα signaling is necessary but not sufficient for vascular remodeling. PMID:24726646

  19. Vascular remodeling after ischemic stroke: mechanisms and therapeutic potentials

    PubMed Central

    Liu, Jialing; Wang, Yongting; Akamatsu, Yosuke; Lee, Chih Cheng; Stetler, R Anne; Lawton, Michael T.; Yang, Guo-Yuan

    2014-01-01

    The brain vasculature has been increasingly recognized as a key player that directs brain development, regulates homeostasis, and contributes to pathological processes. Following ischemic stroke, the reduction of blood flow elicits a cascade of changes and leads to vascular remodeling. However, the temporal profile of vascular changes after stroke is not well understood. Growing evidence suggests that the early phase of cerebral blood volume (CBV) increase is likely due to the improvement in collateral flow, also known as arteriogenesis, whereas the late phase of CBV increase is attributed to the surge of angiogenesis. Arteriogenesis is triggered by shear fluid stress followed by activation of endothelium and inflammatory processes, while angiogenesis induces a number of pro-angiogenic factors and circulating endothelial progenitor cells (EPCs). The status of collaterals in acute stroke has been shown to have several prognostic implications, while the causal relationship between angiogenesis and improved functional recovery has yet to be established in patients. A number of interventions aimed at enhancing cerebral blood flow including increasing collateral recruitment are under clinical investigation. Transplantation of EPCs to improve angiogenesis is also underway. Knowledge in the underlying physiological mechanisms for improved arteriogenesis and angiogenesis shall lead to more effective therapies for ischemic stroke. PMID:24291532

  20. Drinking citrus fruit juice inhibits vascular remodeling in cuff-induced vascular injury mouse model.

    PubMed

    Ohnishi, Arika; Asayama, Rie; Mogi, Masaki; Nakaoka, Hirotomo; Kan-No, Harumi; Tsukuda, Kana; Chisaka, Toshiyuki; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-01-01

    Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Citrus unshiu (CU) juice (CU10), 3) 40% CU juice (CU40), 4) 10% Citrus iyo (CI) juice (CI10), and 5) 40% CI juice (CI40). After drinking them for 2 weeks from 8 weeks of age, cuff injury was induced by polyethylene cuff placement around the femoral artery. Neointima formation was significantly attenuated in CU40, CI10 and CI40 compared with C; however, no remarkable preventive effect was observed in CU10. The increases in levels of various inflammatory markers including cytokines such as monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α in response to vascular injury did not differ significantly between C, CU10 and CI10. The increases in cell proliferation and superoxide anion production were markedly attenuated in CI10, but not in CU10 compared with C. The increase in phosphorylated ERK expression was markedly attenuated both in CU10 and CI10 without significant difference between CU10 and CI10. Accumulation of immune cells did not differ between CU10 and CI10. These results indicate that drinking citrus fruit juice attenuates vascular remodeling partly via a reduction of oxidative stress. Interestingly, the preventive efficacy on neointima formation was stronger in CI than in CU at least in part due to more prominent inhibitory effects on oxidative stress by CI. PMID:25692290

  1. Drinking Citrus Fruit Juice Inhibits Vascular Remodeling in Cuff-Induced Vascular Injury Mouse Model

    PubMed Central

    Ohnishi, Arika; Asayama, Rie; Mogi, Masaki; Nakaoka, Hirotomo; Kan-no, Harumi; Tsukuda, Kana; Chisaka, Toshiyuki; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-01-01

    Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Citrus unshiu (CU) juice (CU10), 3) 40% CU juice (CU40), 4) 10% Citrus iyo (CI) juice (CI10), and 5) 40% CI juice (CI40). After drinking them for 2 weeks from 8 weeks of age, cuff injury was induced by polyethylene cuff placement around the femoral artery. Neointima formation was significantly attenuated in CU40, CI10 and CI40 compared with C; however, no remarkable preventive effect was observed in CU10. The increases in levels of various inflammatory markers including cytokines such as monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α in response to vascular injury did not differ significantly between C, CU10 and CI10. The increases in cell proliferation and superoxide anion production were markedly attenuated in CI10, but not in CU10 compared with C. The increase in phosphorylated ERK expression was markedly attenuated both in CU10 and CI10 without significant difference between CU10 and CI10. Accumulation of immune cells did not differ between CU10 and CI10. These results indicate that drinking citrus fruit juice attenuates vascular remodeling partly via a reduction of oxidative stress. Interestingly, the preventive efficacy on neointima formation was stronger in CI than in CU at least in part due to more prominent inhibitory effects on oxidative stress by CI. PMID:25692290

  2. Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

    SciTech Connect

    Gao, Fu; Chambon, Pierre; Tellides, George; Kong, Wei; Zhang, Xiaoming; Li, Wei

    2014-11-07

    Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2{sup f/f}) and their corresponding wild-type background mice (MyhCre.Tgfbr2{sup WT/WT}) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.

  3. The Amiloride Derivative Phenamil Attenuates Pulmonary Vascular Remodeling by Activating NFAT and the Bone Morphogenetic Protein Signaling Pathway ▿

    PubMed Central

    Chan, Mun Chun; Weisman, Alexandra S.; Kang, Hara; Nguyen, Peter H.; Hickman, Tyler; Mecker, Samantha V.; Hill, Nicholas S.; Lagna, Giorgio; Hata, Akiko

    2011-01-01

    Pulmonary artery hypertension (PAH) is characterized by elevated pulmonary artery resistance and increased medial thickness due to deregulation of vascular remodeling. Inactivating mutations of the BMPRII gene, which encodes a receptor for bone morphogenetic proteins (BMPs), are identified in ∼60% of familial PAH (FPAH) and ∼30% of idiopathic PAH (IPAH) patients. It has been hypothesized that constitutive reduction in BMP signal by BMPRII mutations may cause abnormal vascular remodeling by promoting dedifferentiation of vascular smooth muscle cells (vSMCs). Here, we demonstrate that infusion of the amiloride analog phenamil during chronic-hypoxia treatment in rat attenuates development of PAH and vascular remodeling. Phenamil induces Tribbles homolog 3 (Trb3), a positive modulator of the BMP pathway that acts by stabilizing the Smad family signal transducers. Through induction of Trb3, phenamil promotes the differentiated, contractile vSMC phenotype characterized by elevated expression of contractile genes and reduced cell growth and migration. Phenamil activates the Trb3 gene transcription via activation of the calcium-calcineurin-nuclear factor of activated T cell (NFAT) pathway. These results indicate that constitutive elevation of Trb3 by phenamil is a potential therapy for IPAH and FPAH. PMID:21135135

  4. Mechanical Stress Induces Remodeling of Vascular Networks in Growing Leaves

    PubMed Central

    Bar-Sinai, Yohai; Julien, Jean-Daniel; Sharon, Eran; Armon, Shahaf; Nakayama, Naomi; Adda-Bedia, Mokhtar; Boudaoud, Arezki

    2016-01-01

    Differentiation into well-defined patterns and tissue growth are recognized as key processes in organismal development. However, it is unclear whether patterns are passively, homogeneously dilated by growth or whether they remodel during tissue expansion. Leaf vascular networks are well-fitted to investigate this issue, since leaves are approximately two-dimensional and grow manyfold in size. Here we study experimentally and computationally how vein patterns affect growth. We first model the growing vasculature as a network of viscoelastic rods and consider its response to external mechanical stress. We use the so-called texture tensor to quantify the local network geometry and reveal that growth is heterogeneous, resembling non-affine deformations in composite materials. We then apply mechanical forces to growing leaves after veins have differentiated, which respond by anisotropic growth and reorientation of the network in the direction of external stress. External mechanical stress appears to make growth more homogeneous, in contrast with the model with viscoelastic rods. However, we reconcile the model with experimental data by incorporating randomness in rod thickness and a threshold in the rod growth law, making the rods viscoelastoplastic. Altogether, we show that the higher stiffness of veins leads to their reorientation along external forces, along with a reduction in growth heterogeneity. This process may lead to the reinforcement of leaves against mechanical stress. More generally, our work contributes to a framework whereby growth and patterns are coordinated through the differences in mechanical properties between cell types. PMID:27074136

  5. Kinetics of Vascular Remodeling: Comparison of Solver Approaches

    NASA Astrophysics Data System (ADS)

    Ward, R. C.; Nutaro, J. J.; Kruse, K. L.; O'Quinn, E. C.; Reedy-Jackson, A. R.; Woerner, M. M.

    2006-11-01

    Results will be presented for kinetics of matrix metalloproteinases (MMP), enzymes that play a significant role in vascular remodeling. Three different computational approaches for well-mixed kinetics processes will be analyzed and compared. The kinetics of one MMP, namely MMP2, were elucidated using a model and rate constants from published literature^1 and implemented using the JSim environment (see nsr.bioeng.washington.edu).^ Further investigations of this pathway were undertaken using System Biology Workbench (SBW) (see sbw.kgi.edu), where the system of kinetic equations was created using an interactive visual interface. Using SBW the complexity of the kinetics was evaluated using phase space analysis. Finally, we implemented the kinetics model using Discrete Event System Specification (DEVS). Using adev (see www.ece.arizona.edu/˜nutaro), an open-source DEVS modeling environment we demonstrate that continuous, well-mixed, enzyme kinetics can be modeled using discrete event simulation. The three computational environments will be compared and their utility and comprehensiveness evaluated. 1. Karagiannis, E. D. and Popel, A. S., J. of Biological Chemistry, 279 (37):39105--39114, 2004.

  6. Transdifferentiation of endothelial cells to smooth muscle cells play an important role in vascular remodelling.

    PubMed

    Coll-Bonfill, Núria; Musri, Melina Mara; Ivo, Victor; Barberà, Joan Albert; Tura-Ceide, Olga

    2015-01-01

    Pulmonary artery remodelling it is a major feature of pulmonary hypertension (PH). It is characterised by cellular and structural changes of the pulmonary arteries causing higher pulmonar vascular resistance and right ventricular failure. Abnormal deposition of smooth muscle-like (SM-like) cells in normally non-muscular, small diameter vessels and a deregulated control of endothelial cells are considered pathological features of PH. The origin of the SM-like cells and the mechanisms underlying the development and progression of this remodelling process are not understood. Endothelial cells within the intima may migrate from their organised layer of cells and transition to mesenchymal or SM-like phenotype in a process called endothelial-mesenchymal transition (EnMT). Traditionally, Waddington's epigenetic landscape illustrates that fates of somatic cells are progressively determined to compulsorily follow a downhill differentiation pathway. EnMT induces the transformation of cells with stem cell traits, therefore contrasting Waddington's theory and confirming that cell fate seems to be far more flexible than previously thought. The prospect of therapeutic inhibition of EnMT to delay or prevent PH may represent a promising new treatment modality. PMID:25973327

  7. Induction of vascular remodeling in the lung by chronic house dust mite exposure.

    PubMed

    Rydell-Törmänen, Kristina; Johnson, Jill R; Fattouh, Ramzi; Jordana, Manel; Erjefält, Jonas S

    2008-07-01

    Structural changes to the lung are associated with chronic asthma. In addition to alterations to the airway wall, asthma is associated with vascular modifications, although this aspect of remodeling is poorly understood. We sought to evaluate the character and kinetics of vascular remodeling in response to chronic aeroallergen exposure. Because many ovalbumin-driven models used to investigate allergic airway disease do so in the absence of persistent airway inflammation, we used a protocol of chronic respiratory exposure to house dust mite extract (HDME), which has been shown to induce persistent airway inflammation consistent with that seen in humans with asthma. Mice were exposed to HDME intranasally for 7 or 20 consecutive weeks, and resolution of the inflammatory and remodeling response to allergen was investigated 4 weeks after the end of a 7-week exposure protocol. Measures of vascular remodeling, including total collagen deposition, procollagen I production, endothelial and smooth muscle cell proliferation, smooth muscle area, and presence of myofibroblasts, were investigated histologically in lung vessels of different sizes and locations. We observed an increase in total collagen content, which did not resolve upon cessation of allergen exposure. Other parameters were significantly increased after 7 and/or 20 weeks of allergen exposure but returned to baseline after allergen withdrawal. We conclude that respiratory HDME exposure induces airway remodeling and pulmonary vascular remodeling, and, in accordance with airway remodeling, some components of these structural changes may be irreversible. PMID:18314535

  8. Changes in vascular extracellular matrix composition during decidual spiral arteriole remodeling in early human pregnancy.

    PubMed

    Smith, Samantha D; Choudhury, Ruhul H; Matos, Patricia; Horn, James A; Lye, Stephen J; Dunk, Caroline E; Aplin, John D; Jones, Rebecca L; Harris, Lynda K

    2016-05-01

    Uterine spiral arteriole (SA) remodeling in early pregnancy involves a coordinated series of events including decidual immune cell recruitment, vascular cell disruption and loss, and colonization by placental-derived extravillous trophoblast (EVT). During this process, decidual SA are converted from narrow, muscular vessels into dilated channels lacking vasomotor control. We hypothesized that this extensive alteration in SA architecture must require significant reorganization and/or breakdown of the vascular extracellular matrix (ECM). First trimester decidua basalis (30 specimens) was immunostained to identify spiral arterioles undergoing trophoblast-independent and -dependent phases of remodeling. Serial sections were then immunostained for a panel of ECM markers, to examine changes in vascular ECM during the remodeling process. The initial stages of SA remodeling were characterized by loss of laminin, elastin, fibrillin, collagen types III, IV and VI from the basement membrane, vascular media and/or adventitia, and surrounding decidual stromal cells. Loss of ECM correlated with disruption and disorganization of vascular smooth muscle cells, and the majority of changes occurred prior to extensive colonization of the vessel wall by EVT. The final stages of SA remodeling, characterized by the arrival of EVT, were associated with the increased mural deposition of fibronectin and fibrinoid. This study provides the first detailed analysis of the spatial and temporal loss of ECM from the walls of remodeling decidual SA in early pregnancy. PMID:26602431

  9. Abnormalities of vascular structure and function in pediatric hypertension.

    PubMed

    Urbina, Elaine M

    2016-07-01

    Hypertension is associated with adverse cardiovascular (CV) events in adults. Measures of vascular structure and function, including increased carotid intima-media thickness (cIMT) and elevated arterial stiffness predict hard CV events in adulthood. Newer data suggest that abnormalities in target organ damage are occurring in adolescents and young adults with high blood pressure. In this review, we discuss the techniques for measuring vascular dysfunction in young people and the evidence linking blood pressure levels to this type of target organ damage. PMID:26275663

  10. Class A scavenger receptor deficiency augments angiotensin II-induced vascular remodeling.

    PubMed

    Qian, Lingling; Li, Xiaoyu; Fang, Ru; Wang, Zhuoyun; Xu, Yiming; Zhang, Hanwen; Bai, Hui; Yang, Qing; Zhu, Xudong; Ben, Jingjing; Xu, Yong; Chen, Qi

    2014-08-01

    Class A scavenger receptor (SR-A) is a multifunctional molecule that participates in macrophage-mediated inflammation. Here we evaluated the role of SR-A in angiotensin II (Ang II)-induced hypertensive vascular remodeling. Chronic infusion of Ang II leads to an increased systolic blood pressure both in SR-A knockout (SR-A(-/-)) and wild type (SR-A(+/+)) mice with no significant difference between these two groups. SR-A(-/-) hypertensive mice, however, exhibited a marked augmentation of arterial wall thickening and vascular cell proliferation compared with SR-A(+/+) hypertensive mice. M1 macrophage markers were increased whereas M2 macrophage markers were decreased in vascular tissues of SR-A(-/-) mice. Co-culture experiments revealed that more pro-inflammatory cytokines like TNF-α were produced by SR-A(-/-) peritoneal macrophages leading to a stronger proliferation of primary vascular smooth muscle cells in vitro. In addition, SR-A(-/-) macrophages were more prone to lipopolysaccharide-induced M1 differentiation while resisting interleukin-4-induced M2 differentiation. Importantly, transplantation of SR-A(-/-) bone marrow into SR-A(+/+) mice significantly augmented Ang II-induced vascular remodeling. These results show that SR-A is critical for Ang II-induced vascular remodeling by regulating macrophage polarization. Therefore, SR-A may be a useful therapeutic target for the intervention of hypertensive vascular remodeling. PMID:24875449

  11. Spatial and phenotypic characterization of vascular remodeling in a mouse model of asthma.

    PubMed

    Su, Xinming; Taniuchi, Namiko; Jin, Enjing; Fujiwara, Masakazu; Zhang, Lei; Ghazizadeh, Mohammad; Tashimo, Hiroyuki; Yamashita, Naomi; Ohta, Ken; Kawanami, Oichi

    2008-01-01

    Asthma is a chronic inflammatory disease characterized by airway wall remodeling in which vascular remodeling is thought to be a main contributor. Vascular endothelial growth factor (VEGF) is known as a major regulator of angiogenesis and enhancer of vascular permeability. Here, we define the spatial nature of vascular remodeling and the role of VEGF and its receptors (Flt-1 and Flk-1) in the allergic response in mice (A/J) susceptible to the development of allergen-induced airway hyperresponsiveness using morphometric and quantitative approaches. Increased vascularity, vasodilatation, and endothelial cell proliferation were found in the tracheal and bronchial walls in the early and late phases of asthma. Vascular changes were observed not only in small vessels but also in larger vessels. In contrast to normal control, lung tissue from the asthma model showed dual expression for CD31 and von Willebrand factor in the endothelial cells and alpha-smooth muscle actin and desmin in the mural cells of the vessels, suggesting a phenotypic and functional transformation. The mRNA levels of VEGF isoforms, VEGF(164) and VEGF(188), were significantly increased in the tracheal and lung tissue, respectively. In addition, the mRNA level of VEGF receptor Flk-1 was significantly increased in the trachea. These results establish the existence of vascular remodeling in the airways in a mouse model of allergic asthma and support a key role for the expression of unique VEGF isoform genes as mediators of structural changes. PMID:18334839

  12. Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome

    PubMed Central

    Belperio, John A.; Keane, Michael P.; Burdick, Marie D.; Gomperts, Brigitte; Xue, Ying Ying; Hong, Kurt; Mestas, Javier; Ardehali, Abbas; Mehrad, Borna; Saggar, Rajan; Lynch, Joseph P.; Ross, David J.; Strieter, Robert M.

    2005-01-01

    Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR+ CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR+ CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR+ CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2–/– mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment. PMID:15864347

  13. Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.

    PubMed

    Belperio, John A; Keane, Michael P; Burdick, Marie D; Gomperts, Brigitte; Xue, Ying Ying; Hong, Kurt; Mestas, Javier; Ardehali, Abbas; Mehrad, Borna; Saggar, Rajan; Lynch, Joseph P; Ross, David J; Strieter, Robert M

    2005-05-01

    Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR(+) CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR(+) CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR(+) CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2(-/-) mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment. PMID:15864347

  14. Overexpression of the SK3 channel alters vascular remodeling during pregnancy, leading to fetal demise

    PubMed Central

    Rada, Cara C.; Pierce, Stephanie L.; Nuno, Daniel W.; Zimmerman, Kathy; Lamping, Kathryn G.; Bowdler, Noelle C.; Weiss, Robert M.

    2012-01-01

    The maternal cardiovascular system undergoes hemodynamic changes during pregnancy via angiogenesis and vasodilation to ensure adequate perfusion of the placenta. Improper vascularization at the maternal-fetal interface can cause pregnancy complications and poor fetal outcomes. Recent evidence indicates that small conductance Ca2+-activated K+ channel subtype 3 (SK3) contributes to vascular remodeling during pregnancy, and we hypothesized that abnormal SK3 channel expression would alter the ability of the maternal cardiovascular system to adapt to pregnancy demands and lead to poor fetal outcomes. We investigated this hypothesis using transgenic Kcnn3tm1Jpad/Kcnn3tm1Jpad (SK3T/T) mice that overexpress the channel. Isolated pressurized uterine arteries from nonpregnant transgenic SK3T/T mice had larger basal diameters and decreased agonist-induced constriction than those from their wild-type counterparts; however, non-receptor-mediated depolarization remained intact. In addition to vascular changes, heart rates and ejection fraction were increased, whereas end systolic volume was reduced in SK3T/T mice compared with their wild-type littermates. Uterine sonography of the fetuses on pregnancy day 14 showed a significant decrease in fetal size in SK3T/T compared with wild-type mice; thus, SK3T/T mice displayed an intrauterine growth-restricted phenotype. The SK3T/T mice showed decreased placental thicknesses and higher incidence of fetal loss, losing over half of their complement of pups by midgestation. These results establish that the SK3 channel contributes to both maternal and fetal outcomes during pregnancy and point to the importance of SK3 channel regulation in maintaining a healthy pregnancy. PMID:22785240

  15. Region-specific vascular remodeling and its prevention by artificial gravity in weightless environment.

    PubMed

    Zhang, Li-Fan

    2013-12-01

    Evidence from recent ground and spaceflight studies with animals and humans supports the notion that microgravity-induced vascular remodeling contributes to postflight orthostatic intolerance. In the vascular beds of lower body, such as in splanchnic and lower limb circulation, resistance vessels would undergo hypotrophy and decrement in myogenic tone and vasoreactivity. Thus, despite the concurrent sympathetic activation, the increase in peripheral vascular resistance would still be compromised while astronauts were re-exposed to Earth's 1-G gravity, since ~75 % of the total vascular conductance lies below the heart. On the contrary, cerebral arteries would undergo hypertrophy and vasoreactivity enhancement due to adaptation to cerebral hypertension, which protects the down-stream microcirculation in the brain during spaceflight. However, the enhanced vasoreactivity of cerebral vessels might also aggravate postflight orthostatic intolerance, particularly after long-duration spaceflight. Animal studies have indicated that the underlying mechanisms may involve ion-channel remodeling in vascular smooth muscle cells and vascular NO-NOS and local renin-angiotensin system (L-RAS). Furthermore, vascular remodeling and associated ion-channel and L-RAS changes can be prevented by a countermeasure of daily short-duration restoring to normal standing posture. These findings substantiate in general the hypothesis that redistribution of transmural pressure along the arterial vasculature due to the removal of gravity might be the primary factor that initiates vascular remodeling in microgravity, and daily short-duration restoring its normal distribution by intermittent artificial gravity (IAG) can effectively prevent the vascular adaptation and hence postflight cardiovascular deconditioning. IAG might also be beneficial in maintaining vascular health during future long-duration space flight. PMID:23525669

  16. Changes in pulmonary arterial wall mechanical properties and lumenal architecture with induced vascular remodeling

    NASA Astrophysics Data System (ADS)

    Molthen, Robert C.; Heinrich, Amy E.; Haworth, Steven T.; Dawson, Christopher A.

    2004-04-01

    To explore and quantify pulmonary arterial remodeling we used various methods including micro-CT, high-resolution 3-dimensional x-ray imaging, to examine the structure and function of intact pulmonary vessels in isolated rat lungs. The rat is commonly used as an animal model for studies of pulmonary hypertension (PH) and the accompanying vascular remodeling, where vascular remodeling has been defined primarily by changes in the vessel wall composition in response to hypertension inducing stimuli such as chronic hypoxic exposure (CHE) or monocrotaline (MCT) injection. Little information has been provided as to how such changes affect the vessel wall mechanical properties or the lumenal architecture of the pulmonary arterial system that actually account for the hemodynamic consequences of the remodeling. In addition, although the link between primary forms of pulmonary hypertension and inherited genetics is well established, the role that genetic coding plays in hemodynamics and vascular remodeling is not. Therefore, we are utilizing Fawn-Hooded (FH), Sprague-Dawley (SD) and Brown Norway (BN)rat strains along with unique imaging methods to parameterize both vessel distensibility and lumenal morphometry using a principal pulmonary arterial pathway analysis based on self-consistency. We have found for the hypoxia model, in addition to decreased body weight, increased hematocrit, increased right ventricular hypertrophy, the distensibility of the pulmonary arteries is shown to decrease significantly in the presence of remodeling.

  17. Long Noncoding RNA-GAS5: A Novel Regulator of Hypertension-Induced Vascular Remodeling.

    PubMed

    Wang, Yang-Ning-Zhi; Shan, Kun; Yao, Mu-Di; Yao, Jin; Wang, Jia-Jian; Li, Xiang; Liu, Ban; Zhang, Yang-Yang; Ji, Yong; Jiang, Qin; Yan, Biao

    2016-09-01

    Vascular remodeling is an important pathological feature of hypertension, leading to increased vascular resistance and reduced compliance. Endothelial cell (EC) and vascular smooth muscle cell (VSMC) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of EC and VSMC function. Herein, we determined whether long noncoding RNA-growth arrest-specific 5 (GAS5) is involved in hypertension-related vascular remodeling. We revealed that GAS5 knockdown aggravated hypertension-induced microvascular dysfunction as shown by increased retinal neovascularization and capillary leakage. GAS5 regulated the remodeling of arteries, including caudal arteries, carotid arteries, renal arteries, and thoracic arteries. GAS5 was mainly expressed in ECs and VSMCs, and its expression was significantly downregulated in hypertension. GAS5 knockdown affected endothelial activation, endothelial proliferation, VSMC phenotypic conversion, and EC-VSMC communication in vivo and in vitro. Mechanistically, GAS5 regulated EC and VSMC function through β-catenin signaling. This study identified GAS5 as a critical regulator in hypertension and demonstrated the potential of gene therapy and drug development for treating hypertension. PMID:27432865

  18. VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy

    PubMed Central

    Kim, Minah; Park, Hyeung Ju; Seol, Jae Won; Jang, Jeon Yeob; Cho, Young-Suk; Kim, Kyu Rae; Choi, Youngsok; Lydon, John P; DeMayo, Francesco J; Shibuya, Masabumi; Ferrara, Napoleone; Sung, Hoon-Ki; Nagy, Andras; Alitalo, Kari; Koh, Gou Young

    2013-01-01

    The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined. Here we show that dynamic and variable decidual angiogenesis (sprouting, intussusception and networking), and active vigorous vascular remodelling such as enlargement and elongation of ‘vascular sinus folding’ (VSF) and mural cell drop-out occur distinctly in a spatiotemporal manner in the rapidly growing mouse uterus during early pregnancy — just after implantation but before placentation. Decidual angiogenesis is mainly regulated through VEGF-A secreted from the progesterone receptor (PR)-expressing decidual stromal cells which are largely distributed in the anti-mesometrial region (AMR). In comparison, P4-PR-regulated VEGF-A-VEGFR2 signalling, ligand-independent VEGFR3 signalling and uterine natural killer (uNK) cells positively and coordinately regulate enlargement and elongation of VSF. During the postpartum period, Tie2 signalling could be involved in vascular maturation at the endometrium in a ligand-independent manner, with marked reduction of VEGF-A, VEGFR2 and PR expressions. Overall, we show that two key vascular growth factor receptors — VEGFR2 and Tie2 — strikingly but differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri in an organotypic manner. PMID:23853117

  19. Slug Is Increased in Vascular Remodeling and Induces a Smooth Muscle Cell Proliferative Phenotype

    PubMed Central

    Coll-Bonfill, Núria; Peinado, Victor I.; Pisano, María V.; Párrizas, Marcelina; Blanco, Isabel; Evers, Maurits; Engelmann, Julia C.; García-Lucio, Jessica; Tura-Ceide, Olga; Meister, Gunter

    2016-01-01

    Objective Previous studies have confirmed Slug as a key player in regulating phenotypic changes in several cell models, however, its role in smooth muscle cells (SMC) has never been assessed. The purpose of this study was to evaluate the expression of Slug during the phenotypic switch of SMC in vitro and throughout the development of vascular remodeling. Methods and Results Slug expression was decreased during both cell-to-cell contact and TGFβ1 induced SMC differentiation. Tumor necrosis factor-α (TNFα), a known inductor of a proliferative/dedifferentiated SMC phenotype, induces the expression of Slug in SMC. Slug knockdown blocked TNFα-induced SMC phenotypic change and significantly reduced both SMC proliferation and migration, while its overexpression blocked the TGFβ1-induced SMC differentiation and induced proliferation and migration. Genome-wide transcriptomic analysis showed that in SMC, Slug knockdown induced changes mainly in genes related to proliferation and migration, indicating that Slug controls these processes in SMC. Notably, Slug expression was significantly up-regulated in lungs of mice using a model of pulmonary hypertension-related vascular remodeling. Highly remodeled human pulmonary arteries also showed an increase of Slug expression compared to less remodeled arteries. Conclusions Slug emerges as a key transcription factor driving SMC towards a proliferative phenotype. The increased Slug expression observed in vivo in highly remodeled arteries of mice and human suggests a role of Slug in the pathogenesis of pulmonary vascular diseases. PMID:27441378

  20. Yiqihuoxuejiedu Formula Inhibits Vascular Remodeling by Reducing Proliferation and Secretion of Adventitial Fibroblast after Balloon Injury

    PubMed Central

    Zhao, Ming-Jing; Wang, Jie; Gao, Yong-Hong; Liu, Hui-Min; Lv, Xi-Ying; Lei, Huan; Sun, Qing-Qin; Xu, Ying; He, Ying-Kun; Wang, Shuo-Ren

    2014-01-01

    Vascular remodeling occurs in atherosclerosis, hypertension, and restenosis after percutaneous coronary intervention. Adventitial remodeling may be a potential therapeutic target. Yiqihuoxuejiedu formula uses therapeutic principles from Chinese medicine to supplement Qi, activate blood circulation, and resolve toxin and it has been shown to inhibit vascular stenosis. To investigate effects and mechanisms of the formula on inhibiting vascular remodeling, especially adventitial remodeling, rats with a balloon injury to their common carotid artery were used and were treated for 7 or 28 days after injury. The adventitial area and α-SMA expression increased at 7 days after injury, which indicated activation and proliferation of adventitial fibroblasts. Yiqihuoxuejiedu formula reduced the adventitial areas at 7 days, attenuated the neointima and vessel wall area, stenosis percent, and α-SMA expression in the neointima, and reduced collagen content and type I/III collagen ratio in the adventitia at 28 days. Yiqihuoxuejiedu formula had more positive effects than Captopril in reducing intimal proliferation and diminishing stenosis, although Captopril lowered neointimal α-SMA expression and reduced the collagen content at 28 days. Yiqihuoxuejiedu formula has inhibitory effects on positive and negative remodeling by reducing adventitial and neointimal proliferation, reducing content, and elevating adventitial compliance. PMID:24987435

  1. Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling.

    PubMed

    Chistiakov, Dmitry A; Sobenin, Igor A; Orekhov, Alexander N; Bobryshev, Yuri V

    2015-01-01

    A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). These miRNAs contribute to vascular remodeling, an adaptive process involving phenotypic and behavioral changes in vascular cells in response to vascular injury. In proliferative vascular diseases such as atherosclerosis, pathological vascular remodeling plays a prominent role. The miR-221/222 cluster controls development and differentiation of ECs but inhibits their proangiogenic activation, proliferation, and migration. miR-221/222 are primarily implicated in maintaining endothelial integrity and supporting quiescent EC phenotype. Vascular expression of miR-221/222 is upregulated in initial atherogenic stages causing inhibition of angiogenic recruitment of ECs and increasing endothelial dysfunction and EC apoptosis. In contrast, these miRNAs stimulate VSMCs and switching from the VSMC "contractile" phenotype to the "synthetic" phenotype associated with induction of proliferation and motility. In atherosclerotic vessels, miR-221/222 drive neointima formation. Both miRNAs contribute to atherogenic calcification of VSMCs. In advanced plaques, chronic inflammation downregulates miR-221/222 expression in ECs that in turn could activate intralesion neoangiogenesis. In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles. PMID:26221589

  2. Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling

    PubMed Central

    Chistiakov, Dmitry A.; Sobenin, Igor A.; Orekhov, Alexander N.; Bobryshev, Yuri V.

    2015-01-01

    A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). These miRNAs contribute to vascular remodeling, an adaptive process involving phenotypic and behavioral changes in vascular cells in response to vascular injury. In proliferative vascular diseases such as atherosclerosis, pathological vascular remodeling plays a prominent role. The miR-221/222 cluster controls development and differentiation of ECs but inhibits their proangiogenic activation, proliferation, and migration. miR-221/222 are primarily implicated in maintaining endothelial integrity and supporting quiescent EC phenotype. Vascular expression of miR-221/222 is upregulated in initial atherogenic stages causing inhibition of angiogenic recruitment of ECs and increasing endothelial dysfunction and EC apoptosis. In contrast, these miRNAs stimulate VSMCs and switching from the VSMC “contractile” phenotype to the “synthetic” phenotype associated with induction of proliferation and motility. In atherosclerotic vessels, miR-221/222 drive neointima formation. Both miRNAs contribute to atherogenic calcification of VSMCs. In advanced plaques, chronic inflammation downregulates miR-221/222 expression in ECs that in turn could activate intralesion neoangiogenesis. In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles. PMID:26221589

  3. SIGNALING HIERARCHY THAT REGULATES ENDOTHELIAL CELL PROLIFERATION AND VASCULAR REMODELING DURING VASCULOGENESIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We previously demonstrated that during vascular morphogenesis, retinoic acid (RA) is required for the control of endothelial cell proliferation and capillary plexus remodeling. In the present studies, we define the signaling hierarchy downstream of RA that independently regulates these cellular eve...

  4. The role of vascular remodeling and inflammation in the pathogenesis of intracranial aneurysms.

    PubMed

    Penn, David L; Witte, Samantha R; Komotar, Ricardo J; Sander Connolly, E

    2014-01-01

    While the mechanisms triggering pathogenesis of intracranial aneurysms have not been fully elucidated, different mechanisms have been proposed ranging from hemodynamic mechanisms to genetic predispositions. One mechanism that has been thoroughly explored is the physiological and pathological vascular remodeling that occurs in conjunction with inflammatory reactions resulting in the initiation and progression of these lesions. Both hemodynamic stimuli and vascular inflammation can trigger a series of biochemical reactions resulting in vascular smooth muscle cell apoptosis and migration causing thinned, dilated areas of the cerebral vasculature. In addition, an imbalance between extracellular matrix remodeling proteins, such as matrix metalloproteinases and their inhibitors, can result in accelerated degradation of the internal elastic lamina and the adventitial layers, further weakening the vessel. While these processes occur under normal physiological conditions, situations that alter their balance such as inflammation caused by cigarette smoking or cocaine usage or hypoxia induced under chronic hypertensive conditions can alter the delicate balance of these reactions potentiating pathological remodeling and aneurysm development. The present study represents a thorough literature review of the vascular remodeling and inflammatory components to aneurysmal pathogenesis. PMID:24120708

  5. βA3/A1-crystallin is required for proper astrocyte template formation and vascular remodeling in the retina

    PubMed Central

    Sinha, Debasish; Valapala, Mallika; Bhutto, Imran; Patek, Bonnie; Zhang, Cheng; Hose, Stacey; Yang, Fang; Cano, Marisol; Stark, Walter J.; Lutty, Gerard A.; Zigler, J. Samuel; Wawrousek, Eric F.

    2013-01-01

    Nuc1 is a spontaneous rat mutant resulting from a mutation in the Cryba1 gene, coding for βA3/A1-crystallin. Our earlier studies with Nuc1 provided novel evidence that astrocytes, which express βA3/A1-crystallin, have a pivotal role in retinal remodeling. The role of astrocytes in the retina is only beginning to be explored. One of the limitations in the field is the lack of appropriate animal models to better investigate the function of astrocytes in retinal health and disease. We have now established transgenic mice that overexpress the Nuc1 mutant form of Cryba1, specifically in astrocytes. Astrocytes in wild type mice show normal compact stellate structure, producing a honeycomb-like network. In contrast, in transgenics over-expressing the mutant (Nuc1) Cryba1 in astrocytes, bundle-like structures with abnormal patterns and morphology were observed. In the nerve fiber layer of the transgenic mice, an additional layer of astrocytes adjacent to the vitreous is evident. This abnormal organization of astrocytes affects both the superficial and deep retinal vascular density and remodeling. Fluorescein angiography showed increased venous dilation and tortuosity of branches in the transgenic retina, as compared to wild type. Moreover, there appear to be fewer interactions between astrocytes and endothelial cells in the transgenic retina than in normal mouse retina. Further, astrocytes overexpressing the mutant βA3/A1-crystallin migrate into the vitreous, and ensheath the hyaloid artery, in a manner similar to that seen in the Nuc1 rat. Together, these data demonstrate that developmental abnormalities of astrocytes can affect the normal remodeling process of both fetal and retinal vessels of the eye and that βA3/A1-crystallin is essential for normal astrocyte function in the retina. PMID:22427112

  6. Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model

    PubMed Central

    Wong, ChunYu; Bezhaeva, Taisiya; Rothuizen, Tonia C.; Metselaar, Josbert M.; de Vries, Margreet R.; Verbeek, Floris P. R.; Vahrmeijer, Alexander L.; Wezel, Anouk; van Zonneveld, Anton-Jan; Rabelink, Ton J.; Quax, Paul H. A.; Rotmans, Joris I.

    2016-01-01

    Arteriovenous fistulas (AVF) for hemodialysis access have a 1-year primary patency rate of only 60%, mainly as a result of maturation failure that is caused by insufficient outward remodeling and intimal hyperplasia. The exact pathophysiology remains unknown, but the inflammatory vascular response is thought to play an important role. In the present study we demonstrate that targeted liposomal delivery of prednisolone increases outward remodeling of the AVF in a murine model. Liposomes accumulate in the post-anastomotic area of the venous outflow tract in which the vascular pathology is most prominent in failed AVFs. On a histological level, we observed a reduction of lymphocytes and granulocytes in the vascular wall. In addition, a strong anti-inflammatory effect of liposomal prednisolone on macrophages was demonstrated in vitro. Therefore, treatment with liposomal prednisolone might be a valuable strategy to improve AVF maturation. PMID:27460883

  7. Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model.

    PubMed

    Wong, ChunYu; Bezhaeva, Taisiya; Rothuizen, Tonia C; Metselaar, Josbert M; de Vries, Margreet R; Verbeek, Floris P R; Vahrmeijer, Alexander L; Wezel, Anouk; van Zonneveld, Anton-Jan; Rabelink, Ton J; Quax, Paul H A; Rotmans, Joris I

    2016-01-01

    Arteriovenous fistulas (AVF) for hemodialysis access have a 1-year primary patency rate of only 60%, mainly as a result of maturation failure that is caused by insufficient outward remodeling and intimal hyperplasia. The exact pathophysiology remains unknown, but the inflammatory vascular response is thought to play an important role. In the present study we demonstrate that targeted liposomal delivery of prednisolone increases outward remodeling of the AVF in a murine model. Liposomes accumulate in the post-anastomotic area of the venous outflow tract in which the vascular pathology is most prominent in failed AVFs. On a histological level, we observed a reduction of lymphocytes and granulocytes in the vascular wall. In addition, a strong anti-inflammatory effect of liposomal prednisolone on macrophages was demonstrated in vitro. Therefore, treatment with liposomal prednisolone might be a valuable strategy to improve AVF maturation. PMID:27460883

  8. Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

    PubMed Central

    Ali, Ziad A.; de Jesus Perez, Vinicio; Yuan, Ke; Orcholski, Mark; Pan, Stephen; Qi, Wei; Chopra, Gaurav; Adams, Christopher; Kojima, Yoko; Leeper, Nicholas J.; Qu, Xiumei; Zaleta-Rivera, Kathia; Kato, Kimihiko; Yamada, Yoshiji; Oguri, Mitsutoshi; Kuchinsky, Allan; Hazen, Stanley L.; Jukema, J. Wouter; Ganesh, Santhi K.; Nabel, Elizabeth G.; Channon, Keith; Leon, Martin B.; Charest, Alain; Quertermous, Thomas; Ashley, Euan A.

    2014-01-01

    Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling. PMID:25401476

  9. Ultrasonographic diagnosis of unusual portal vascular abnormalities in two cats.

    PubMed

    McConnell, J F; Sparkes, A H; Ladlow, J; Doust, R; Davies, S

    2006-06-01

    Two cases of ascites secondary to portal vascular abnormalities associated with portal hypertension are described. In the first case a five-month-old cat was presented with recurrent ascites and investigations showed that the underlying cause was a hepatic arteriovenous fistula. Ultrasonography showed direct communication of the coeliac artery and right branch of the portal vein. There was also hepatofugal flow in the main portal vein consistent with portal hypertension. The ultrasonographic features were similar to those seen in dogs with hepatic arteriovenous fistulae. In the second case, ascites, portal hypertension and an intraluminal mass in the main portal vein was diagnosed in a 16-year-old cat that had been presented with hyperthyroidism and hepatomegaly. Acquired portosystemic collaterals involving the left renal vein were present. Additional diagnostic investigations were not permitted. Ultrasonography was useful in both cases to document portal hypertension and the underlying cause. PMID:16761986

  10. Antagonism of Stem Cell Factor/c-kit Signaling Attenuates Neonatal Chronic Hypoxia-Induced Pulmonary Vascular Remodeling

    PubMed Central

    Young, Karen C; Torres, Eneida; Hehre, Dorothy; Wu, Shu; Suguihara, Cleide; Hare, Joshua M.

    2015-01-01

    Background Accumulating evidence suggests that c-kit positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/ c-kit regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis. Methods Neonatal FVB/NJ mice treated with non-immune IgG (PL), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1- Kit W− v/ +) and their congenic controls, were exposed to normoxia (FiO2=0.21) or hypoxia (FiO2=0.12) for two weeks. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation and remodeling were evaluated. Results As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. Conclusion SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH. PMID:26705118

  11. Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect.

    PubMed

    Tanaka, Leonardo Y; Araújo, Haniel A; Hironaka, Gustavo K; Araujo, Thaís L S; Takimura, Celso K; Rodriguez, Andres I; Casagrande, Annelise S; Gutierrez, Paulo S; Lemos-Neto, Pedro Alves; Laurindo, Francisco R M

    2016-03-01

    Whole-vessel remodeling critically determines lumen caliber in vascular (patho)physiology, and it is reportedly redox-dependent. We hypothesized that the cell-surface pool of the endoplasmic reticulum redox chaperone protein disulfide isomerase-A1 (peri/epicellular=pecPDI), which is known to support thrombosis, also regulates disease-associated vascular architecture. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling and plaque stability. In a rabbit iliac artery overdistension model, there was unusually high PDI upregulation (≈25-fold versus basal, 14 days postinjury), involving both intracellular and pecPDI. PecPDI neutralization with distinct anti-PDI antibodies did not enhance endoplasmic reticulum stress or apoptosis. In vivo pecPDI neutralization with PDI antibody-containing perivascular gel from days 12 to 14 post injury promoted 25% decrease in the maximally dilated arteriographic vascular caliber. There was corresponding whole-vessel circumference loss using optical coherence tomography without change in neointima, which indicates constrictive remodeling. This was accompanied by decreased hydrogen peroxide generation. Constrictive remodeling was corroborated by marked changes in collagen organization, that is, switching from circumferential to radial fiber orientation and to a more rigid fiber type. The cytoskeleton architecture was also disrupted; there was a loss of stress fiber coherent organization and a switch from thin to medium thickness actin fibers, all leading to impaired viscoelastic ductility. Total and PDI-associated expressions of β1-integrin, and levels of reduced cell-surface β1-integrin, were diminished after PDI antibody treatment, implicating β1-integrin as a likely pecPDI target during vessel repair. Indeed, focal adhesion kinase phosphorylation, a downstream β1-integrin effector, was decreased by PDI antibody. Thus, the upregulated pecPDI pool tunes matrix/cytoskeleton reshaping to

  12. A 3-D constrained mixture model for mechanically mediated vascular growth and remodeling

    PubMed Central

    Wan, William; Hansen, Laura

    2010-01-01

    In contrast to the widely applied approach to model soft tissue remodeling employing the concept of volumetric growth, microstructurally motivated models are capable of capturing many of the underlying mechanisms of growth and remodeling; i.e., the production, removal, and remodeling of individual constituents at different rates and to different extents. A 3-dimensional constrained mixture computational framework has been developed for vascular growth and remodeling, considering new, microstructurally motivated kinematics and constitutive equations and new stress and muscle activation mediated evolution equations. Our computational results for alterations in flow and pressure, using reasonable physiological values for rates of constituent growth and turnover, concur with findings in the literature. For example, for flow-induced remodeling, our simulations predict that, although the wall shear stress is restored completely, the circumferential stress is not restored employing realistic physiological rate parameters. Also, our simulations predict different levels of thickening on inner versus outer wall locations, as shown in numerous reports of pressure-induced remodeling. Whereas the simulations are meant to be illustrative, they serve to highlight the experimental data currently lacking to fully quantify mechanically mediated adaptations in the vasculature. PMID:20039091

  13. Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors.

    PubMed

    Briet, Marie; Barhoumi, Tlili; Mian, Muhammad Oneeb Rehman; Coelho, Suellen C; Ouerd, Sofiane; Rautureau, Yohann; Coffman, Thomas M; Paradis, Pierre; Schiffrin, Ernesto L

    2016-05-01

    We investigated the role of angiotensin type 1a receptors (AGTR1a) in vascular injury induced by aldosterone activation of mineralocorticoid receptors in Agtr1a(-/-) and wild-type (WT) mice infused with aldosterone for 14 days while receiving 1% NaCl in drinking water. Aldosterone increased systolic blood pressure (BP) by ≈30 mm Hg in WT mice and ≈50 mm Hg in Agtr1a(-/-) mice. Aldosterone induced aortic and small artery remodeling, impaired endothelium-dependent relaxation in WT mice, and enhanced fibronectin and collagen deposition and vascular inflammation. None of these vascular effects were observed in Agtr1a(-/-) mice. Aldosterone effects were prevented by the AGTR1 antagonist losartan in WT mice. In contrast to aldosterone, norepinephrine caused similar BP increase and mesenteric artery remodeling in WT and Agtr1a(-/-) mice. Agtr1a(-/-) mice infused with aldosterone did not increase sodium excretion in response to a sodium chloride challenge, suggesting that sodium retention could contribute to the exaggerated BP rise induced by aldosterone. Agtr1a(-/-) mice had decreased mesenteric artery expression of the calcium-activated potassium channel Kcnmb1, which may enhance myogenic tone and together with sodium retention, exacerbate BP responses to aldosterone/salt in Agtr1a(-/-) mice. We conclude that although aldosterone activation of mineralocorticoid receptors raises BP more in Agtr1a(-/-) mice, AGTR1a is required for mineralocorticoid receptor stimulation to induce vascular remodeling and inflammation and endothelial dysfunction. PMID:27045029

  14. Axl, a receptor tyrosine kinase, mediates flow-induced vascular remodeling.

    PubMed

    Korshunov, Vyacheslav A; Mohan, Amy M; Georger, Mary A; Berk, Bradford C

    2006-06-01

    Intima-media thickening (IMT) in response to hemodynamic stress is a physiological process that requires coordinated signaling among endothelial, inflammatory, and vascular smooth muscle cells (VSMC). Axl, a receptor tyrosine kinase, whose ligand is Gas6, is highly induced in VSMC after carotid injury. Because Axl regulates cell migration, phagocytosis and apoptosis, we hypothesized that Axl would play a role in IMT. Vascular remodeling in mice deficient in Axl (Axl(-/-)) and wild-type littermates (Axl(+/+)) was induced by ligation of the left carotid artery (LCA) branches maintaining flow via the left occipital artery. Both genotypes had similar baseline hemodynamic parameters and carotid artery structure. Partial ligation altered blood flow equally in both genotypes: increased by 60% in the right carotid artery (RCA) and decreased by 80% in the LCA. There were no significant differences in RCA remodeling between genotypes. However, in the LCA Axl(-/-) developed significantly smaller intima+media compared with Axl(+/+) (31+/-4 versus 42+/-6x10(-6) microm3, respectively). Quantitative immunohistochemistry of Axl(-/-) LCA showed increased apoptosis compared with Axl(+/+) (5-fold). As expected, p-Akt was decreased in Axl(-/-), whereas there was no difference in Gas6 expression. Cell composition also changed significantly, with increases in CD45+ cells and decreases in VSMC, macrophages, and neutrophils in Axl(-/-) compared with Axl(+/+). These data demonstrate an important role for Axl in flow-dependent remodeling by regulating vascular apoptosis and vascular inflammation. PMID:16627783

  15. Abnormal deposition of collagen/elastic vascular fibres and prognostic significance in idiopathic interstitial pneumonias

    PubMed Central

    Parra, Edwin Roger; Kairalla, Ronaldo Adib; de Carvalho, Carlos Roberto Ribeiro; Capelozzi, Vera Luiza

    2007-01-01

    Background Vascular remodelling has recently been shown to be a promising pathogenetic indicator in idiopathic interstitial pneumonias (IIPs). Aim To validate the importance of the collagen/elastic system in vascular remodelling and to study the relationships between the collagen/elastic system, survival and the major histological patterns of IIPs. Methods Collagen/elastic system fibres were studied in 25 patients with acute interstitial pneumonia/diffuse alveolar damage, 22 with non‐specific interstitial pneumonia/non‐specific interstitial pneumonia and 55 with idiopathic pulmonary fibrosis/usual interstitial pneumonia. The Picrosirius polarisation method and Weigert's resorcin–fuchsin histochemistry and morphometric analysis were used to evaluate the amount of vascular collagen/elastic system fibres and their association with the histological pattern of IIPs. The association between vascular remodelling and the degree of parenchymal fibrosis in usual interstitial pneumonia (UIP) was also considered. Results The vascular measurement of collagen/elastic fibres was significantly higher in UIP than in the lungs of controls, and in those with diffuse alveolar damage and those with non‐specific interstitial pneumonia. In addition, the increment of collagen/elastic fibres in UIP varied according to the degree and activity of the parenchymal fibrosis. The most important predictors of survival in UIP were vascular remodelling classification and vascular collagen deposition. Conclusion A progressive vascular fibroelastosis occurs in IIP histological patterns, probably indicating evolutionarily adapted responses to parenchymal injury. The vascular remodelling classification and the increase in vascular collagen were related to survival in IIP and possibly play a role in its pathogenesis. Further studies are needed to determine whether this relationship is causal or consequential. PMID:17251318

  16. Gax regulates human vascular smooth muscle cell phenotypic modulation and vascular remodeling

    PubMed Central

    Zheng, Hui; Hu, Zhenlei; Zhai, Xinming; Wang, Yongyi; Liu, Jidong; Wang, Weijun; Xue, Song

    2016-01-01

    Abnormal phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of cardiovascular diseases such as atherosclerosis, hypertension and restenosis after angioplasty. Transcription factors have emerged as critical regulators for VSMCs function, and recently we verified inhibiting transcription factor Gax was important for controlling VSMCs proliferation and migration. This study aimed to determine its role in phenotypic modulation of VSMCs. Western blot revealed that overexpression of Gax increased expression of VSMCs differentiation marker genes such as calponin and SM-MHC 11. Then, Gax overexpression potently suppressed proliferation and migration of VSMCs with or without platelet-derived growth factor-induced-BB (PDGF-BB) stimuli whereas Gax silencing inhibited these processes. Furthermore, cDNA array analysis indicated that Rap1A gene was the downstream target of Gax in human VSMCs. And overexpression of Gax significantly inhibited expression of Rap1A in VSMCs with or without PDGF-BB stimuli. Moreover, overexpression of Rap1A decreased expression of VSMCs differentiation marker genes and increased proliferation and migration of VSMCs with or without PDGF-BB stimuli. Finally, Gax overexpression significantly inhibited the neointimal formation in carotid artery injury of mouse models, specifically through maintaining VSMCs contractile phenotype by decreasing Rap1A expression. In conclusion, these results indicated that Gax was a regulator of human VSMCs phenotypic modulation by targeting Rap1A gene, which suggested that targeting Gax or its downstream targets in human VSMCs may provide an attractive approach for the prevention and treatment of cardiovascular diseases. PMID:27508012

  17. Tetrahydrocurcumin Protects against Cadmium-Induced Hypertension, Raised Arterial Stiffness and Vascular Remodeling in Mice

    PubMed Central

    Sangartit, Weerapon; Kukongviriyapan, Upa; Donpunha, Wanida; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Surawattanawan, Praphassorn; Greenwald, Stephen E.

    2014-01-01

    Background Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice. Methods Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. Results Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues. Conclusions Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure. PMID:25502771

  18. Excitation-contraction coupling and excitation-transcription coupling in blood vessels: their possible interactions in hypertensive vascular remodeling.

    PubMed

    Misárková, E; Behuliak, M; Bencze, M; Zicha, J

    2016-06-20

    Vascular smooth muscle cells (VSMC) display considerable phenotype plasticity which can be studied in vivo on vascular remodeling which occurs during acute or chronic vascular injury. In differentiated cells, which represent contractile phenotype, there are characteristic rapid transient changes of intracellular Ca(2+) concentration ([Ca(2+)]i), while the resting cytosolic [Ca(2+)]i concentration is low. It is mainly caused by two components of the Ca(2+) signaling pathways: Ca(2+) entry via L-type voltage-dependent Ca(2+) channels and dynamic involvement of intracellular stores. Proliferative VSMC phenotype is characterized by long-lasting [Ca(2+)]i oscillations accompanied by sustained elevation of basal [Ca(2+)]i. During the switch from contractile to proliferative phenotype there is a general transition from voltage-dependent Ca(2+) entry to voltage-independent Ca(2+) entry into the cell. These changes are due to the altered gene expression which is dependent on specific transcription factors activated by various stimuli. It is an open question whether abnormal VSMC phenotype reported in rats with genetic hypertension (such as spontaneously hypertensive rats) might be partially caused by a shift from contractile to proliferative VSMC phenotype. PMID:27322009

  19. Activation of Calpain-2 by Mediators in Pulmonary Vascular Remodeling of Pulmonary Arterial Hypertension.

    PubMed

    Kovacs, Laszlo; Han, Weihong; Rafikov, Ruslan; Bagi, Zsolt; Offermanns, Stefan; Saido, Takaomi C; Black, Stephen M; Su, Yunchao

    2016-03-01

    Calpain mediates collagen synthesis and cell proliferation and plays an important role in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). In the present study, we investigated whether and how calpain is activated by PAH mediators in pulmonary artery smooth muscle cells (PASMCs). These data show that smooth muscle-specific knockout of calpain attenuated and knockout of calpastatin potentiated pulmonary vascular remodeling and pulmonary hypertension. Treatment of PASMCs with the PAH mediators platelet-derived growth factor (PDGF), serotonin, H2O2, endothelin-1, and IL-6 caused significant increases in calpain activity, cell proliferation, and collagen-I protein level without changes in protein levels of calpain-1 and -2. The calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA/AM) did not affect calpain activation, but the extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD98059 and knocking down of calpain-2 prevented calpain activation in PAH mediator-treated PASMCs. Mass spectrometry data showed that the phosphorylation of calpain-2 at serine (Ser) 50 was increased and the phosphorylation of calpain-2 at Ser369 was decreased in PDGF-treated PASMCs. The PDGF-induced increase in Ser50 phosphorylation of calpain-2 was prevented by PD98059, whereas dephosphorylation of calpain-2 at Ser369 was blocked by the protein phosphatase 2A inhibitor fostriecin. Furthermore, smooth muscle of pulmonary arteries in PAH animal models and patients with PAH showed higher levels of phospho-Ser50-calpain-2 (P-Ser50) and lower levels of phospho-Ser369-calpain-2 (P-Ser369). These data support that calpain modulates pulmonary vascular remodeling in PAH. PAH mediator-induced activation of calpain is caused by ERK1/2-dependent phosphorylation of calpain-2 at Ser50 and protein phosphatase 2A-dependent dephosphorylation of calpain-2 at Ser369 in pulmonary vascular remodeling of PAH. PMID:26248159

  20. Vascular and right ventricular remodelling in chronic thromboembolic pulmonary hypertension.

    PubMed

    Delcroix, Marion; Vonk Noordegraaf, Anton; Fadel, Elie; Lang, Irene; Simonneau, Gérald; Naeije, Robert

    2013-01-01

    In chronic thromboembolic pulmonary hypertension (CTEPH) increased pulmonary vascular resistance is caused by fibrotic organisation of unresolved thromboemboli. CTEPH mainly differs from pulmonary arterial hypertension (PAH) by the proximal location of pulmonary artery obliteration, although distal arteriopathy can be observed as a consequence of non-occluded area over-perfusion. Accordingly, there is proportionally more wave reflection in CTEPH, impacting on pressure and flow wave morphology. However, the time constant, i.e. resistance × compliance, is not different in CTEPH and PAH, indicating only trivial effects of proximal wave reflection on hydraulic right ventricular load. More discriminative is the analysis of the pressure decay after pulmonary arterial occlusion, which is more rapid in the absence of significant distal arteriopathy. Structure and function of the right ventricle show a similar pattern to right ventricular hypertrophy, namely dilatation and wall thickening, as well as loss of function in CTEPH and PAH. This is probably related to similar loading conditions. Hyperventilation with hypocapnia is characteristic of both PAH and CTEPH. Ventilatory equivalents for carbon dioxide, as a function of arterial carbon dioxide tension, conform to the alveolar ventilation equation in both conditions, indicating a predominant role of increased chemosensitivity. However, a slight increase in the arterial to end-tidal carbon dioxide tension gradient in CTEPH shows a contribution of increased dead space ventilation. PMID:22903956

  1. Plasma concentrations of endothelin in patients with abnormal vascular reactivity

    SciTech Connect

    Predel, H.G.; Meyer-Lehnert, H.; Baecker, A.; Stelkens, H.; Kramer, H.J. )

    1990-01-01

    We measured circulating concentrations of endothelin in healthy subjects and in patients with abnormal vascular reactivity. Endothelin concentrations were determined by radioimmunoassay after extraction of plasma using Sep-Pak C-18 cartridges in healthy subjects, in patients with diabetes mellitus type I, in patients with mild to moderate essential hypertension and in non-dialyzed patients with stable chronic renal failure. Plasma concentrations were similar in healthy controls, in diabetics and in hypertensive patients averaging 5.0{plus minus}0.6 pg/ml, 4.7{plus minus}0.2 pg/ml and 6.5{plus minus}1.0 pg/ml, respectively. In contrast, plasma concentrations of endothelin were markedly elevated in patients with chronic renal failure averaging 16.6{plus minus}2.9 pg/ml. No correlations were observed between serum creatinine concentrations ranging from 124 to 850 {mu}mol/l or blood pressure and plasma concentrations of endothelin. Bicycle ergometric exercise in six healthy subjects and an acute modest i.v. saline load of 1,000 ml of 0.45% NaCl administered within 60 min in six patients with mild essential hypertension did not affect plasma concentrations of endothelin.

  2. Variation in Cardiac Pulse Frequencies Modulates vSMC Phenotype Switching During Vascular Remodeling.

    PubMed

    Tosun, Zehra; McFetridge, Peter S

    2015-03-01

    In vitro perfusion systems have exposed vascular constructs to mechanical conditions that emulate physiological pulse pressure and found significant improvements in graft development. However, current models maintain constant, or set pulse/shear mechanics that do not account for the natural temporal variation in frequency. With an aim to develop clinically relevant small diameter vascular grafts, these investigations detail a perfusion culture model that incorporates temporal pulse pressure variation. Our objective was to test the hypothesis that short-term variation in heart rate, such as changes in respiratory activity, plays a significant role in vascular remodeling and graft development. The pulse rate of a healthy volunteer was logged to model the effect of daily activities on heart rate. Vascular bioreactors were used to deliver perfusion conditions based on modeled frequencies of temporal pulse variability, termed Physiologically Modeled Pulse Dynamics (PMPD). Acellular scaffolds derived from the human umbilical vein were seeded with human vascular smooth muscle cells and perfused under defined pulsatile conditions. vSMC exposed to constant pulse frequencies expressed a contractile phenotype, while exposure to PMPD drove cells to a synthetic state with continued cell proliferation, increased tensile strength and stiffness as well as diminished vasoactivity. Results show the temporal variation associated with normal heart physiology to have a profound effect on vascular remodeling and vasoactive function. While these models are representative of vascular regeneration further investigation is required to understanding these and other key regulators in vSMC phenotype switching in non-pathological or wound healing states. This understanding has important clinical implications that may lead to improved treatments that enhance vessel regeneration. PMID:26577103

  3. Impaired Glutathione Redox System Paradoxically Suppresses Angiotensin II-Induced Vascular Remodeling

    PubMed Central

    Izawa, Kazuma; Okada, Motoi; Sumitomo, Kazuhiro; Nakagawa, Naoki; Aizawa, Yoshiaki; Kawabe, Junichi; Kikuchi, Kenjiro; Hasebe, Naoyuki

    2014-01-01

    Background Angiotensin II (AII) plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH) redox status in cardiovascular remodeling remains unknown. Methods In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute) to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU) was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs). Results BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215±4 mmHg by AII at 4 weeks (p<0.01), which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52±0.08, 2.50±0.09 and 2.10±0.07 mg/g respectively, p<0.05). Surprisingly, the co-treatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester. Conclusions We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII. PMID

  4. IgE mediates broncho-vascular remodeling after neonatal sensitization in mice.

    PubMed

    Chetty, Anne; Cao, Gong-Jie; Sharda, Azeem; Tsay, Theresia; Nielsen, Heber C

    2016-01-01

    The temporal origins of childhood asthma are incompletely understood. We hypothesize that allergen sensitization which begins in early infancy causes IgE-mediated airway and vascular remodeling, and airway hyper-responsiveness. Mice were sensitized with ovalbumin (OVA) without or with anti-IgE antibody from postnatal day (P) 10 through P42. We studied airway resistance in response to Methacholine (MCh) challenge, bronchoalveolar lavage fluid (BAL) inflammatory cell content, immunohistochemistry for inflammation, alpha-smooth muscle actin (alpha-SMA) and platelet/endothelial cell adhesion molecule (PECAM) proteins, and Western blotting for vascular endothelial growth factor (VEGF) protein. Compared to controls, mice treated with OVA had increased airway resistance (baseline: 192% of control; MCH 12 mg/mL 170% of control; P less than 0.0.5). OVA treatment also increased lung alpha-SMA, VEGF and PECAM compared to controls. Inflammatory cells in the BAL and perivascular and peribronchiolar inflammatory cell infiltrates increased over controls with OVA exposure. These changes were counteracted by anti-IgE treatment. We conclude that mice sensitized in early infancy develop an IgE-mediated hyper-reactive airway disease with airway and vascular remodeling. Preventive approaches in early infancy of at-risk individuals may reduce childhood asthma. PMID:27100345

  5. Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension

    PubMed Central

    Liu, Fei; Haeger, Christina Mallarino; Dieffenbach, Paul B.; Sicard, Delphine; Chrobak, Izabela; Coronata, Anna Maria F.; Suárez Velandia, Margarita M.; Vitali, Sally; Colas, Romain A.; Norris, Paul C.; Marinković, Aleksandar; Liu, Xiaoli; Ma, Jun; Rose, Chase D.; Lee, Seon-Jin; Comhair, Suzy A.A.; Erzurum, Serpil C.; McDonald, Jacob D.; Serhan, Charles N.; Walsh, Stephen R.; Tschumperlin, Daniel J.; Fredenburgh, Laura E.

    2016-01-01

    Pulmonary arterial (PA) stiffness is associated with increased mortality in patients with pulmonary hypertension (PH); however, the role of PA stiffening in the pathogenesis of PH remains elusive. Here, we show that distal vascular matrix stiffening is an early mechanobiological regulator of experimental PH. We identify cyclooxygenase-2 (COX-2) suppression and corresponding reduction in prostaglandin production as pivotal regulators of stiffness-dependent vascular cell activation. Atomic force microscopy microindentation demonstrated early PA stiffening in experimental PH and human lung tissue. Pulmonary artery smooth muscle cells (PASMC) grown on substrates with the stiffness of remodeled PAs showed increased proliferation, decreased apoptosis, exaggerated contraction, enhanced matrix deposition, and reduced COX-2–derived prostanoid production compared with cells grown on substrates approximating normal PA stiffness. Treatment with a prostaglandin I2 analog abrogated monocrotaline-induced PA stiffening and attenuated stiffness-dependent increases in proliferation, matrix deposition, and contraction in PASMC. Our results suggest a pivotal role for early PA stiffening in PH and demonstrate the therapeutic potential of interrupting mechanobiological feedback amplification of vascular remodeling in experimental PH. PMID:27347562

  6. Regression and persistence: remodelling in a tissue engineered axial vascular assembly

    PubMed Central

    Polykandriotis, E; Euler, S; Arkudas, A; Pryymachuk, G; Beier, J P; Greil, P; Dragu, A; Lametschwandtner, A; Kneser, U; Horch, R E

    2009-01-01

    In later stages of vasculoangiogenesis a vascular network is going through a metamorphosis for optimal perfusion and economy of energy. In this study we make a quantitative approach to phenomena of remodelling in a bioartificial neovascular network and suggest variance of calibre as a parameter of neovascular maturation. For this study, 18 male Lewis rats were subjected to the AV loop operation in combination with a hard porous biogenic matrix and an isolation chamber. The animals were allocated into three groups for different explantation intervals set to 2, 4 and 8 weeks, respectively. Collective attributes like vascular density, percent fractional area and variance of calibre were evaluated for a predefined region of interest (ROI). Late morphogenesis was evaluated by means of scanning electron microscopy. After the fourth week the absolute number of vessels within the ROI decreased (P < 0.03) whereas, on the contrary, the fractional area of all segments increased (P < 0.02). The variance in calibre was significantly increased in the 8-week group (P < 0.05). Lymphatic growth after week 4, early pericyte migration as well as intussusceptive angiogenesis were identified immunohistologically. Phenomena of remodelling were evaluated quantitatively in a neovascular network and variance could be proposed as a parameter of net vascular maturation. PMID:19555425

  7. The role of cystatin C in vascular remodeling of balloon-injured abdominal aorta of rabbits.

    PubMed

    Wu, Xiang-Jun; Dong, Zhao-Qiang; Lu, Qing-Hua

    2014-09-01

    This study aimed to evaluate the role of cystatin C (CysC) in the vascular remodeling of balloon-injured abdominal aorta of rabbits. Forty-eight New Zealand white rabbits were randomly divided into three groups: the balloon-injured injury group (n = 16), the CysC monoclonal antibody group (n = 16), and the sham-operative group (n = 16). Serum CysC levels were detected by enzyme linked immunosorbent assay. Changes in adventitial area, adventitial thickness, lumen area (LA), neointimal area (IA), internal elastic lamina area (IELA), external elastic lamina area (EELA), vascular remodeling index (VRI) and residual stenosis (RS) were measured by the Leica image analysis system. Immunohistochemical analysis of α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) were performed. Serum CysC levels of rabbits in the balloon-injured injury group were significantly higher than those in the CysC monoclonal antibody group and the sham-operative group (both P < 0.05). At 6 weeks after balloon injury, the adventitial area and thickness, LA, IA, IELA and EELA in the balloon-injured injury group were also higher than those in the CysC monoclonal antibody and sham-operative groups (all P < 0.05). In addition, the balloon-injured injury group showed higher VRI and RS than those of the CysC monoclonal antibody group (both P < 0.05). The positive expression of α-SMA in the vascular adventitia and media in the balloon-injured group were higher than that of the CysC monoclonal antibody and sham-operative groups. The balloon-injured group also showed a stronger expression of α-SMA in the neointima than that of the CysC monoclonal antibody group. There was a strong positive expression of PCNA in the vascular adventitia and neointima in the balloon-injured and CysC monoclonal antibody groups. However, the number of PCNA-positive cells in the balloon-injured group was higher than that of the CysC monoclonal antibody group (25.45 ± 4.21 vs. 6.75 ± 1.11, P = 0

  8. Assessment of Maternal Vascular Remodeling During Pregnancy in the Mouse Uterus

    PubMed Central

    Kieckbusch, Jens; Gaynor, Louise M.; Colucci, Francesco

    2015-01-01

    The placenta mediates the exchange of factors such as gases and nutrients between mother and fetus and has specific demands for supply of blood from the maternal circulation. The maternal uterine vasculature needs to adapt to this temporary demand and the success of this arterial remodeling process has implications for fetal growth. Cells of the maternal immune system, especially natural killer (NK) cells, play a critical role in this process. Here we describe a method to assess the degree of remodeling of maternal spiral arteries during mouse pregnancy. Hematoxylin and eosin-stained tissue sections are scanned and the size of the vessels analysed. As a complementary validation method, we also present a qualitative assessment for the success of the remodeling process by immunohistochemical detection of smooth muscle actin (SMA), which normally disappears from within the arterial vascular media at mid-gestation. Together, these methods enable determination of an important parameter of the pregnancy phenotype. These results can be combined with other endpoints of mouse pregnancy to provide insight into the mechanisms underlying pregnancy-related complications. PMID:26710086

  9. The Fractal-based Analysis of the Regulation of Vascular Remodeling in the Quail Chorioallantoic Membrane

    NASA Technical Reports Server (NTRS)

    Smith, Genee S.

    2004-01-01

    Critical to the advancement of space exploration is the safety and well being of astronauts while in space. This study focuses on the second highest of NASA-defined risk categories for human space exploration, cardiovascular alterations. Current research of this problem is being tackled by investigating angiogenesis through vascular remodeling. Angiogenesis is the growth and formation of new blood vessels. Angiogenesis is an important part of maintaining normal development and bodily functions. The loss of control of this process, either insufficient or excessive vascular growth, is considered a common denominator in many diseases, such as cancer, diabetes, and coronary artery disease. Objectives are presently being met by observing the effects of various regulators, like thrombospondin 1 (TSP-1) and a novel vessel tortuosity factor (TF), through the use of the chorioallantoic membrane (CAM) of Japanese quail embryos, which enables the direct optical imaging of 2-dimensional vascular branching trees. Research within the CAM is being performed to deduce numerous methods of regulating vessel growth. This project centers on the ability of a novel vessel regulator to affect angiogenesis. For example, it is hypothesized that the TSP-1 will inhibit the growth of CAM vasculature. Fractal/VESGEN-based techniques and PTV analysis are the methodologies used to investigate vascular differentiation. This tactic is used to quantify results and measure the growth patterns and morphology of blood vessels. The regulatory mechanisms posed by this vessel regulator can be deduced by alterations found within the vasculature patterns of quail embryos.

  10. TLR4 regulates pulmonary vascular homeostasis and remodeling via redox signaling

    PubMed Central

    Ma, Liping; Ambalavanan, Namasivayam; Liu, Hui; Sun, Yong; Jhala, Nirag; Bradley, Wayne E.; Dell’Italia, Louis J.; Michalek, Sue; Wu, Hui; Steele, Chad; Benza, Raymond L; Chen, Yabing

    2016-01-01

    Pulmonary arterial hypertension (PAH) contributes to morbidity and mortality of patients with lung and heart diseases. We demonstrated that hypoxia induced PAH and increased pulmonary arterial wall thickness in wild-type mice. Mice deficient in toll-like receptor 4 (TLR4−/−) spontaneously developed PAH, which was not further enhanced by hypoxia. Echocardiography determined right ventricular hypertrophy and decreased pulmonary arterial acceleration time were associated with the development of PAH in TLR4−/− mice. In pulmonary arterial smooth muscle cells (PASMC), hypoxia decreased TLR4 expression and induced reactive oxygen species (ROS) and Nox1/Nox4. Inhibition of NADPH oxidase decreased hypoxia-induced proliferation of wild-type PASMC. PASMC derived from TLR4−/− mice exhibited increased ROS and Nox4/Nox1 expression. Our studies demonstrate an important role of TLR4 in maintaining normal pulmonary vasculature and in hypoxia-induced PAH. Inhibition of TLR4, by genetic ablation or hypoxia, increases the expression of Nox1/Nox4 and induces PASMC proliferation and vascular remodeling. These results support a novel function of TLR4 in regulating the development of PAH and reveal a new regulatory axis contributing to TLR4 deficiency-induced vascular hypertrophy and remodeling. PMID:26709781

  11. Improved Recellularization of Ex Vivo Vascular Scaffolds using Directed Transport Gradients to Modulate ECM Remodeling

    PubMed Central

    Tosun, Zehra; McFetridge, Peter S.

    2015-01-01

    The regeneration of functional, clinically viable, tissues from acellular ex vivo tissues has been problematic largely due to poor nutrient transport conditions that limit cell migration and integration. Compounding these issues are subcellular pore sizes that necessarily requires extracellular matrix (ECM) remodeling in order for cells to migrate and regenerate the tissue. The aim of the present work was to create a directed growth environment that allows cells to fully populate an ex vivo-derived vascular scaffold and maintain viability over extended periods. Three different culture conditions using single (one nutrient source) or dual perfusion bioreactor systems (two nutrients sources) were designed to assess the effect of pressure and nutrient gradients under either low (50/30 mmHg) or high (120/80) relative pressure conditions. Human myofibroblasts were seeded to the ablumenal periphery of an ex vivo-derived vascular scaffold using a collagen/hydrogel cell delivery system. After 30 days culture, total cell density was consistent between groups; however, significant variation was noted in cell distribution and construct mechanics as a result of differing perfusion conditions. The most aggressive transport gradient was developed by the single perfusion low-pressure circuits and resulted in a higher proportion of cells migrating across the scaffold toward the vessel lumen (nutrient source). These investigations illustrate the influence of directed nutrient gradients where precisely controlled perfusion conditions significantly affects cell migration, distribution and function, resulting in pronounced effects on construct mechanics during early remodeling events. PMID:23613430

  12. KLF5 mediates vascular remodeling via HIF-1α in hypoxic pulmonary hypertension.

    PubMed

    Li, Xiaochen; He, Yuanzhou; Xu, Yongjian; Huang, Xiaomin; Liu, Jin; Xie, Min; Liu, Xiansheng

    2016-02-15

    Hypoxic pulmonary hypertension (HPH) is characterized by active vasoconstriction and profound vascular remodeling. KLF5, a zinc-finger transcription factor, is involved in the excessive proliferation and apoptotic resistance phenotype associated with monocrotaline-induced pulmonary hypertension. However, the molecular mechanisms of KLF5-mediated pathogenesis of HPH are largely undefined. Adult male Sprague-Dawley rats were exposed to normoxia or hypoxia (10% O2) for 4 wk. Hypoxic rats developed pulmonary arterial remodeling and right ventricular hypertrophy with significantly increased right ventricular systolic pressure. The levels of KLF5 and hypoxia-inducible factor-1α (HIF-1α) were upregulated in distal pulmonary arterial smooth muscle from hypoxic rats. The knockdown of KLF5 via short-hairpin RNA attenuated chronic hypoxia-induced hemodynamic and histological changes in rats. The silencing of either KLF5 or HIF-1α prevented hypoxia-induced (5%) proliferation and migration and promoted apoptosis in human pulmonary artery smooth muscle cells. KLF5 was immunoprecipitated with HIF-1α under hypoxia and acted as an upstream regulator of HIF-1α. The cell cycle regulators cyclin B1 and cyclin D1 and apoptosis-related proteins including bax, bcl-2, survivin, caspase-3, and caspase-9, were involved in the regulation of KLF5/HIF-1α-mediated cell survival. This study demonstrated that KLF5 plays a crucial role in hypoxia-induced vascular remodeling in an HIF-1α-dependent manner and provided a better understanding of the pathogenesis of HPH. PMID:26702149

  13. Metabolic reprogramming and inflammation act in concert to control vascular remodeling in hypoxic pulmonary hypertension.

    PubMed

    Stenmark, Kurt R; Tuder, Rubin M; El Kasmi, Karim C

    2015-11-15

    Pulmonary hypertension (PH) is a complex, multifactorial syndrome that remains poorly understood despite decades of research. PH is characterized by profound pulmonary artery (PA) remodeling that includes significant fibro-proliferative and inflammatory changes of the PA adventitia. In line with the emerging concept that PH shares key features with cancer, recent work centers on the idea that PH results from a multistep process driven by reprogramming of gene-expression patterns that govern changes in cell metabolism, inflammation, and proliferation. Data demonstrate that in addition to PA endothelial cells and smooth muscle cells, adventitial fibroblasts from animals with experimental hypoxic PH and from humans with PH (hereafter, termed PH-Fibs) exhibit proinflammatory activation, increased proliferation, and apoptosis resistance, all in the context of metabolic reprogramming to aerobic glycolysis. PH-Fibs can also recruit, retain, and activate naïve macrophages (Mϕ) toward a proinflammatory/proremodeling phenotype through secretion of chemokines, cytokines, and glycolytic metabolites, among which IL-6 and lactate play key roles. Furthermore, these fibroblast-activated Mϕ (hereafter, termed FAMϕ) exhibit aerobic glycolysis together with high expression of arginase 1, Vegfa, and I1lb, all of which require hypoxia-inducible factor 1α and STAT3 signaling. Strikingly, in situ, the adventitial Mϕ phenotype in the remodeled PA closely resembles the Mϕ phenotype induced by fibroblasts in vitro (FAMϕ), suggesting that FAMϕ crosstalk involving metabolic and inflammatory signals is a critical, pathogenetic component of vascular remodeling. This review discusses metabolic and inflammatory changes in fibroblasts and Mϕ in PH with the goal of raising ideas about new interventions to abrogate remodeling in hypoxic forms of PH. PMID:25930027

  14. Arterial grafts exhibiting unprecedented cellular infiltration and remodeling in vivo: the role of cells in the vascular wall

    PubMed Central

    Row, Sindhu; Peng, Haofan; Schlaich, Evan M.; Koenigsknecht, Carmon; Andreadis, Stelios T.; Swartz, Daniel D.

    2015-01-01

    Objective To engineer and implant vascular grafts in the arterial circulation of a pre-clinical animal model and assess the role of donor medial cells in graft remodeling and function. Approach and results Vascular grafts were engineered using Small Intestinal Submucosa (SIS)-fibrin hybrid scaffold and implanted interpositionally into the arterial circulation of an ovine model. We sought to demonstrate implantability of SIS-Fibrin based grafts; examine the remodeling; and determine whether the presence of vascular cells in the medial wall was necessary for cellular infiltration from the host and successful remodeling of the implants. We observed no occlusions or anastomotic complications in 18 animals that received these grafts. Notably, the grafts exhibited unprecedented levels of host cell infiltration that was not limited to the anastomotic sites but occurred through the lumen as well as the extramural side, leading to uniform cell distribution. Incoming cells remodeled the extracellular matrix and matured into functional smooth muscle cells as evidenced by expression of myogenic markers and development of vascular reactivity. Interestingly, tracking the donor cells revealed that their presence was beneficial but not necessary for successful grafting. Indeed, the proliferation rate and number of donor cells decreased over time as the vascular wall was dominated by host cells leading to significant remodeling and development of contractile function. Conclusions These results demonstrate that SIS-Fibrin grafts can be successfully implanted into the arterial circulation of a clinically relevant animal model, improve our understanding of vascular graft remodeling and raise the possibility of engineering mural cell-free arterial grafts. PMID:25736502

  15. Qingxuan Jiangya Decoction Reverses Vascular Remodeling by Inducing Vascular Smooth Muscle Cell Apoptosis in Spontaneously Hypertensive Rats.

    PubMed

    Xiao, Fei; He, Fei; Chen, Hongwei; Lin, Shan; Shen, Aling; Chen, Youqin; Chu, Jianfeng; Peng, Jun

    2016-01-01

    Qingxuan Jiangya Decoction (QXJYD), a traditional Chinese medicine formula prescribed by academician Ke-ji Chen, has been used in China to clinically treat hypertension for decades of years. However, the molecular mechanisms of its action remain largely unknown. In this study, we examined the therapeutic efficacy of QXJYD against elevated systolic blood pressure in the spontaneously hypertensive rat (SHR) model, and investigated the underlying molecular mechanisms. We found that oral administration of QXJYD significantly reduced the elevation of systolic blood pressure in SHR but had no effect on body weight change. Additionally, QXJYD treatment significantly decreased the media thickness and ratio of media thickness/lumen diameter in the carotid arteries of SHR. Moreover, QXJYD remarkably promoted apoptosis of vascular smooth muscle cells and reduced the expression of anti-apoptotic B-cell leukemia/lymphoma 2. Furthermore, QXJYD significantly decreased the plasma Angiotensin II level in SHR. Collectively, our findings suggest that reversing vascular remodeling via inducing VSMC apoptosis could be one of the mechanisms whereby QXJYD treats hypertension. PMID:27455221

  16. Coupled Simulation of Hemodynamics and Vascular Growth and Remodeling in a Subject-Specific Geometry.

    PubMed

    Wu, Jiacheng; Shadden, Shawn C

    2015-07-01

    A computational framework to couple vascular growth and remodeling (G&R) with blood flow simulation in a 3D patient-specific geometry is presented. Hyperelastic and anisotropic properties are considered for the vessel wall material and a constrained mixture model is used to represent multiple constituents in the vessel wall, which was modeled as a membrane. The coupled simulation is divided into two time scales-a longer time scale for G&R and a shorter time scale for fluid dynamics simulation. G&R is simulated to evolve the boundary of the fluid domain, and fluid simulation is in turn used to generate wall shear stress and transmural pressure data that regulates G&R. To minimize required computation cost, the fluid dynamics are only simulated when G&R causes significant vascular geometric change. For demonstration, this coupled model was used to study the influence of stress-mediated growth parameters, and blood flow mechanics, on the behavior of the vascular tissue growth in a model of the infrarenal aorta derived from medical image data. PMID:25731141

  17. Pericytes Regulate Vascular Basement Membrane Remodeling and Govern Neutrophil Extravasation during Inflammation

    PubMed Central

    Wang, Shijun; Cao, Canhong; Chen, Zhongming; Bankaitis, Vytas; Tzima, Eleni; Sheibani, Nader; Burridge, Keith

    2012-01-01

    During inflammation polymorphonuclear neutrophils (PMNs) traverse venular walls, composed of the endothelium, pericyte sheath and vascular basement membrane. Compared to PMN transendothelial migration, little is known about how PMNs penetrate the latter barriers. Using mouse models and intravital microscopy, we show that migrating PMNs expand and use the low expression regions (LERs) of matrix proteins in the vascular basement membrane (BM) for their transmigration. Importantly, we demonstrate that this remodeling of LERs is accompanied by the opening of gaps between pericytes, a response that depends on PMN engagement with pericytes. Exploring how PMNs modulate pericyte behavior, we discovered that direct PMN-pericyte contacts induce relaxation rather than contraction of pericyte cytoskeletons, an unexpected response that is mediated by inhibition of the RhoA/ROCK signaling pathway in pericytes. Taking our in vitro results back into mouse models, we present evidence that pericyte relaxation contributes to the opening of the gaps between pericytes and to the enlargement of the LERs in the vascular BM, facilitating PMN extravasation. Our study demonstrates that pericytes can regulate PMN extravasation by controlling the size of pericyte gaps and thickness of LERs in venular walls. This raises the possibility that pericytes may be targeted in therapies aimed at regulating inflammation. PMID:23029055

  18. Coupled simulation of hemodynamics and vascular growth and remodeling in a subject-specific geometry

    PubMed Central

    Wu, Jiacheng; Shadden, Shawn C.

    2015-01-01

    A computational framework to couple vascular growth and remodeling (G&R) with blood flow simulation in a 3D patient-specific geometry is presented. Hyperelastic and anisotropic properties are considered for the vessel wall material and a constrained mixture model is used to represent multiple constituents in the vessel wall, which was modeled as a membrane. The coupled simulation is divided into two time scales–a longer time scale for G&R and a shorter time scale for fluid dynamics simulation. G&R is simulated to evolve the boundary of the fluid domain, and fluid simulation is in turn used to generate wall shear stress and transmural pressure data that regulates G&R. To minimize required computation cost, the fluid dynamics are only simulated when G&R causes significant vascular geometric change. For demonstration, this coupled model was used to study the influence of stress-mediated growth parameters, and blood flow mechanics, on the behavior of the vascular tissue growth in a model of the infrarenal aorta derived from medical image data. PMID:25731141

  19. Abnormal uterine artery remodelling in the stroke prone spontaneously hypertensive rat

    PubMed Central

    Small, Heather Y.; Morgan, Hannah; Beattie, Elisabeth; Griffin, Sinead; Indahl, Marie; Delles, Christian; Graham, Delyth

    2016-01-01

    Introduction The stroke prone spontaneously hypertensive rat (SHRSP) is an established model of human cardiovascular risk. We sought to characterise the uteroplacental vascular response to pregnancy in this model and determine whether this is affected by the pre-existing maternal hypertension. Methods Doppler ultrasound and myography were utilised to assess uterine artery functional and structural changes pre-pregnancy and at gestational day 18 in SHRSP (untreated and nifedipine treated) and in the normotensive Wistar-Kyoto (WKY) rat. Maternal adaptations to pregnancy were also assessed along with histology and expression of genes involved in oxidative stress in the placenta. Results SHRSP uterine arteries had a pulsatile blood flow and were significantly smaller (70906 ± 3903 μm2 vs. 95656 ± 8524 μm2 cross-sectional area; p < 0.01), had a significant increase in contractile response (57.3 ± 10.5 kPa vs 27.7 ± 1.9 kPa; p < 0.01) and exhibited impaired endothelium-dependent vasorelaxation (58.0 ± 5.9% vs 13.9 ± 4.6%; p < 0.01) compared to WKY. Despite significant blood pressure lowering, nifedipine did not improve uterine artery remodelling, function or blood flow in SHRSP. Maternal plasma sFLT-1/PlGF ratio (5.3 ± 0.3 vs 4.6 ± 0.1; p < 0.01) and the urinary albumin/creatinine ratio (1.9 ± 0.2 vs 0.6 ± 0.1; p < 0.01) was increased in SHRSP vs WKY. The SHRSP placenta had a significant reduction in glycogen cell content and an increase in Hif1α, Sod1 and Vegf. Discussion We conclude that the SHRSP exhibits a number of promising characteristics as a model of spontaneous deficient uteroplacental remodelling that adversely affect pregnancy outcome, independent of pre-existing hypertension. PMID:26612342

  20. Calcium antagonist verapamil prevented pulmonary arterial hypertension in broilers with ascites by arresting pulmonary vascular remodeling.

    PubMed

    Yang, Ying; Qiao, Jian; Wang, Huiyu; Gao, Mingyu; Ou, Deyuan; Zhang, Jianjun; Sun, Maohong; Yang, Xin; Zhang, Xiaobo; Guo, Yuming

    2007-04-30

    Calcium signaling has been reported to be involved in the pathogenesis of hypertension. Verapamil, one of the calcium antagonists, is used to characterize the role of calcium signaling in the development of pulmonary arterial hypertension syndrome in broilers. The suppression effect of verapamil on pulmonary arterial hypertension and pulmonary vascular remodeling was examined in broilers, from the age of 16 days to 43 days. Our results showed that oral administration of lower dose of verapamil (5 mg/kg body weight every 12 h) prevented the mean pulmonary arterial pressure, the ascites heart index and the erythrocyte packed cell volume of birds at low temperature from increasing, the heart rate from decreasing, and pulmonary arteriole median from thickening, and no pulmonary arteriole remodeling in broilers treated with the two doses of verapamil at low temperature was observed. Our results indicated that calcium signaling was involved in the development of broilers' pulmonary arterial hypertension, which leads to the development of ascites, and we suggest that verapamil may be used as a preventive agent to reduce the occurrence and development of pulmonary arterial hypertension in broilers. PMID:17320074

  1. OBESITY INCREASES BLOOD PRESSURE, CEREBRAL VASCULAR REMODELING, AND SEVERITY OF STROKE IN THE ZUCKER RAT

    PubMed Central

    Osmond, Jessica M.; Mintz, James D.; Dalton, Brian; Stepp, David W.

    2009-01-01

    Obesity is a risk factor for stroke, but the mechanisms by which obesity increases stroke risk are unknown. Because microvascular architecture contributes to the outcome of stroke, we hypothesized that middle cerebral arteries (MCA) from obese Zucker rats (OZR) undergo inward remodeling and develop increased myogenic tone compared to lean Zucker rats (LZR). We further hypothesized that OZR have an increased infarct following cerebral ischemia and that changes in vascular structure and function correlate with the development of hypertension in OZR. Blood pressure was measured by telemetery in LZR and OZR from 6 to 17 weeks of age. Vessel structure and function were assessed in isolated MCAs. Stroke damage was assessed after ischemia was induced for 60 minutes followed by 24 hours of reperfusion. While mean arterial pressure (MAP) was similar between young rats (6–8 weeks old), MAP was higher in adult (14–17 weeks old) OZR than LZR. MCAs from OZR had a smaller lumen diameter and increased myogenic vasoconstriction compared to those from LZR. Following ischemia, infarction was 58% larger in OZR than LZR. Prior to the development of hypertension, MCA myogenic reactity and lumen diameter as well as infarct size were similar between young LZR and OZR. Our results indicate that the MCAs of OZR undergo structural remodeling and that these rats have greater cerebral injury following cerebral ischemia. These cerebrovascular changes correlate with the development of hypertension and suggest that the increased blood pressure may be the major determinant for stroke risk in obese individuals. PMID:19104000

  2. Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.

    PubMed

    Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J; Obama, Takashi; Tsuji, Toshiyuki; Fukuda, Yamato; Elliott, Katherine J; Tilley, Douglas G; Davisson, Robin L; Park, Joon-Young; Eguchi, Satoru

    2015-06-01

    The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. PMID:25916723

  3. 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

  4. Impact of experimental diabetes on the maternal uterine vascular remodeling during rat pregnancy.

    PubMed

    Phillips, Julie K; Vance, Amanda M; Raj, Renju S; Mandalà, Maurizio; Linder, Erika A; Gokina, Natalia I

    2012-03-01

    Normal pregnancy is associated with an increase in uteroplacental blood flow in part due to growth and remodeling of the maternal uterine vasculature. In this study, we characterized the effect of diabetic pregnancy on vascular growth of the maternal uterine vasculature and on the passive mechanical properties of the uterine resistance arteries. Diabetes was induced in pregnant rats by injection of streptozotocin and confirmed by development of hyperglycemia. Fetuses of diabetic rats were significantly smaller and placentas larger compared to controls. Pregnancy-induced axial elongation of the mesometrial uterine vasculature was not altered by diabetes. Vascular wall thickness was unchanged between groups. Wall distensibility was increased and the rate constant of an exponential function fitted to stress-strain curve was significantly reduced demonstrating decreased wall stiffness in diabetic uterine radial arteries compared to controls. We conclude that experimental diabetes in rat pregnancy does not compromise the growth of maternal uterine vasculature but alters passive mechanical properties of the uterine radial arteries. PMID:22383782

  5. Vascular remodeling and its role in the pathogenesis of ascites in fast growing commercial broilers.

    PubMed

    Nain, S; Wojnarowicz, C; Laarveld, B; Olkowski, A A

    2009-06-01

    This study examined the putative role of blood vessel pathology in the development of ascites in broilers. Major blood vessels (aorta, brachiocephalic arteries, pulmonary arteries, and vena cava) from normal commercial male broiler chickens, and broilers that developed congestive heart failure (CHF) with or without ascites were subjected to gross and microscopic examination. On cross-section, grossly, the arteries from normal broilers and those showing dilated cardiomyopathy without ascites appeared circular, with firm wall tone characteristic of the normal artery. In contrast, the arteries from ascitic broilers appeared flaccid and lacked elasticity, which was evidenced by collapsing, ellipsoid cross-sectional arterial lumen owing to the structural weakness of the arterial walls. Microscopically, ascitic broilers showed thinning or occasionally total loss of elastic elements in the arterial wall, and reduced network density of the structural matrix of the vascular wall, as well as increased thickness of fibers in vena cava. The structural changes seen in the major arteries from ascitic broilers are maladaptive, and as such would definitively impose an increased hemodynamic burden on the already failing heart pump. The changes in veins are indicative of pathological remodeling conducive to increased permeability of the vascular wall, particularly in the situation when a poorly distensible structure is further subjected to wall stress associated with increased pressure and volume overload. Taken together, increased hemodynamic burden and reduced structural density of the venous wall constitute conditions conducive for seepage and accumulation of ascitic fluid. PMID:18947843

  6. Role of a molecular variant of rat atrial natriuretic Peptide gene in vascular remodeling.

    PubMed

    De Paolis, Paola; Nobili, Valerio; Lombardi, Alessia; Tarasi, David; Barbato, Daniela; Marchitti, Simona; Ganten, Ursula; Brunetti, Ercole; Volpe, Massimo; Rubattu, Speranza

    2007-01-01

    Previous studies in a hypertensive animal model of stroke and in humans showed that mutations of the atrial natriuretic peptide (ANP) gene are associated with increased risk of stroke. To elucidate the vascular disease mechanisms that result from structural modifications of the ANP gene, we investigated a coding mutation of the ANP gene in stroke-prone spontaneously hypertensive rats (SHRsp). This mutation leads to a Gly/Ser transposition in the prosegment of ANP. We found that presence of this mutation is associated with increased immunostaining of ANP in the wall of SHRsp cerebral vessels. The mutation causes a major inhibitory effect on endothelial cell proliferation, as assessed by thymidine incorporation, and on angiogenesis, as determined by an endothelial cell tube formation assay, in human umbilical vein endothelial cells (HUVEC) exposed to ANP/SHRsp. These in vitro findings show that the SHRsp-derived form of ANP has an inhibitory effect on vascular remodeling and they provide further support for a role of the ANP gene in the pathogenesis of cerebrovascular disease in the animal model. PMID:17522368

  7. Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling.

    PubMed

    Rodriguez-Menocal, Luis; Faridi, Mohd Hafeez; Martinez, Laisel; Shehadeh, Lina A; Duque, Juan C; Wei, Yuntao; Mesa, Annia; Pena, Angela; Gupta, Vineet; Pham, Si M; Vazquez-Padron, Roberto I

    2014-03-01

    Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-γ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation. PMID:24414074

  8. Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

    PubMed Central

    Rodriguez-Menocal, Luis; Faridi, Mohd Hafeez; Martinez, Laisel; Shehadeh, Lina A.; Duque, Juan C.; Wei, Yuntao; Mesa, Annia; Pena, Angela; Gupta, Vineet; Pham, Si M.

    2014-01-01

    Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-γ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation. PMID:24414074

  9. Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduced hypoxia in tumors

    PubMed Central

    Sasajima, Junpei; Mizukami, Yusuke; Sugiyama, Yoshiaki; Nakamura, Kazumasa; Kawamoto, Toru; Koizumi, Kazuya; Fujii, Rie; Motomura, Wataru; Sato, Kazuya; Suzuki, Yasuaki; Tanno, Satoshi; Fujiya, Mikihiro; Sasaki, Katsunori; Shimizu, Norihiko; Karasaki, Hidenori; Kono, Toru; Kawabe, Jun-ichi; Ii, Masaaki; Yoshiara, Hiroki; Kamiyama, Naohisa; Ashida, Toshifumi; Bardeesy, Nabeel; Chung, Daniel C.; Kohgo, Yutaka

    2011-01-01

    Blood vessels deliver oxygen and nutrients to tissues and vascular networks are spatially organized to meet metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair “injured” blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in tumor vasculature. Culturing BMMNC with endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with pro-angiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-KrasG12D;p53lox/+ genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in the vascularized area within VPC-injected xenografts were visualized with the ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional “normalization” of the tumor vasculature. In addition, gene expression profiles on the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and “stemness” of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve delivery and efficacy of anti-cancer drugs to hypoxic tumors. PMID:20631070

  10. Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors.

    PubMed

    Sasajima, Junpei; Mizukami, Yusuke; Sugiyama, Yoshiaki; Nakamura, Kazumasa; Kawamoto, Toru; Koizumi, Kazuya; Fujii, Rie; Motomura, Wataru; Sato, Kazuya; Suzuki, Yasuaki; Tanno, Satoshi; Fujiya, Mikihiro; Sasaki, Katsunori; Shimizu, Norihiko; Karasaki, Hidenori; Kono, Toru; Kawabe, Jun-ichi; Ii, Masaaki; Yoshiara, Hiroki; Kamiyama, Naohisa; Ashida, Toshifumi; Bardeesy, Nabeel; Chung, Daniel C; Kohgo, Yutaka

    2010-08-01

    Blood vessels deliver oxygen and nutrients to tissues, and vascular networks are spatially organized to meet the metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair "injured" blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in the tumor vasculature. Culturing BMMNCs in endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with proangiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-Kras(G12D);p53(lox/+) genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in vascularized areas within VPC-injected xenografts were visualized with an ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional "normalization" of the tumor vasculature. In addition, gene expression profiles in the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and "stemness" of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve the delivery and efficacy of anticancer drugs to hypoxic tumors. PMID:20631070

  11. The NuRD Chromatin-Remodeling Enzyme CHD4 Promotes Embryonic Vascular Integrity by Transcriptionally Regulating Extracellular Matrix Proteolysis

    PubMed Central

    Ingram, Kyle G.; Curtis, Carol D.; Silasi-Mansat, Robert; Lupu, Florea; Griffin, Courtney T.

    2013-01-01

    The extracellular matrix (ECM) supports vascular integrity during embryonic development. Proteolytic degradation of ECM components is required for angiogenesis, but excessive ECM proteolysis causes blood vessel fragility and hemorrhage. Little is understood about how ECM proteolysis is transcriptionally regulated during embryonic vascular development. We now show that the NuRD ATP-dependent chromatin-remodeling complex promotes vascular integrity by preventing excessive ECM proteolysis in vivo. Mice lacking endothelial CHD4—a catalytic subunit of NuRD complexes—died at midgestation from vascular rupture. ECM components surrounding rupture-prone vessels in Chd4 mutants were significantly downregulated prior to embryonic lethality. Using qPCR arrays, we found two critical mediators of ECM stability misregulated in mutant endothelial cells: the urokinase-type plasminogen activator receptor (uPAR or Plaur) was upregulated, and thrombospondin-1 (Thbs1) was downregulated. Chromatin immunoprecipitation assays showed that CHD4-containing NuRD complexes directly bound the promoters of these genes in endothelial cells. uPAR and THBS1 respectively promote and inhibit activation of the potent ECM protease plasmin, and we detected increased plasmin activity around rupture-prone vessels in Chd4 mutants. We rescued ECM components and vascular rupture in Chd4 mutants by genetically reducing urokinase (uPA or Plau), which cooperates with uPAR to activate plasmin. Our findings provide a novel mechanism by which a chromatin-remodeling enzyme regulates ECM stability to maintain vascular integrity during embryonic development. PMID:24348274

  12. The Effects of Protein Regulators on the Vascular Remodeling of Japanese Quail Chorioallantoic Membrane

    NASA Technical Reports Server (NTRS)

    Deshpande, Arati

    2004-01-01

    Contributing to NASA s mission, the Microgravity Fluid Physics research program conducts experiments to promote space exploration and improvement of processes and products on Earth. One of the projects through this program deals with the affect of regulators on vascular remodeling and angiogenesis. This project is being led by Dr. Patricia Parsons-Wingerter. To perform the experiments, protein regulators are tested on the chorioallantoic membrane (CAM) of the Japanese quail embryos. The different types of regulators used can be broken down into two major groups of stimulators, and inhibitors. Stimulators increase the rate of blood vessel growth and inhibitors decrease of blood vessel growth. The specified regulator proteins include thrombospondin 1 (TSP-1) and a novel vessel tortuosity factor (TF), these are just the ones used in this specific experiment; other various protein regulators can also be used. The novel vessel tortuosity factor (TF) is a special kind of stimulator because it stimulates vessel tortuosity and curvature, rather than actual blood vessel growth. These regulators are being tested on Japanese quail embryos. The Japanese quail embryos naturally form a chorioallantoic membrane (CAM) from which blood flow, vascular remodeling, and angiogenesis can be observed. Chorioallantoic membranes are also easier to use because they are two dimensional when mounted onto a slide for examination. The analysis of the affect of the regulators on the CAM can be studied through PIVPROC; the program is used to analyze the altered blood flow in response to application of TF. Regulators are being thoroughly studied because cardiovascular alterations are the second highest, NASA-defined, risk categories in human space exploration. This research done on the quail is extending to even more projects that will be done on lab animals such as mice and also in human clinical studies like the diabetic retina. Not only will this research be beneficial to further space

  13. Abnormal Vascular Function and Hypertension in Mice Deficient in Estrogen Receptor β

    NASA Astrophysics Data System (ADS)

    Zhu, Yan; Bian, Zhao; Lu, Ping; Karas, Richard H.; Bao, Lin; Cox, Daniel; Hodgin, Jeffrey; Shaul, Philip W.; Thorén, Peter; Smithies, Oliver; Gustafsson, Jan-Åke; Mendelsohn, Michael E.

    2002-01-01

    Blood vessels express estrogen receptors, but their role in cardiovascular physiology is not well understood. We show that vascular smooth muscle cells and blood vessels from estrogen receptor β (ERβ)-deficient mice exhibit multiple functional abnormalities. In wild-type mouse blood vessels, estrogen attenuates vasoconstriction by an ERβ-mediated increase in inducible nitric oxide synthase expression. In contrast, estrogen augments vasoconstriction in blood vessels from ERβ-deficient mice. Vascular smooth muscle cells isolated from ERβ-deficient mice show multiple abnormalities of ion channel function. Furthermore, ERβ-deficient mice develop sustained systolic and diastolic hypertension as they age. These data support an essential role for ERβ in the regulation of vascular function and blood pressure.

  14. 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

    2015-12-01

    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. PMID:26645582

  15. Vascular Wall-Resident Multipotent Stem Cells of Mesenchymal Nature within the Process of Vascular Remodeling: Cellular Basis, Clinical Relevance, and Implications for Stem Cell Therapy

    PubMed Central

    Klein, Diana

    2016-01-01

    Until some years ago, the bone marrow and the endothelial cell compartment lining the vessel lumen (subendothelial space) were thought to be the only sources providing vascular progenitor cells. Now, the vessel wall, in particular, the vascular adventitia, has been established as a niche for different types of stem and progenitor cells with the capacity to differentiate into both vascular and nonvascular cells. Herein, vascular wall-resident multipotent stem cells of mesenchymal nature (VW-MPSCs) have gained importance because of their large range of differentiation in combination with their distribution throughout the postnatal organism which is related to their existence in the adventitial niche, respectively. In general, mesenchymal stem cells, also designated as mesenchymal stromal cells (MSCs), contribute to the maintenance of organ integrity by their ability to replace defunct cells or secrete cytokines locally and thus support repair and healing processes of the affected tissues. This review will focus on the central role of VW-MPSCs within vascular reconstructing processes (vascular remodeling) which are absolute prerequisite to preserve the sensitive relationship between resilience and stability of the vessel wall. Further, a particular advantage for the therapeutic application of VW-MPSCs for improving vascular function or preventing vascular damage will be discussed. PMID:26880936

  16. Major and minor arterial malformations in patients with cutaneous vascular abnormalities.

    PubMed

    Pascual-Castroviejo, Ignacio; Pascual-Pascual, Samuel I; Viaño, Juan; López-Gutierrez, Juan C; Palencia, Rafael

    2010-05-01

    The association of persistent embryonic arteries and the absence of 1 carotid or vertebral arteries with facial or neck hemangioma or vascular malformation have been frequently described. The abnormalities can involve major or minor vessels. Of 22 patients of our series with this neurocutaneous syndrome, 20 had the origin of both anterior cerebral arteries from the same internal carotid artery. Thirteen patients showed absence or hypoplasia of 1 carotid artery and 10 of 1 vertebral artery; 10 showed persistence of the trigeminal artery; 3 had persistent proatlantal artery; 6 showed the absence of the posterior communicating artery; and 4 had hypoplastic posterior cerebral artery. Other less frequent abnormalities were found in 7 patients. Intellectual level of most patients was either borderline or below normal. Abnormalities in the vascularization and perfusion of the frontal lobes may contribute to the borderline or lower mental level of these patients. PMID:19808986

  17. Magnolol inhibits migration of vascular smooth muscle cells via cytoskeletal remodeling pathway to attenuate neointima formation

    SciTech Connect

    Karki, Rajendra; Kim, Seong-Bin; Kim, Dong-Wook

    2013-12-10

    Background: Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration. Methods: The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury. Results: VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity. Conclusions: Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation. General significance: This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis. - Highlights: • Magnolol strongly inhibited migration of VSMCs. • Magnolol inhibited stress fibers formation. • MLC20 phosphorylation was also inhibited by magnolol. • Anti

  18. Comparison between Stromal Vascular Fraction and Adipose Mesenchymal Stem Cells in Remodeling Hypertrophic Scars

    PubMed Central

    Maumus, Marie; Toupet, Karine; Frouin, Eric; Rigau, Valérie; Vozenin, Marie-Catherine; Magalon, Guy; Jorgensen, Christian; Noël, Danièle

    2016-01-01

    Hypertrophic scars (HTS) are characterized by excessive amount of collagen deposition and principally occur following burn injuries or surgeries. In absence of effective treatments, the use of mesenchymal stem/stromal cells, which have been shown to attenuate fibrosis in various applications, seems of interest. The objectives of the present study were therefore to evaluate the effect of human adipose tissue-derived mesenchymal stem cells (hASC) on a pre-existing HTS in a humanized skin graft model in Nude mice and to compare the efficacy of hASCs versus stromal vascular fraction (SVF). We found that injection of SVF or hASCs resulted in an attenuation of HTS as noticed after clinical evaluation of skin thickness, which was associated with lower total collagen contents in the skins of treated mice and a reduced dermis thickness after histological analysis. Although both SVF and hASCs were able to significantly reduce the clinical and histological parameters of HTS, hASCs appeared to be more efficient than SVF. The therapeutic effect of hASCs was attributed to higher expression of TGFβ3 and HGF, which are important anti-fibrotic mediators, and to higher levels of MMP-2 and MMP-2/TIMP-2 ratio, which reflect the remodelling activity responsible for fibrosis resorption. These results demonstrated the therapeutic potential of hASCs for clinical applications of hypertrophic scarring. PMID:27227960

  19. Unique remodeling processes after vascular injury in intracranial arteries: analysis using a novel mouse model.

    PubMed

    Shimamura, Munehisa; Nakagami, Hironori; Sata, Masataka; Takaoka, Minoru; Azuma, Junya; Kiomy Osako, Mariana; Koriyama, Hiroshi; Kurinami, Hitomi; Wakayama, Kouji; Miyake, Takashi; Morishita, Ryuichi

    2013-08-01

    The effectiveness of angioplasty and stenting in intracranial atherosclerotic diseases is controversial due to high rates of delayed restenosis and hemorrhage compared with extracranial arteries. However, the mechanisms underlying these differences are still unclear, because their pathophysiology is yet to be examined. To address this issue, we established a novel vascular injury model in the intracranial internal carotid arteries (IICAs) in mice, and analyzed the remodeling process in comparison to that of the femoral arteries (FAs). In IICAs, neointimal hyperplasia was observed from day 14 and grew until day 56. Although smooth muscle cells (SMCs) emerged in the neointima from day 28, SMCs in the injured media were continuously lost with eventual extinction of the media. Re-endothelialization was started from day 7 and completed on day 28. Accumulation of macrophages was continued in the adventitia until day 56. Compared with FAs, the following points are unique in IICAs: (1) delayed continuous formation of neointima; (2) accumulation of macrophages in the media on day 14; (3) continuous loss of SMCs in the media followed by extinction of the media itself; and (4) continuously growing adventitia. These pathophysiologic differences might be associated with unfavorable outcomes in percutaneous transluminal angioplasty and stenting in intracranial arteries. PMID:23571280

  20. Gene silencing of TACE enhances plaque stability and improves vascular remodeling in a rabbit model of atherosclerosis

    PubMed Central

    Zhao, Xueqiang; Kong, Jing; Zhao, Yuxia; Wang, Xuping; Bu, Peili; Zhang, Cheng; Zhang, Yun

    2015-01-01

    We aimed to test the hypothesis that gene silencing of tumor necrosis factor alpha converting enzyme (TACE) may attenuate lesion inflammation and positive vascular remodeling and enhance plaque stability in a rabbit model of atherosclerosis. Lentivirus-mediated TACE shRNA was injected into the abdominal aortic plaques of rabbits which effectively down-regulated TACE expression and activities from week 8 to week 16. TACE gene silencing reduced remodeling index and plaque burden, and diminished the content of macrophages and lipids while increased that of smooth muscle cells and collagen in the aortic plaques. In addition, TACE gene silencing attenuated the local expression of P65, iNOS, ICAM-1, VEGF and Flt-1 and activities of MMP9 and MMP2 while increased the local expression of TGF-β1 together with reduced number of neovessels in the aorta. TACE shRNA treatment resulted in down-regulated expression of TACE in macrophages and blunted ERK-P38 phosphorylation and tube formation of co-cultured mouse vascular smooth muscle cells or human umbilical vein endothelial cells. In conclusion, gene silencing of TACE enhanced plaque stability and improved vascular positive remodeling. The mechanisms may involve attenuated local inflammation, neovascularization and MMP activation, as well as enhanced collagen production probably via down-regulated ERK-NF-κB and up-regulated TGF-β1 signaling pathways. PMID:26655882

  1. 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. PMID:25571442

  2. Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin.

    PubMed

    Cui, Mingli; Cai, Zhaohua; Chu, Shichun; Sun, Zhe; Wang, Xiaolei; Hu, Liuhua; Yi, Jing; Shen, Linghong; He, Ben

    2016-01-01

    Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases. PMID:26597820

  3. Levofloxacin decreased chest wall mechanical inhomogeneities and airway and vascular remodeling in rats with induced hepatopulmonary syndrome.

    PubMed

    Gaio, Eduardo; Amado, Veronica; Rangel, Leonardo; Huang, Wilson; Storck, Rodrigo; Melo-Silva, César Augusto

    2013-12-01

    The administration of antibiotics decreases bacterial translocation, reduces the activity of nitric oxide synthase and improves the gas exchange of hepatopulmonary syndrome (HPS) in rats. We hypothesized that levofloxacin could reduce HPS-induced respiratory mechanical inhomogeneities and airway and pulmonary vascular remodeling. We assessed the respiratory mechanical properties and lung tissue structure in 24 rats assigned to the control, HPS (eHPS) and HPS+levofloxacin (eHPS+L) groups. The administration of levofloxacin reduced the HPS-induced chest wall but not the lung mechanical inhomogeneities. The eHPS airway proportion of elastic fibers increased 20% but was similar between the control and eHPS+L groups. The eHPS vascular collagen increased 25% in eHPS but was similar between the control and eHPS+L groups. Compared to the control group, the vascular proportion of elastic fibers of the eHPS and eHPS+L groups increased by 60% and 16%, respectively. The administration of levofloxacin decreased the HPS-induced chest wall mechanical inhomogeneities and airway and vascular remodeling. PMID:23994178

  4. Effect of Cocaine on Pulmonary Vascular Remodeling and Hemodynamics in Human Immunodeficiency Virus-Transgenic Rats.

    PubMed

    Dalvi, Pranjali; Spikes, Leslie; Allen, Julie; Gupta, Vijayalaxmi G; Sharma, Himanshu; Gillcrist, Marion; Montes de Oca, Jamison; O'Brien-Ladner, Amy; Dhillon, Navneet K

    2016-08-01

    Human immunodeficiency virus (HIV)-related pulmonary arterial hypertension has been found to be more prevalent in intravenous drug users. Our earlier cell-culture findings reported down-regulation of bone morphogenetic protein receptors (BMPRs) in combination with enhanced proliferation of human pulmonary arterial smooth muscle cells (PASMCs) in the presence of HIV-Trans-activator of transcription (Tat) and cocaine compared with either treatment alone. Here, we report physiologic evidence of significant increases in mean pulmonary arterial pressure in HIV-transgenic (Tg) rats intraperitoneally administered 40 mg/kg body weight cocaine (HIV-cocaine group) once daily for 21 days when compared with HIV-Tg rats given saline (HIV group) or wild-type (WT) Fischer 334 rats treated with (WT-cocaine group) and without cocaine (WT group). In addition, right ventricle systolic pressure was also found to be significantly higher in the HIV-cocaine rats compared with the WT group. Significant down-regulation in protein expression of BMPR-2 and BMPR-1B was observed in total lung extract from HIV-cocaine rats compared with the other three groups. Furthermore, the PASMCs isolated from HIV-cocaine rats demonstrated a higher level of proliferation and lower levels of apoptosis compared with cells isolated from other rat groups. Interestingly, corroborating our earlier cell-culture findings, we observed higher expression of BMPR-2 and BMPR-1B messenger RNA and significantly lower levels of BMPR-2 and BMPR-1B protein in HIV-cocaine PASMCs compared with cells isolated from all other groups. In conclusion, our findings support an additive effect of cocaine and HIV on smooth muscle dysfunction, resulting in enhanced pulmonary vascular remodeling with associated elevation of mean pulmonary arterial pressure and right ventricle systolic pressure in HIV-Tg rats exposed to cocaine. PMID:26820592

  5. Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye.

    PubMed

    Jia, Yali; Bailey, Steven T; Hwang, Thomas S; McClintic, Scott M; Gao, Simon S; Pennesi, Mark E; Flaxel, Christina J; Lauer, Andreas K; Wilson, David J; Hornegger, Joachim; Fujimoto, James G; Huang, David

    2015-05-01

    Retinal vascular diseases are important causes of vision loss. A detailed evaluation of the vascular abnormalities facilitates diagnosis and treatment in these diseases. Optical coherence tomography (OCT) angiography using the highly efficient split-spectrum amplitude decorrelation angiography algorithm offers an alternative to conventional dye-based retinal angiography. OCT angiography has several advantages, including 3D visualization of retinal and choroidal circulations (including the choriocapillaris) and avoidance of dye injection-related complications. Results from six illustrative cases are reported. In diabetic retinopathy, OCT angiography can detect neovascularization and quantify ischemia. In age-related macular degeneration, choroidal neovascularization can be observed without the obscuration of details caused by dye leakage in conventional angiography. Choriocapillaris dysfunction can be detected in the nonneovascular form of the disease, furthering our understanding of pathogenesis. In choroideremia, OCT's ability to show choroidal and retinal vascular dysfunction separately may be valuable in predicting progression and assessing treatment response. OCT angiography shows promise as a noninvasive alternative to dye-based angiography for highly detailed, in vivo, 3D, quantitative evaluation of retinal vascular abnormalities. PMID:25897021

  6. Trophoblast- and Vascular Smooth Muscle Cell-Derived MMP-12 Mediates Elastolysis during Uterine Spiral Artery Remodeling

    PubMed Central

    Harris, Lynda K.; Smith, Samantha D.; Keogh, Rosemary J.; Jones, Rebecca L.; Baker, Philip N.; Knöfler, Martin; Cartwright, Judith E.; Whitley, Guy St. J.; Aplin, John D.

    2010-01-01

    During the first trimester of pregnancy, the uterine spiral arteries are remodeled, creating heavily dilated conduits that lack maternal vasomotor control but allow the placenta to meet an increasing requirement for nutrients and oxygen. To effect permanent vasodilatation, the internal elastic lamina and medial elastin fibers must be degraded. In this study, we sought to identify the elastolytic proteases involved in this process. Primary first-trimester cytotrophoblasts (CTBs) derived from the placenta exhibited intracellular and membrane-associated elastase activity; membrane-associated activity was primarily attributable to matrix metalloproteinases (MMP). Indeed, Affymetrix microarray analysis and immunocytochemistry implicated MMP-12 (macrophage metalloelastase) as a key mediator of elastolysis. Cultured human aortic smooth muscle cells (HASMCs) exhibited constitutive membrane-associated elastase activity and inducible intracellular elastase activity; these cells also expressed MMP-12 protein. Moreover, a specific inhibitor of MMP-12 significantly reduced CTB- and HASMC-mediated elastolysis in vitro, to 31.7 ± 10.9% and 23.3 ± 8.7% of control levels, respectively. MMP-12 is expressed by both interstitial and endovascular trophoblasts in the first-trimester placental bed and by vascular SMCs (VSMCs) in remodeling spiral arteries. Perfusion of isolated spiral artery segments with CTB-conditioned medium stimulated MMP-12 expression in medial VSMCs. Our data support a model in which trophoblasts and VSMCs use MMP-12 cooperatively to degrade elastin during vascular remodeling in pregnancy, with the localized release of elastin peptides and CTB-derived factors amplifying elastin catabolism. PMID:20802175

  7. Changes of cell-vascular complex in zones of adaptive remodeling of the bone tissue under microgravity conditions

    NASA Astrophysics Data System (ADS)

    Rodionova, N. V.; Oganov, V. S.

    2003-10-01

    We examined the peculiarities of the structure of the blood-vascular bed and perivascular cells in zones of osteogenesis in the epiphyses and metaphises of femoral bones of rats, flown aboard the US laboratory SLS-2 for two weeks by electron microscopy and histochemistry. In zones of bone remodeling, there was a tendency for a reduction of sinusoid capillary specific volume. Endotheliocytes preserve the typical structure. In the population of perivascular cells, we discovered differentiating osteogenic cells that contained alkaline phosphomonoesterase as well as cells that don't contain this enzyme and differentiate into fibroblasts. The fibroblasts genesis in zones of adaptive remodeling of spongy bones leads to a further development of fibrous tissue that is not subject to mineralization.

  8. Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities.

    PubMed

    Bhardwaj, Pooja; Khanna, Deepa; Balakumar, Pitchai

    2014-03-01

    Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED), an initial event that could lead to the pathogenesis of atherosclerosis and hypertension. Previous studies showed that catechin, a key component of green tea, possesses vascular beneficial effects. We investigated the effect of catechin hydrate in diabetes mellitus-induced experimental vascular endothelial abnormalities (VEA). Streptozotocin (50 mg/kg, i.p., once) administration to rats produced diabetes mellitus, which subsequently induced VEA in 8 weeks by markedly attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentrations and impairing aortic endothelial integrity. These abnormalities in diabetic rats were accompanied with elevated aortic superoxide anion generation and serum lipid peroxidation in addition to hyperglycemia. Catechin hydrate treatment (50 mg/kg/day p.o., 3 weeks) markedly prevented diabetes mellitus-induced VEA and vascular oxidative stress. Intriguingly, in vitro incubation of L-NAME (100 μM), an inhibitor of nitric oxide synthase, or Wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), markedly prevented catechin hydrate-induced improvement in acetylcholine-provoked endothelium-dependent relaxation in the diabetic rat aorta. Moreover, catechin hydrate treatment considerably reduced the elevated level of serum glucose in diabetic rats. In conclusion, catechin hydrate treatment prevents diabetes mellitus-induced VED through the activation of endothelial PI3K signal and subsequent activation of eNOS and generation of nitric oxide. In addition, reduction in high glucose, vascular oxidative stress, and lipid peroxidation might additionally contribute to catechin hydrate-associated prevention of diabetic VEA. PMID:24048981

  9. HIF-2α-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction

    PubMed Central

    Labrousse-Arias, David; Castillo-González, Raquel; Rogers, Natasha M.; Torres-Capelli, Mar; Barreira, Bianca; Aragonés, Julián; Cogolludo, Ángel; Isenberg, Jeffrey S.; Calzada, María J.

    2016-01-01

    Aims Hypoxic conditions stimulate pulmonary vasoconstriction and vascular remodelling, both pathognomonic changes in pulmonary arterial hypertension (PAH). The secreted protein thrombospondin-1 (TSP1) is involved in the maintenance of lung homeostasis. New work identified a role for TSP1 in promoting PAH. Nonetheless, it is largely unknown how hypoxia regulates TSP1 in the lung and whether this contributes to pathological events during PAH. Methods and results In cell and animal experiments, we found that hypoxia induces TSP1 in lungs, pulmonary artery smooth muscle cells and endothelial cells, and pulmonary fibroblasts. Using a murine model of constitutive hypoxia, gene silencing, and luciferase reporter experiments, we found that hypoxia-mediated induction of pulmonary TSP1 is a hypoxia-inducible factor (HIF)-2α-dependent process. Additionally, hypoxic tsp1−/− pulmonary fibroblasts and pulmonary artery smooth muscle cell displayed decreased migration compared with wild-type (WT) cells. Furthermore, hypoxia-mediated induction of TSP1 destabilized endothelial cell–cell interactions. This provides genetic evidence that TSP1 contributes to vascular remodelling during PAH. Expanding cell data to whole tissues, we found that, under hypoxia, pulmonary arteries (PAs) from WT mice had significantly decreased sensitivity to acetylcholine (Ach)-stimulated endothelial-dependent vasodilation. In contrast, hypoxic tsp1−/− PAs retained sensitivity to Ach, mediated in part by TSP1 regulation of pulmonary Kv channels. Translating these preclinical studies, we find in the lungs from individuals with end-stage PAH, both TSP1 and HIF-2α protein expression increased in the pulmonary vasculature compared with non-PAH controls. Conclusions These findings demonstrate that HIF-2α is clearly implicated in the TSP1 pulmonary regulation and provide new insights on its contribution to PAH-driven vascular remodelling and vasoconstriction. PMID:26503986

  10. ITE and TCDD differentially regulate the vascular remodeling of rat placenta via the activation of AhR.

    PubMed

    Wu, Yanming; Chen, Xiao; Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  11. ITE and TCDD Differentially Regulate the Vascular Remodeling of Rat Placenta via the Activation of AhR

    PubMed Central

    Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  12. Small-Nucleic-Acid-Based Therapeutic Strategy Targeting the Transcription Factors Regulating the Vascular Inflammation, Remodeling and Fibrosis in Atherosclerosis

    PubMed Central

    Youn, Sung Won; Park, Kwan-Kyu

    2015-01-01

    Atherosclerosis arises when injury to the arterial wall induces an inflammatory cascade that is sustained by a complex network of cytokines, together with accumulation of lipids and fibrous material. Inflammatory cascades involve leukocyte adherence and chemotaxis, which are coordinated by the local secretion of adhesion molecules, chemotactic factors, and cytokines. Transcription factors are critical to the integration of the various steps of the cascade response to mediators of vascular injury, and are induced in a stimulus-dependent and cell-type-specific manner. Several small-nucleic-acid-based therapeutic strategies have recently been developed to target transcription factors: antisense oligodeoxynucleotides, RNA interference, microRNA, and decoy oligodeoxynucleotides. The aim of this review was to provide an overview of these particular targeted therapeutic strategies, toward regulation of the vascular inflammation, remodeling and fibrosis associated with atherosclerosis. PMID:26006249

  13. A Theoretical Model for F-actin Remodeling in Vascular Smooth Muscle Cells Subjected to Cyclic Stretch

    PubMed Central

    Na, S.; Meininger, G.A.; Humphrey, J.D.

    2007-01-01

    A constrained mixture theory model was developed and used to estimate remodeling of F-actin in vascular smooth muscle cells that were subjected to 10% equibiaxial stretching for up to 30 minutes. The model was based on a synthesis of data on time-dependent changes in atomic force microscopy measured cell stiffness and immunofluorescence measured focal adhesion associated vinculin as well as data on stress fiber stiffness and pre-stretch. Results suggest that an observed acute (after 2 minutes of stretching) increase in cell stiffness is consistent with an increased stretch of the originally present F-actin plus an assembly of new F-actin having nearly homeostatic values of stretch. Moreover, the subsequent (after 30 minutes of stretching) decrease in cell stiffness back towards the baseline value is consistent with a replacement of the overstretched original filaments with the new (reassembled), less stretched filaments. That is, overall cell response is consistent with a recently proposed concept of “tensional homeostasis” whereby cells seek to maintain constant certain mechanical factors via a remodeling of intracellular and transmembrane proteins. Although there is a need to refine the model based on more comprehensive data sets, using multiple experimental approaches, the present results suggest that a constrained mixture theory can capture salient features of the dynamics of F-actin remodeling and that it offers some advantages over many past methods of modeling, particularly those based on classical linearized viscoelasticity. PMID:17240401

  14. Hypertensive vascular remodeling was inhibited by Xuezhikang through the regulation of Fibulin-3 and MMPs in spontaneously hypertensive rats

    PubMed Central

    Lin, Zhong-Wei; Wang, Zhuo; Zhu, Gui-Ping; Li, Bo-Wei; Xie, Wen-Lin; Xiang, Ding-Cheng

    2015-01-01

    Fibulin-3, an extracellular glycoprotein, has been suggested as having functions in vessels. In hypertension, extracellular matrix, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play important roles in cardiovascular remodeling. However, the role of Fibulin-3 as an extracellular glycoprotein in hypertensive vascular remodeling remains unclear. Our study was to determine whether Fibulin-3 and TIMPs/MMPs would affect vascular structure during hypertension and the treatment of Xuezhikang. Thirty spontaneously hypertensive rats (SHRs) aged 8 weeks were randomized to three groups: SHRs control group (SHRs group, n=10), group treated with low dose Xuezhikang (XZK-L, 20 mg/kg/d, n=10) and group treated with high dose Xuezhikang (XZK-H, 200 mg/kg/d, n=10), the normal group was comprised of ten Wistar-Kyoto (WKY) rats of the same age. We showed that serum nitric oxide (NO) in control group was significantly lower than WKY group (P<0.05). Concomitantly, serum oxidized low-density lipoprotein (ox-LDL) was higher than WKY group (P<0.05). The treatment of high dose Xuezhikang significantly dicreased ox-LDL, left ventricular mass index (LVMI) and Wall-to-lumen area ratio (W/L) of thoracic aorta (P<0.05), while serum NO was significantly increasing (P<0.05). Moreover, the expressions of Fibulin-3 and MMP-2, 9 at both protein and mRNA levels were significantly higher in thoracic aorta of SHRs group compared to WKY group by immunohistochemistry and western blotting (P<0.05). However, the levels of Fibulin-3 and MMP-2, 9 were significantly decreased in XZK-H group compared to control group (P<0.05). The level of TIMP-3 had no significance difference between SHRs and WKY groups (P>0.05). So the levels of Fibulin-3 and MMP-2, 9 in SHRs could be inhibited by Xuezhikang. Furthermore, a strong correlation in transcript expression was established between Fibulin-3, and MMP-2 (r=0.81, P<0.05) and MMP-9 (r=0.92, P<0.05) through immunohistochemistry. In

  15. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

    PubMed

    Grasemann, Hartmut; Dhaliwal, Rupinder; Ivanovska, Julijana; Kantores, Crystal; McNamara, Patrick J; Scott, Jeremy A; Belik, Jaques; Jankov, Robert P

    2015-03-15

    Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. PMID:25595650

  16. Hemangiomas, angiosarcomas, and vascular malformations represent the signaling abnormalities of pathogenic angiogenesis.

    PubMed

    Arbiser, J L; Bonner, M Y; Berrios, R L

    2009-11-01

    Angiogenesis is a major factor in the development of benign, inflammatory, and malignant processes of the skin. Endothelial cells are the effector cells of angiogenesis, and understanding their response to growth factors and inhibitors is critical to understanding the pathogenesis and treatment of skin disease. Hemangiomas, benign tumors of endothelial cells, represent the most common tumor of childhood. In our previous studies, we have found that tumor vasculature in human solid tumors expresses similarities in signaling to that of hemangiomas, making the knowledge of signaling in hemangiomas widely applicable. These similarities include expression of reactive oxygen, NFkB and akt in tumor vasculature. Furthermore, we have studied malignant vascular tumors, including hemangioendothelioma and angiosarcoma and have shown distinct signaling abnormalities in these tumors. The incidence of these tumors is expected to rise due to environmental insults, such as radiation and lumpectomy for breast cancer, dietary and industrial carcinogens (hepatic angiosarcoma), and chronic ultraviolet exposure and potential Agent Orange exposure. I hypothesize that hemangiomas, angiosarcomas, and vascular malformations represent the extremes of signaling abnormalities seen in pathogenic angiogenesis. PMID:19925405

  17. Hydrogen Sulfide Stimulates Ischemic Vascular Remodeling Through Nitric Oxide Synthase and Nitrite Reduction Activity Regulating Hypoxia‐Inducible Factor‐1α and Vascular Endothelial Growth Factor–Dependent Angiogenesis

    PubMed Central

    Bir, Shyamal C.; Kolluru, Gopi K.; McCarthy, Paul; Shen, Xinggui; Pardue, Sibile; Pattillo, Christopher B.; Kevil, Christopher G.

    2012-01-01

    Background Hydrogen sulfide (H2S) therapy is recognized as a modulator of vascular function during tissue ischemia with the notion of potential interactions of nitric oxide (NO) metabolism. However, little is known about specific biochemical mechanisms or the importance of H2S activation of NO metabolism during ischemic tissue vascular remodeling. The goal of this study was to determine the effect of H2S on NO metabolism during chronic tissue ischemia and subsequent effects on ischemic vascular remodeling responses. Methods and Results The unilateral, permanent femoral artery ligation model of hind‐limb ischemia was performed in C57BL/6J wild‐type and endothelial NO synthase–knockout mice to evaluate exogenous H2S effects on NO bioavailability and ischemic revascularization. We found that H2S selectively restored chronic ischemic tissue function and viability by enhancing NO production involving both endothelial NO synthase and nitrite reduction mechanisms. Importantly, H2S increased ischemic tissue xanthine oxidase activity, hind‐limb blood flow, and angiogenesis, which were blunted by the xanthine oxidase inhibitor febuxostat. H2S treatment increased ischemic tissue and endothelial cell hypoxia‐inducible factor‐1α expression and activity and vascular endothelial growth factor protein expression and function in a NO‐dependent manner that was required for ischemic vascular remodeling. Conclusions These data demonstrate that H2S differentially regulates NO metabolism during chronic tissue ischemia, highlighting novel biochemical pathways to increase NO bioavailability for ischemic vascular remodeling. PMID:23316304

  18. Retinal Vascular Abnormalities in NEMO-Deficient Mice: An Animal Model for Incontinentia Pigmenti

    PubMed Central

    Oster, Stephen F.; McLeod, D. Scott; Otsuji, T.; Goldberg, Morton F.; Lutty, Gerard A.

    2016-01-01

    The majority of patients with incontinentia pigmenti (IP) have a mutation in the nuclear factor-kappa-β essential modulator (NEMO) gene, and mice with a targeted deletion of NEMO exhibit skin pathology remarkably similar to the human disease. This study characterizes the retinal vascular abnormalities of NEMO-deficient mice, and compares this phenotype to known features of human IP. Nineteen heterozygous NEMO-deficient female mice, ages ranging from post-natal day 8 (P-8) through 6.5 months of life, were studied. Eyes were sectioned and stained either whole or as retinal flat mounts after incubation for enzyme histochemical demonstration of ADPase, which labels the vasculature. With maturation, retinal arteriolar abnormalities became evident at 3 months of age. Global assessment of the retinal vasculature with ADPase staining showed increased arteriolar tortuosity. Microscopic examination of sections of ADPase-incubated retinas revealed arteriolar luminal narrowing due to endothelial cell hypertrophy and increased basement membrane deposition. Venous morphology was normal. This study characterized the histological retinal phenotype of heterozygous NEMO-deficient female mice. Most striking were retinal arteriolar abnormalities, including luminal narrowing, endothelial cell hypertrophy, and basement membrane thickening. Retinal flat mounts revealed arteriolar tortuosity without evidence of vaso-occlusion or neovascularization. PMID:19068214

  19. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity.

    PubMed

    Luo, Ting; Nocon, Allison; Fry, Jessica; Sherban, Alex; Rui, Xianliang; Jiang, Bingbing; Xu, X Julia; Han, Jingyan; Yan, Yun; Yang, Qin; Li, Qifu; Zang, Mengwei

    2016-08-01

    Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-β1 (TGF-β1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-β1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-β1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-β1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-β1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity. PMID:27207538

  20. Focal 123I-FP-CIT SPECT Abnormality in Midbrain Vascular Parkinsonism

    PubMed Central

    Solla, Paolo; Cannas, Antonino; Arca, Roberta; Fonti, Davide; Orofino, Gianni; Marrosu, Francesco

    2015-01-01

    Cerebrovascular diseases are considered among possible causes of acute/subacute parkinsonism, representing up to 22% of secondary movement disorders. In cases of suspected vascular parkinsonism (VP), dopamine transporter SPECT has been highly recommended to exclude nigrostriatal dopaminergic degeneration. We report the case of a hemiparkinsonism related to a left midbrain infarct with focal lateralized putaminal abnormalities at 123I-FP-CIT SPECT imaging. The asymmetric uptake at dopamine transporter SPECT was different to findings commonly observed in typical PD pattern, because the ipsilateral striatum, in opposite to idiopathic PD, showed normal tracer binding. However, this selective parkinsonism after infarction of the midbrain was responsive to levodopa. In conclusion, we retain that there is a need of more functional imaging studies in VP addressed to a more consistent classification of its different clinical forms and to a better understanding of the adequate pharmacological management. PMID:26550502

  1. An unusual case of vascular abnormality mimicking a lateral meniscal cyst.

    PubMed

    Vergis, A; Maletius, W; Messner, K

    1995-10-01

    An unusual case of a vascular abnormality mimicking a lateral meniscal cyst is reported. The patient was a 31-year-old active sportsman who presented with intermittent pain over the lateral aspect of the left knee joint line, occurring only during activities involving twisting motions such as playing soccer. He did not experience local tenderness or swelling, clicking, locking, or giving way. The magnetic resonance imaging, which was done after a diagnostic arthroscopy with normal intra-articular findings, showed a cyst formation of approximately 4-mm diameter adjacent to the lateral meniscus periphery, but no meniscal tissue degeneration. Exactly at the preoperatively marked site of most intensive pain sensation during twisting motions, surgical exposure showed a venous-aneurysm-like tumor, which was removed. The operation resulted in complete relief of symptoms and undisturbed sporting activities including soccer. PMID:8534307

  2. Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-β/Smad pathway in vascular smooth muscle cells

    PubMed Central

    Huang, Yaqian; Shen, Zhizhou; Chen, Qinghua; Huang, Pan; Zhang, Heng; Du, Shuxu; Geng, Bin; Zhang, Chunyu; Li, Kun; Tang, Chaoshu; Du, Junbao; Jin, Hongfang

    2016-01-01

    The study was designed to investigate the role of endogenous sulfur dioxide (SO2) in collagen remodeling and its mechanisms in vascular smooth muscle cells (VSMCs). Overexpression of endogenous SO2 synthase aspartate aminotransferase (AAT) 1 or 2 increased SO2 levels and inhibited collagen I and III expressions induced by transforming growth factor (TGF)-β1 in VSMCs. In contrast, AAT1 or AAT2 knockdown induced a severe collagen deposition in TGF-β1-treated VSMCs. Furthermore, AAT1 or AAT2 overexpression suppressed procollagen I and III mRNA, upregulated matrix metalloproteinase (MMP)-13 expression, downregulated tissue inhibitors of MMP-1 level, and vice versa. Mechanistically, AAT1 or AAT2 overexpression inhibited phosphorylation of type I TGF-β receptor (TβRI) and Smad2/3 in TGF-β1-stimulated VSMCs. Whereas SB431542, an inhibitor of TGF-β1/Smad signaling pathway, attenuated excessive collagen deposition induced by AAT knockdown. Most importantly, ectopically expressing AAT or exogenous addition of 100 μM SO2 blocked AAT deficiency-aggravated collagen accumulation in TGF-β1-stimulatd VSMCs, while no inhibition was observed at 100 μM ethyl pyruvate. These findings indicated that endogenous SO2 alleviated collagen remodeling by controlling TGF-β1/TβRI/Smad2/3-mediated modulation of collagen synthesis and degradation. PMID:26762477

  3. Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-β/Smad pathway in vascular smooth muscle cells.

    PubMed

    Huang, Yaqian; Shen, Zhizhou; Chen, Qinghua; Huang, Pan; Zhang, Heng; Du, Shuxu; Geng, Bin; Zhang, Chunyu; Li, Kun; Tang, Chaoshu; Du, Junbao; Jin, Hongfang

    2016-01-01

    The study was designed to investigate the role of endogenous sulfur dioxide (SO2) in collagen remodeling and its mechanisms in vascular smooth muscle cells (VSMCs). Overexpression of endogenous SO2 synthase aspartate aminotransferase (AAT) 1 or 2 increased SO2 levels and inhibited collagen I and III expressions induced by transforming growth factor (TGF)-β1 in VSMCs. In contrast, AAT1 or AAT2 knockdown induced a severe collagen deposition in TGF-β1-treated VSMCs. Furthermore, AAT1 or AAT2 overexpression suppressed procollagen I and III mRNA, upregulated matrix metalloproteinase (MMP)-13 expression, downregulated tissue inhibitors of MMP-1 level, and vice versa. Mechanistically, AAT1 or AAT2 overexpression inhibited phosphorylation of type I TGF-β receptor (TβRI) and Smad2/3 in TGF-β1-stimulated VSMCs. Whereas SB431542, an inhibitor of TGF-β1/Smad signaling pathway, attenuated excessive collagen deposition induced by AAT knockdown. Most importantly, ectopically expressing AAT or exogenous addition of 100 μM SO2 blocked AAT deficiency-aggravated collagen accumulation in TGF-β1-stimulatd VSMCs, while no inhibition was observed at 100 μM ethyl pyruvate. These findings indicated that endogenous SO2 alleviated collagen remodeling by controlling TGF-β1/TβRI/Smad2/3-mediated modulation of collagen synthesis and degradation. PMID:26762477

  4. Delineating the angiogenic gene expression profile before pulmonary vascular remodeling in a lamb model of congenital heart disease

    PubMed Central

    Tian, Jing; Fratz, Sohrab; Hou, Yali; Lu, Qing; Görlach, Agnes; Hess, John; Schreiber, Christian; Datar, Sanjeev A.; Oishi, Peter; Nechtman, John; Podolsky, Robert; She, Jin-Xiong; Fineman, Jeffrey R.

    2011-01-01

    Disordered angiogenesis is implicated in pulmonary vascular remodeling secondary to congenital heart diseases (CHD). However, the underlying genes are not well delineated. We showed previously that an ovine model of CHD with increased pulmonary blood flow (PBF, Shunt) has an “angiogenesis burst” between 1 and 4 wk of age. Thus we hypothesized that the increased PBF elicited a proangiogenic gene expression profile before onset of vessel growth. To test this we utilized microarray analysis to identify genes that could be responsible for the angiogenic response. Total RNA was isolated from lungs of Shunt and control lambs at 3 days of age and hybridized to Affymetrix gene chips for microarray analyses (n = 8/group). Eighty-nine angiogenesis-related genes were found to be upregulated and 26 angiogenesis-related genes downregulated in Shunt compared with control lungs (cutting at 1.2-fold difference, P < 0.05). We then confirmed upregulation of proangiogenic genes FGF2, Angiopoietin2 (Angpt2), and Birc5 at mRNA and protein levels and upregulation of ccl2 at mRNA level in 3-day Shunt lungs. Furthermore, we found that pulmonary arterial endothelial cells (PAEC) isolated from fetal lambs exhibited increased expression of FGF2, Angpt2, Birc5, and ccl2 and enhanced angiogenesis when exposed to elevated shear stress (35 dyn/cm2) compared with cells exposed to more physiological shear stress (20 dyn/cm2). Finally, we demonstrated that blocking FGF2, Angpt2, Birc5, or ccl2 signaling with neutralizing antibodies or small interfering RNA (siRNA) significantly decreased the angiogenic response induced by shear stress. In conclusion, we have identified a “proangiogenic” gene expression profile in a lamb model of CHD with increased PBF that precedes onset of pulmonary vascular remodeling. Our data indicate that FGF2, Angpt2, Birc5, and ccl2 may play important roles in the angiogenic response. PMID:20978110

  5. Fasudil, a Rho-kinase inhibitor, prevents intima-media thickening in a partially ligated carotid artery mouse model: Effects of fasudil in flow-induced vascular remodeling

    PubMed Central

    Zhang, Xiangyu; Zhang, Tao; Gao, Fu; Li, Qingle; Shen, Chenyang; Li, Yankui; Li, Wei; Zhang, Xiaoming

    2015-01-01

    Vascular remodeling in response to hemodynamic alterations is a physiological process that requires coordinated signaling between endothelial, inflammatory and vascular smooth muscle cells (VSMCs). Extensive experimental and clinical studies have indicated the critical role of the Ras homolog gene family, member A/Rho-associated kinase (ROCK) signaling pathway in the pathogenesis of cardiovascular disease, where ROCK activation has been demonstrated to promote inflammation and remodeling through inducing the expression of proinflammatory cytokines and adhesion molecules in endothelial cells and VSMCs. However, the role of ROCK in flow-induced vascular remodeling has not been fully defined. The current study aimed to investigate the effect of the ROCK signaling pathway in flow-induced vascular remodeling by comparing the responses to partial carotid artery ligation in mice treated with fasudil (a ROCK inhibitor) and untreated mice. Intima-media thickness and neointima formation were evaluated by morphology. VSMC proliferation and inflammation of the vessel wall were assessed by immunohistochemistry. In addition, the expression levels of ROCK and the downstream effectors of ROCK, myosin light chain (MLC) and phosphorylated-MLC (p-MLC), were quantified by western blot analysis. Following a reduction in blood flow, ROCK1 and p-MLC expression increased in the untreated left common carotid arteries (LCA). Fasudil-treated mice developed a significantly smaller intima-media thickness compared with the untreated mice. Quantitative immunohistochemistry of the fasudil-treated LCA indicated that there was a reduction in proliferation when compared with untreated vessels. There were fewer CD45+ cells observed in the fasudil-treated LCA compared with the untreated LCA. In conclusion, the expression of ROCK was enhanced in flow-induced carotid artery remodeling and ROCK inhibition as a result of fasudil treatment may attenuate flow-induced carotid artery remodeling. PMID:26458725

  6. From Here to There, Progenitor Cells and Stem Cells Are Everywhere in Lung Vascular Remodeling.

    PubMed

    Heise, Rebecca L; Link, Patrick A; Farkas, Laszlo

    2016-01-01

    The field of stem cell biology, cell therapy, and regenerative medicine has expanded almost exponentially, in the last decade. Clinical trials are evaluating the potential therapeutic use of stem cells in many adult and pediatric lung diseases with vascular component, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or pulmonary arterial hypertension (PAH). Extensive research activity is exploring the lung resident and circulating progenitor cells and their contribution to vascular complications of chronic lung diseases, and researchers hope to use resident or circulating stem/progenitor cells to treat chronic lung diseases and their vascular complications. It is becoming more and more clear that progress in mechanobiology will help to understand the various influences of physical forces and extracellular matrix composition on the phenotype and features of the progenitor cells and stem cells. The current review provides an overview of current concepts in the field. PMID:27583245

  7. From Here to There, Progenitor Cells and Stem Cells Are Everywhere in Lung Vascular Remodeling

    PubMed Central

    Heise, Rebecca L.; Link, Patrick A.; Farkas, Laszlo

    2016-01-01

    The field of stem cell biology, cell therapy, and regenerative medicine has expanded almost exponentially, in the last decade. Clinical trials are evaluating the potential therapeutic use of stem cells in many adult and pediatric lung diseases with vascular component, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or pulmonary arterial hypertension (PAH). Extensive research activity is exploring the lung resident and circulating progenitor cells and their contribution to vascular complications of chronic lung diseases, and researchers hope to use resident or circulating stem/progenitor cells to treat chronic lung diseases and their vascular complications. It is becoming more and more clear that progress in mechanobiology will help to understand the various influences of physical forces and extracellular matrix composition on the phenotype and features of the progenitor cells and stem cells. The current review provides an overview of current concepts in the field. PMID:27583245

  8. Mechanism of IFN-γ in regulating OPN/Th17 pathway during vascular collagen remodeling of hypertension induced by ANG II

    PubMed Central

    Jiang, Lei; He, Pengcheng; Liu, Yong; Chen, Jiyan; Wei, Xuebiao; Tan, Ning

    2015-01-01

    More and more researches show that hypertensive vascular remodeling is closely related to the imbalance of immune system in recent years. IFN-γ is natural protein with the function of immune regulation and has resistance effect on vascular remodeling. However, the mechanism of IFN-γ is to be defined. This paper is to explore the mechanism of IFN-γ in regulating OPN/Th17 pathway. In this research, animal models of vascular collagen remodeling were established by inducing hypertensive mice with ANG II. There was no statistical significance when the systolic blood pressures and the percentages of wall thickness/lumen diameter in both groups of WT + AngII + IFN-γ and WT + PBS were compared (P=0.219>0.05, P=0.118>0.05). The concentration of serum precollagen-type I and III and their ratio in WT + AngII + IFN-γ group were decreased after the IFN-γ being given (P<0.01). Expression of OPN within tissue in WT + Ang II group was relatively high, but lowered after treated by IFN-γ. Th17 cell ratio was decreased in WT + AngII + IFN-γ group (P<0.01). Expressions of RORα and RORγt mRNA within Th17 cell were decreased (P<0.01). The content of IL-23 in WT + AngII + IFN-γ group was increased, while IL-10 and TGF-β decreased. It has proved that IFN-γ can regulate the hypertensive vascular collagen remodeling induced by ANG II, lower the systolic pressure and reduce the pathological damage of vascular collagen remodeling and the collagen synthesis. The mechanism may that the differentiation of Th17 is inhibited by suppressing the OPN expression and regulating the secretion of inflammatory cytokines. PMID:26823760

  9. Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling

    PubMed Central

    Franco, Claudio A; Jones, Martin L; Bernabeu, Miguel O; Vion, Anne-Clemence; Barbacena, Pedro; Fan, Jieqing; Mathivet, Thomas; Fonseca, Catarina G; Ragab, Anan; Yamaguchi, Terry P; Coveney, Peter V; Lang, Richard A; Gerhardt, Holger

    2016-01-01

    Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus. DOI: http://dx.doi.org/10.7554/eLife.07727.001 PMID:26845523

  10. C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

    PubMed Central

    Oller, Jorge; Alfranca, Arántzazu; Méndez-Barbero, Nerea; Villahoz, Silvia; Lozano-Vidal, Noelia; Martín-Alonso, Mara; Arroyo, Alicia G.; Escolano, Amelia; Armesilla, Angel Luis

    2015-01-01

    Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease. PMID:26217013

  11. Physiological and Therapeutic Vascular Remodeling Mediated by Hypoxia-Inducible Factor 1

    NASA Astrophysics Data System (ADS)

    Sarkar, Kakali; Semenza, Gregg L.

    Angiogenesis along with arteriogenesis and vasculogenesis is a fundamental process in ischemic repair in adult animals including humans. Hypoxia-inducible factor 1 (HIF-1) plays a central role in mediating adaptive responses to hypoxia/ischemia by expressing angiogenic cytokines/growth factors and their cognate receptors. Angiogenic growth factors are the homing signal for circulating angiogenic cells (CACs), which are mobilized to peripheral blood from bone marrow, recruited to target tissues, and promote vascularization. Impairment of HIF-1-mediated gene transcription contributes to the impaired vascular responses in peripheral vascular disease that are associated with aging and diabetes. Promoting neovascularization in ischemic tissues is a promising strategy for the treatment of peripheral vascular disease when surgical or catheter-based revascularization is not possible. Intramuscular injection of an adenovirus encoding a constitutively active form of HIF-1α (AdCA5), into the ischemic limb of diabetic mice increases the recovery of limb perfusion and function, rescues the diabetes-associated impairment of CACs, and increases vascularization. Administration of AdCA5 overcomes the effect of aging on recovery of blood flow in middle-aged mice following femoral artery ligation in a mouse model of age-dependent critical limb ischemia. Intramuscular injection of AdCA5 along with intravenous injection of bone-marrow-derived angiogenic cells cultured in the presence of prolyl-4-hydroxylase inhibitor dimethyloxalylglycine, increases blood flow and limb salvage in old mice following femoral artery ligation. HIF-1α gene therapy increases homing of bone-marrow-derived cells, whereas induction of HIF-1 in these cells increases their retention in the ischemic tissue by increasing their adhesion to endothelium leading to synergistic effects of combined therapy on improving blood flow.

  12. Coupled simulation of vascular growth and remodeling, hemodynamics and stress-mediated mechanotransduction

    NASA Astrophysics Data System (ADS)

    Wu, Jiacheng; Shadden, Shawn C.

    2015-11-01

    A computational framework to couple vascular G&R, blood flow simulation and stress-mediated mechanotransduction is derived for patient specific geometry. A hyperelastic constitutive relation is considered for vascular material and vessel wall is modeled via constrained mixture theory. The coupled simulation is divided into three time scales - G&R (weeks-years), hemodynamics (seconds) and stress-mediated mechanotransduction (much less than 1 second). G&R is simulated and vessel wall deformation (and tension) is computed to obtain the current vessel geometry, which defines the new boundary for blood flow. Hemodynamics are then simulated in the updated domain to calculate WSS field. A system of ODE's is derived based on conservation law and phenomenological models to describe the signaling pathways from mechanical stimuli (WSS, wall tension) to mass production rate of vascular constituents, which, in turn, changes the kinetics of G&R. To reduce computation cost, blood flow is only simulated when G&R causes significant change to geometry, and steady state response of the ODE system for mechanotransduction is used to characterize the influence of WSS and wall tension on G&R, due to separation of three time scales.

  13. Rk1, a ginsenoside, is a new blocker of vascular leakage acting through actin structure remodeling.

    PubMed

    Maeng, Yong-Sun; Maharjan, Sony; Kim, Jeong-Hun; Park, Jeong-Hill; Suk Yu, Young; Kim, Young-Myoung; Kwon, Young-Guen

    2013-01-01

    Endothelial barrier integrity is essential for vascular homeostasis and increased vascular permeability and has been implicated in many pathological processes, including diabetic retinopathy. Here, we investigated the effect of Rk1, a ginsenoside extracted from sun ginseng, on regulation of endothelial barrier function. In human retinal endothelial cells, Rk1 strongly inhibited permeability induced by VEGF, advanced glycation end-product, thrombin, or histamine. Furthermore, Rk1 significantly reduced the vessel leakiness of retina in a diabetic mouse model. This anti-permeability activity of Rk1 is correlated with enhanced stability and positioning of tight junction proteins at the boundary between cells. Signaling experiments revealed that Rk1 induces phosphorylation of myosin light chain and cortactin, which are critical regulators for the formation of the cortical actin ring structure and endothelial barrier. These findings raise the possibility that ginsenoside Rk1 could be exploited as a novel prototype compound for the prevention of human diseases that are characterized by vascular leakage. PMID:23894330

  14. Abnormalities associated with progressive aortic vascular dysfunction in chronic kidney disease

    PubMed Central

    Ameer, Omar Z.; Boyd, Rochelle; Butlin, Mark; Avolio, Alberto P.; Phillips, Jacqueline K.

    2015-01-01

    Increased stiffness of large arteries in chronic kidney disease (CKD) has significant clinical implications. This study investigates the temporal development of thoracic aortic dysfunction in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Animals aged 12 and 18 weeks were studied alongside age-matched Lewis controls (total n = 94). LPK rodents had elevated systolic blood pressure, left ventricular hypertrophy and progressively higher plasma creatinine and urea. Relative to Lewis controls, LPK exhibited reduced maximum aortic vasoconstriction (Rmax) to noradrenaline at 12 and 18 weeks, and to K+ (12 weeks). Sensitivity to noradrenaline was greater in 18-week-old LPK vs. age matched Lewis (effective concentration 50%: 24 × 10−9 ± 78 × 10−10 vs. 19 × 10−8 ± 49 × 10−9, P < 0.05). Endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation was diminished in LPK, declining with age (12 vs. 18 weeks Rmax: 80 ± 8% vs. 57 ± 9% and 92 ± 6% vs. 70 ± 9%, P < 0.05, respectively) in parallel with the decline in renal function. L-Arginine restored endothelial function in LPK, and L-NAME blunted acetylcholine relaxation in all groups. Impaired nitric oxide synthase (NOS) activity was recovered with L-Arginine plus L-NAME in 12, but not 18-week-old LPK. Aortic calcification was increased in LPK rats, as was collagen I/III, fibronectin and NADPH-oxidase subunit p47 (phox) mRNAs. Overall, our observations indicate that the vascular abnormalities associated with CKD are progressive in nature, being characterized by impaired vascular contraction and relaxation responses, concurrent with the development of endothelial dysfunction, which is likely driven by evolving deficits in NO signaling. PMID:26042042

  15. Pulmonary vascular remodeling before and after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: a cardiac magnetic resonance study.

    PubMed

    Rolf, Andreas; Rixe, Johannes; Kim, Won K; Guth, Stefan; Körlings, Nils; Möllmann, Helge; Nef, Holger M; Liebetrau, Christoph; Krombach, Gabriele; Kramm, Thorsten; Mayer, Eckhard; Hamm, Christian W

    2015-03-01

    Phase-contrast magnetic resonance imaging (PC-MRI) offers a range of surrogate markers to quantify the hemodynamic changes associated with chronic thromboembolic pulmonary hypertension (CTEPH). Our aim was to noninvasively monitor effects of pulmonary vascular remodeling before and after endarterectomy (PEA) in patients with CTEPH by using PC-MRI. Fifty-seven consecutive patients (mean age 56.7 ± 16, 28 female) underwent PC-MRI before and after PEA as part of their peri-operative routine workup. Pulmonary artery (PA) maximum flow velocity (maxV), acceleration time/ejection time (AT/ET), distensibility [(PA maximum area - PA minimum area)/PA minimum area], mid-systolic flow deceleration (notch), and the timing of deceleration (notch ratio) were recorded. Mean PA pressure was obtained from standard right heart catheter procedures. maxV and AT/ET were decreased before PEA and significantly improved afterwards (60.8 ± 16 vs. 73.8 ± 19 cm/s, p = 0.007; 0.32 ± 0.06 vs. 0.36 ± 0.09, p = 0.0015). Surprisingly, distensibility did not change significantly (30 ± 19 vs. 26 ± 12%, p = 0.11). Forty-five patients (78%) had a systolic notch before PEA that persisted in only 10 (18%; p = 0.00001). Among patients with a persisting notch, the notch ratio did not significantly increase (1.3 ± 0.2 vs. 1.6 ± 1.5, p = 0.32). Our data show early PA reverse remodeling after PEA. Flow velocities increase while PA flow wave reflections represented by mid-systolic flow deceleration are abolished. In some patients a mid-systolic notch persists, suggesting increased downstream resistance as a consequence of small vessel arteriopathy. PMID:25519191

  16. Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study

    PubMed Central

    2010-01-01

    Background Little is known about airway remodelling in bronchial biopsies (BB) in smokers and chronic obstructive pulmonary disease (COPD). We conducted an initial pilot study comparing BB from COPD patients with nonsmoking controls. This pilot study suggested the presence of reticular basement membrane (Rbm) fragmentation and altered vessel distribution in COPD. Methods To determine whether Rbm fragmentation and altered vessel distribution in BB were specific for COPD we designed a cross-sectional study and stained BB from 19 current smokers and 14 ex-smokers with mild to moderate COPD and compared these to 15 current smokers with normal lung function and 17 healthy and nonsmoking subjects. Results Thickness of the Rbm was not significantly different between groups; although in COPD this parameter was quite variable. The Rbm showed fragmentation and splitting in both current smoking groups and ex-smoker COPD compared with healthy nonsmokers (p < 0.02); smoking and COPD seemed to have additive effects. Rbm fragmentation correlated with smoking history in COPD but not with age. There were more vessels in the Rbm and fewer vessels in the lamina propria in current smokers compared to healthy nonsmokers (p < 0.05). The number of vessels staining for vascular endothelial growth factor (VEGF) in the Rbm was higher in both current smoker groups and ex-smoker COPD compared to healthy nonsmokers (p < 0.004). In current smoker COPD VEGF vessel staining correlated with FEV1% predicted (r = 0.61, p < 0.02). Conclusions Airway remodelling in smokers and mild to moderate COPD is associated with fragmentation of the Rbm and altered distribution of vessels in the airway wall. Rbm fragmentation was also present to as great an extent in ex-smokers with COPD. These characteristics may have potential physiological consequences. PMID:20670454

  17. Bioactive glass foam scaffolds are remodelled by osteoclasts and support the formation of mineralized matrix and vascular networks in vitro.

    PubMed

    Midha, Swati; van den Bergh, Wouter; Kim, Taek B; Lee, Peter D; Jones, Julian R; Mitchell, Christopher A

    2013-03-01

    Remodelling of scaffolds and new bone formation is critical for effective bone regeneration. Herein is reported the first demonstration of resorption pits due to osteoclast activity on the surface of sol-gel bioactive glass foam scaffolds. Bioactive glass foam scaffolds are known to have osteogenic potential and suitable pore networks for bone regeneration. Degradation of the scaffolds is known to be initially solution mediated, but for effective bone regeneration, remodelling of the scaffold by osteoclasts and vascularisation of the scaffold is necessary. The culture of C7 macrophages on a bioactive glass scaffold induces the cells to differentiate into (TRAP(+ve) ) osteoclasts. They then form distinctive resorption pits within 3 weeks, while MC3T3-E1 pre-osteoblasts deposit mineralized osteoid on their surfaces in co-culture. The scaffolds are of the 70S30C (70 mol% SiO2 , 30 mol% CaO) composition, with modal pore and interconnect diameters of 373 μm and 172 μm respectively (quantified by X-ray micro-tomography and 3D image analysis). The release of soluble silica and calcium ions from 70S30C scaffolds induces an increase in osteoblast numbers as determined via the MTT assay. Scaffolds also support growth of endothelial cells on their surface and tube formation (characteristic of functional microvasculature) following 4 days in culture. This data supports the hypothesis that 70S30C bioactive glass scaffolds promote the differentiation of the 3 main cell types involved in vascularized bone regeneration. PMID:23184651

  18. Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension.

    PubMed

    Parker, T A; Ivy, D D; Galan, H L; Grover, T R; Kinsella, J P; Abman, S H

    2000-02-01

    Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol (E(2)) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term = 147 days) with daily infusions of E(2) (10 microg; E(2) group, n = 6) or saline (control group, n = 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the E(2)-treated group (2.43 +/- 0.79 vs. 1.48 +/- 0.26 mmHg. ml(-1). min, control vs. E(2), P < 0.05). During the subsequent delivery study, PVR was lower in the E(2)-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% O(2). During mechanical ventilation after delivery, arterial partial O(2) pressure was higher in E(2) animals than controls (41 +/- 11 vs. 80 +/- 35 Torr, control vs. E(2), P < 0. 05). Morphometric studies of hypertensive vascular changes revealed that E(2) treatment decreased wall thickness of small pulmonary arteries (59 +/- 1 vs. 48 +/- 1%, control vs. E(2), P < 0.01). We conclude that chronic E(2) treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs. PMID:10666122

  19. Herpes Virus Infection Is Associated with Vascular Remodeling and Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Calabrese, Fiorella; Kipar, Anja; Lunardi, Francesca; Balestro, Elisabetta; Perissinotto, Egle; Rossi, Emanuela; Nannini, Nazarena; Marulli, Giuseppe; Stewart, James P.; Rea, Federico

    2013-01-01

    Background Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed. Methods Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. Results A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. Conclusion

  20. 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.

  1. Targeting complement component 5a promotes vascular integrity and limits airway remodeling.

    PubMed

    Khan, Mohammad A; Maasch, Christian; Vater, Axel; Klussmann, Sven; Morser, John; Leung, Lawrence L; Atkinson, Carl; Tomlinson, Stephen; Heeger, Peter S; Nicolls, Mark R

    2013-04-01

    Increased microvascular dilatation and permeability is observed during allograft rejection. Because vascular integrity is an important indicator of transplant health, we have sought to limit injury to blood vessels by blocking complement activation. Although complement component 3 (C3) inhibition is known to be vasculoprotective in transplantation studies, we recently demonstrated the paradoxical finding that, early in rejection, C3(-/-) transplant recipients actually exhibit worse microvascular injury than controls. In the genetic absence of C3, thrombin-mediated complement component 5 (C5) convertase activity leads to the generation of C5a (anaphylatoxin), a promoter of vasodilatation and permeability. In the current study, we demonstrated that microvessel thrombin deposition is significantly increased in C3(-/-) recipients during acute rejection. Thrombin colocalization with microvessels is closely associated with remarkably elevated plasma levels of C5a, vasodilatation, and increased vascular permeability. Administration of NOX-D19, a specific C5a inhibitor, to C3(-/-) recipients of airway transplants significantly improved tissue oxygenation, limited microvascular leakiness, and prevented airway ischemia, even in the absence of conventional T-cell-directed immunosuppression. As C3 inhibitors enter the clinics, the simultaneous targeting of this thrombin-mediated complement activation pathway and/or C5a itself may confer significant clinical benefit. PMID:23530212

  2. Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats.

    PubMed

    Nakano, Ayuki; Nakahara, Tsutomu; Mori, Asami; Ushikubo, Hiroko; Sakamoto, Kenji; Ishii, Kunio

    2016-02-01

    Retinal arterial tortuosity and venous dilation are hallmarks of plus disease, which is a severe form of retinopathy of prematurity (ROP). In this study, we examined whether short-term interruption of vascular endothelial growth factor (VEGF) signals leads to the formation of severe ROP-like abnormal retinal blood vessels. Neonatal rats were treated subcutaneously with the VEGF receptor (VEGFR) tyrosine kinase inhibitors, KRN633 (1, 5, or 10 mg/kg) or axitinib (10 mg/kg), on postnatal day (P) 7 and P8. The retinal vasculatures were examined on P9, P14, or P21 in retinal whole-mounts stained with an endothelial cell marker. Prevention of vascular growth and regression of some preformed capillaries were observed on P9 in retinas of rats treated with KRN633. However, on P14 and P21, density of capillaries, tortuosity index of arterioles, and diameter of veins significantly increased in KRN633-treated rats, compared to vehicle (0.5% methylcellulose)-treated animals. Similar observations were made with axitinib-treated rats. Expressions of VEGF and VEGFR-2 were enhanced on P14 in KRN633-treated rat retinas. The second round of KRN633 treatment on P11 and P12 completely blocked abnormal retinal vascular growth on P14, but thereafter induced ROP-like abnormal retinal blood vessels by P21. These results suggest that an interruption of normal retinal vascular development in neonatal rats as a result of short-term VEGFR inhibition causes severe ROP-like abnormal retinal vascular growth in a VEGF-dependent manner. Rats treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms underlying the development of plus disease. PMID:26500193

  3. Early origins of adult disease: low birth weight and vascular remodeling.

    PubMed

    Visentin, Silvia; Grumolato, Francesca; Nardelli, Giovanni Battista; Di Camillo, Barbara; Grisan, Enrico; Cosmi, Erich

    2014-12-01

    Cardiovascular diseases (CVD) and diabetes still represent the main cause of mortality and morbidity in the industrialized world. Low birth weight (LBW), caused by intrauterine growth restriction (IUGR), was recently known to be associated with increased rates of CVD and non-insulin dependent diabetes in adult life (Barker's hypothesis). Well-established animal models have shown that environmentally induced IUGR (diet, diabetes, hormone exposure, hypoxia) increases the risk of a variety of diseases later in life with similar phenotypic outcomes in target organs. This suggests that a range of disruptions in fetal and postnatal growth may act through common pathways to regulate the developmental programming and produce a similar adult phenotype. The identification of all involved signaling cascades, underlying the physiopathology of these damages in IUGR fetuses, with their influence on adult health, is still far from satisfactory. The endothelium may be important for long-term remodeling and in the control of elastic properties of the arterial wall. Several clinical and experimental studies showed that IUGR fetuses, neonates, children and adolescents present signs of endothelial dysfunction, valuated by aorta intima media thickness, carotid intima media thickness and stiffness, central pulse wave velocity, brachial artery flow-mediated dilation, laser Doppler skin perfusion and by the measure of arterial blood pressure. In utero identification of high risk fetuses and long-term follow-up are necessary to assess the effects of interventions aimed at preventing pregnancy-induced hypertension, reducing maternal obesity, encouraging a healthy life style and preventing childhood obesity on adult blood pressure and cardiovascular disease in later life. PMID:25463063

  4. Calcium antagonists, diltiazem and nifedipine, protect broilers against low temperature-induced pulmonary hypertension and pulmonary vascular remodeling.

    PubMed

    Yang, Ying; Gao, Mingyu; Guo, Yuming; Qiao, Jian

    2010-08-01

    This study was designed to determine whether calcium antagonists, diltiazem and nifedipine, can depress low temperature-induced pulmonary hypertension (PH) in broilers (also known as ascites) and to characterize their efficacy on hemodynamics and pulmonary artery function. Chicks were randomly allocated into six experimental groups and orally administered with vehicle, 5.0 mg/kg body weight (BW)/12 h nifedipine or 15.0 mg/kg BW/12 h diltiazem from 16 to 43 days of age under low temperature. The mean pulmonary arterial pressure (mPAP), the ascites heart index (AHI), the erythrocyte packed cell volume (PCV) and the relative percentage of medial pulmonary artery thickness were examined on days 29, 36 and 43. The data showed that administration of diltiazem protected broilers from low temperature-induced pulmonary hypertension and vascular remodeling. Although nifedipine prevented mPAP from increasing during the early stage, it did not suppress the development of PH during the late stage and did not keep heart rate (HR), PCV, AHI and the thickness of pulmonary small artery smooth muscle layer at the normal levels. Taken together, our results showed that diltiazem can effectively prevent low temperature-induced pulmonary hypertension in broilers with fewer side-effects and may be a potential compound for the prevention of this disease in poultry industry. PMID:20662820

  5. Diabetic retinopathy: retina-specific methods for maintenance of diabetic rodents and evaluation of vascular histopathology and molecular abnormalities

    PubMed Central

    Veenstra, Alexander; Liu, Haitao; Lee, Chieh Allen; Du, Yunpeng; Tang, Jie; Kern, Timothy S.

    2015-01-01

    Diabetic retinopathy is a major cause of visual impairment, which continues to increase in prevalence as more and more people develop diabetes. Despite the importance of vision, the retina is one of the smallest tissues in the body, and specialized techniques to study the retinopathy have been developed. This chapter will summarize several methods used to (i) induce diabetes, (ii) maintain the diabetic animals throughout the months required for the development of typical vascular histopathology, (iii) evaluate vascular histopathology of diabetic retinopathy, and (iv) quantitate abnormalities implicated in the development of the retinopathy. PMID:26331759

  6. Adiponectin Attenuates Angiotensin II-Induced Vascular Smooth Muscle Cell Remodeling through Nitric Oxide and the RhoA/ROCK Pathway

    PubMed Central

    Nour-Eldine, Wared; Ghantous, Crystal M.; Zibara, Kazem; Dib, Leila; Issaa, Hawraa; Itani, Hana A.; El-Zein, Nabil; Zeidan, Asad

    2016-01-01

    Introduction: Adiponectin (APN), an adipocytokine, exerts protective effects on cardiac remodeling, while angiotensin II (Ang II) induces hypertension and vascular remodeling. The potential protective role of APN on the vasculature during hypertension has not been fully elucidated yet. Here, we evaluate the molecular mechanisms of the protective role of APN in the physiological response of the vascular wall to Ang II. Methods and Results: Rat aortic tissues were used to investigate the effect of APN on Ang II-induced vascular remodeling and hypertrophy. We investigated whether nitric oxide (NO), the RhoA/ROCK pathway, actin cytoskeleton remodeling, and reactive oxygen species (ROS) mediate the anti-hypertrophic effect of APN. Ang II-induced protein synthesis was attenuated by pre-treatment with APN, NO donor S-nitroso-N-acetylpenicillamine (SNAP), or cGMP. The hypertrophic response to Ang II was associated with a significant increase in RhoA activation and vascular force production, which were prevented by APN and SNAP. NO was also associated with inhibition of Ang II-induced phosphorylation of cofilin. In addition, immunohistochemistry revealed that 24 h Ang II treatment increased the F- to G-actin ratio, an effect that was inhibited by SNAP. Ang II-induced ROS formation and upregulation of p22phox mRNA expression were inhibited by APN and NO. Both compounds failed to inhibit Nox1 and p47phox expression. Conclusion: Our results suggest that the anti-hypertrophic effects of APN are due, in part, to NO-dependent inhibition of the RhoA/ROCK pathway and ROS formation. PMID:27092079

  7. Vascular corrosion casting: analyzing wall shear stress in the portal vein and vascular abnormalities in portal hypertensive and cirrhotic rodents.

    PubMed

    Van Steenkiste, Christophe; Trachet, Bram; Casteleyn, Christophe; van Loo, Denis; Van Hoorebeke, Luc; Segers, Patrick; Geerts, Anja; Van Vlierberghe, Hans; Colle, Isabelle

    2010-11-01

    Vascular corrosion casting is an established method of anatomical preparation that has recently been revived and has proven to be an excellent tool for detailed three-dimensional (3D) morphological examination of normal and pathological microcirculation. In addition, the geometry provided by vascular casts can be further used to calculate wall shear stress (WSS) in a vascular bed using computational techniques. In the first part of this study, the microvascular morphological changes associated with portal hypertension (PHT) and cirrhosis in vascular casts are described. The second part of this study consists of a quantitative analysis of the WSS in the portal vein in casts of different animal models of PHT and cirrhosis using computational fluid dynamics (CFD). Microvascular changes in the splanchnic, hepatic and pulmonary territory of portal hypertensive and cirrhotic mice are described in detail with stereomicroscopic examination and scanning electron microscopy. To our knowledge, our results are the first to report the vascular changes in the common bile duct ligation cirrhotic model. Calculating WSS using CFD methods is a feasible technique in PHT and cirrhosis, enabling the differentiation between different animal models. First, a dimensional analysis was performed, followed by a CFD calculation describing the spatial and temporal WSS distributions in the portal vein. WSS was significantly different between sham/cirrhotic/pure PHT animals with the highest values in the latter. Up till now, no techniques have been developed to quantify WSS in the portal vein in laboratory animals. This study showed for the first time that vascular casting has an important role not only in the morphological evaluation of animal models of PHT and cirrhosis, but also in defining the biological response of the portal vein wall to hemodynamic changes. CFD in 3D geometries can be used to describe the spatial and temporal variations in WSS in the portal vein and to better understand

  8. NO contributes to abnormal vascular calcium regulation and reactivity induced by peritonitis-associated septic shock in rats.

    PubMed

    Chen, Shiu-Jen; Li, Shaio-Yun; Shih, Chih-Chin; Liao, Mei-Huei; Wu, Chin-Chen

    2010-05-01

    Calcium plays an important role in determining vascular smooth muscle tone. Norepinephrine (NE)-induced vascular contraction contains two components: 1) Ca2+ release from the sarcoplasmic reticulum as the fast phase and 2) Ca2+ influx via a voltage-dependent calcium channel as the slow phase. This study used functional isometric tension recording to evaluate mediators contributing to abnormal NE-induced Ca2+ handling and reactivity in isolated thoracic aortas from septic rats. Sepsis was induced by cecal ligation and puncture (CLP), and thoracic aortas were removed at 18 h after CLP. Our results showed that rats that received CLP for 18 h manifested severe hypotension and vascular hyporeactivity to NE in vivo. This vascular hyporeactivity to NE was also observed in the aorta obtained from CLP-induced sepsis rat. Both the fast and slow phases of NE-induced contraction were reduced in aortas from sepsis rats. To clarify what possible mediators contribute to the abnormal Ca2+ handling in aortas from sepsis animals, inhibitors of Ca2+ channel and release were used. Inhibition by 2-aminoethoxy-diphenyl borane, ryanodine, and cyclopiazonic acid of the NE-induced contraction in Ca2+-free solution was greater in the aorta from sepsis rats and inhibitions of cyclopiazonic acid and ryanodine, but not of 2-aminoethoxy-diphenyl borane, were attenuated by NOS inhibitor N[omega]-nitro-l-arginine methyl ester. In addition, the attenuation of NE-induced contraction by nifedipine in the aorta was also greater in the CLP group. Our results suggest that abnormal NE-induced Ca2+ handling associated with vascular hyporeactivity in the CLP-induced sepsis is caused by a major decrease in sarcoplasmic reticulum function and a minor impairment of voltage-dependent Ca2+ channels on membrane to Ca2+ handling, at least, in the aorta, and this could be attributed to an overproduction of NO in sepsis. PMID:19749606

  9. Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice.

    PubMed

    Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert; Navarro, Edwin; Jain, Noopur; Carandang, Francis; Peterson, Joanna; Mokres, Lucia; Milla, Carlos; Preuss, Stefanie; Alcazar, Miguel Alejandre; Khan, Suleman; Masumi, Juliet; Ferreira-Tojais, Nancy; Mujahid, Sana; Starcher, Barry; Rabinovitch, Marlene; Bland, Richard

    2015-03-01

    Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln(+/-)) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln(+/+)) and Eln(+/-) littermates at baseline and after MV with air for 8-24 h. Lungs of unventilated Eln(+/-) mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln(+/+) pups. Eln(+/-) lungs contained fewer capillaries than Eln(+/+) lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln(+/+) neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln(+/-) mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln(+/-) than in Eln(+/+) pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln(+/-) compared with Eln(+/+) mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln(+/+) and Eln(+/-) mice. Paucity of lung capillaries in Eln(+/-) newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln(+/-) mice. PMID:25539853

  10. Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice

    PubMed Central

    Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert; Navarro, Edwin; Jain, Noopur; Carandang, Francis; Peterson, Joanna; Mokres, Lucia; Milla, Carlos; Preuss, Stefanie; Alcazar, Miguel Alejandre; Khan, Suleman; Masumi, Juliet; Ferreira-Tojais, Nancy; Mujahid, Sana; Starcher, Barry; Rabinovitch, Marlene

    2014-01-01

    Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln+/−) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln+/+) and Eln+/− littermates at baseline and after MV with air for 8–24 h. Lungs of unventilated Eln+/− mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln+/+ pups. Eln+/− lungs contained fewer capillaries than Eln+/+ lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln+/+ neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln+/− mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln+/− than in Eln+/+ pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln+/− compared with Eln+/+ mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln+/+ and Eln+/− mice. Paucity of lung capillaries in Eln+/− newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln+/− mice. PMID:25539853

  11. Targeted SPECT/CT Imaging of Matrix Metalloproteinase Activity in the Evaluation of Remodeling Tissue-Engineered Vascular Grafts Implanted in a Growing Lamb Model

    PubMed Central

    Stacy, Mitchel R.; Naito, Yuji; Maxfield, Mark W.; Kurobe, Hirotsugu; Tara, Shuhei; Chan, Chung; Rocco, Kevin A.; Shinoka, Toshiharu; Sinusas, Albert J.; Breuer, Christopher K.

    2014-01-01

    Objective(s) The clinical translation of tissue-engineered vascular grafts has been demonstrated in children. The remodeling of biodegradable, cell-seeded scaffolds to functional neovessels is partially attributed to matrix metalloproteinases. Noninvasive assessment of matrix metalloproteinase activity may indicate graft remodeling and elucidate the progression of neovessel formation. Therefore, matrix metalloproteinase activity was evaluated in grafts implanted in lambs using in vivo and ex vivo hybrid imaging. Graft growth and remodeling was quantified using in vivo X-ray computed tomography angiography. Methods Cell-seeded and unseeded scaffolds were implanted in lambs (n=5) as inferior vena cava interposition grafts. At 2 and 6 months post-implantation, in vivo angiography assessed graft morphology. In vivo and ex vivo single photon emission tomography/X-ray computed tomography imaging was performed with a radiolabeled compound targeting matrix metalloproteinase activity at 6 months. Neotissue was examined at 6 months using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis. Results Seeded grafts demonstrated significant luminal and longitudinal growth from 2 to 6 months. In vivo imaging revealed subjectively higher matrix metalloproteinase activity in grafts vs. native tissue. Ex vivo imaging confirmed a quantitative increase in matrix metalloproteinase activity and demonstrated higher activity in unseeded vs. seeded grafts. Glycosaminoglycan content was increased in seeded grafts vs. unseeded grafts, without significant differences in collagen content. Conclusions Matrix metalloproteinase activity remains elevated in tissue-engineered grafts 6 months post-implantation and may indicate remodeling. Optimization of in vivo imaging to noninvasively evaluate matrix metalloproteinase activity may assist in serial assessment of vascular graft remodeling. PMID:24952823

  12. The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension.

    PubMed

    Church, Alistair C; Martin, Damien H; Wadsworth, Roger; Bryson, Gareth; Fisher, Andrew J; Welsh, David J; Peacock, Andrew J

    2015-08-15

    The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease. PMID:26024891

  13. Monitoring Vascular Permeability and Remodeling After Endothelial Injury in a Murine Model Using a Magnetic Resonance Albumin-Binding Contrast Agent

    PubMed Central

    Phinikaridou, Alkystis; Lorrio, Silvia; Zaragoza, Carlos; Botnar, René M.

    2015-01-01

    Background— Despite the beneficial effects of vascular interventions, these procedures may damage the endothelium leading to increased vascular permeability and remodeling. Re-endothelialization of the vessel wall, with functionally and structurally intact cells, is controlled by endothelial nitric oxide synthase (NOS3) and is crucial for attenuating adverse effects after injury. We investigated the applicability of the albumin-binding MR contrast agent, gadofosveset, to noninvasively monitor focal changes in vascular permeability and remodeling, after injury, in NOS3-knockout (NOS3−/−) and wild-type (WT) mice in vivo. Methods and Results— WT and NOS3−/− mice were imaged at 7, 15, and 30 days after aortic denudation or sham-surgery. T1 mapping (R1=1/T1, s−1) and delayed-enhanced MRI were used as measurements of vascular permeability (R1) and remodeling (vessel wall enhancement, mm2) after gadofosveset injection, respectively. Denudation resulted in higher vascular permeability and vessel wall enhancement 7 days after injury in both strains compared with sham-operated animals. However, impaired re-endothelialization and increased neovascularization in NOS3−/− mice resulted in significantly higher R1 at 15 and 30 days post injury compared with WT mice that showed re-endothelialization and lack of neovascularization (R1 [s−1]=15 days: NOS3−/−4.02 [interquartile range, IQR, 3.77–4.41] versus WT2.39 [IQR, 2.35–2.92]; 30 days: NOS3−/−4.23 [IQR, 3.94–4.68] versus WT2.64 [IQR, 2.33–2.80]). Similarly, vessel wall enhancement was higher in NOS3−/− but recovered in WT mice (area [mm2]=15 days: NOS3−/−5.20 [IQR, 4.68–6.80] versus WT2.13 [IQR, 0.97–3.31]; 30 days: NOS3−/−7.35 [IQR, 5.66–8.61] versus WT1.60 [IQR, 1.40–3.18]). Ex vivo histological studies corroborated the MRI findings. Conclusions— We demonstrate that increased vascular permeability and remodeling, after injury, can be assessed noninvasively using an

  14. Endothelial cell migration during murine yolk sac vascular remodeling occurs by means of a Rac1 and FAK activation pathway in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The molecular mechanism(s) controlling cell migration during vascular morphogenesis in vivo remain largely undefined. To address this within a physiological context, we used retinaldehyde dehydrogenase-2 (Raldh2) null mouse embryos and demonstrate that retinoic acid (RA) deficiency results in abnorm...

  15. Abnormalities in hyperpolarized (129)Xe magnetic resonance imaging and spectroscopy in two patients with pulmonary vascular disease.

    PubMed

    Dahhan, Talal; Kaushik, Shiv S; He, Mu; Mammarappallil, Joseph G; Tapson, Victor F; McAdams, Holman P; Sporn, Thomas A; Driehuys, Bastiaan; Rajagopal, Sudarshan

    2016-03-01

    The diagnosis of pulmonary vascular disease (PVD) is usually based on hemodynamic and/or clinical criteria. Noninvasive imaging of the heart and proximal vasculature can also provide useful information. An alternate approach to such criteria in the diagnosis of PVD is to image the vascular abnormalities in the lungs themselves. Hyperpolarized (HP) (129)Xe magnetic resonance imaging (MRI) is a novel technique for assessing abnormalities in ventilation and gas exchange in the lungs. We applied this technique to two patients for whom there was clinical suspicion of PVD. Two patients who had significant hypoxemia and dyspnea with no significant abnormalities on computed tomography imaging or ventilation-perfusion scan and only mild or borderline pulmonary arterial hypertension at catheterization were evaluated. They underwent HP (129)Xe imaging and subsequently had tissue diagnosis obtained from lung pathology. In both patients, HP (129)Xe imaging demonstrated normal ventilation but markedly decreased gas transfer to red blood cells with focal defects on imaging, a pattern distinct from those previously described for idiopathic pulmonary fibrosis or obstructive lung disease. Pathology on both patients later demonstrated severe PVD. These findings suggest that HP (129)Xe MRI may be useful in the diagnosis of PVD and monitoring response to therapy. Further studies are required to determine its sensitivity and specificity in these settings. PMID:27162620

  16. From the Cover: Zinc Deficiency Worsens and Supplementation Prevents High-Fat Diet Induced Vascular Inflammation, Oxidative Stress, and Pathological Remodeling.

    PubMed

    Chen, Jun; Wang, Shudong; Luo, Manyu; Zhang, Zhiguo; Dai, Xiaozhen; Kong, Maiying; Cai, Lu; Wang, Yuehui; Shi, Bingyin; Tan, Yi

    2016-09-01

    Obesity has become a common public health problem in the world and raises the risk of various cardiovascular diseases. Zinc is essential for multiple organs in terms of normal structure and function. The present study investigated the effects of high fat diet (HFD) induced obesity on the aorta in mice, and evaluated whether it can be affected by zinc deficiency or supplementation. Four-week-old male C57BL/6J mice were fed HFD with varied amounts of zinc (deficiency, adequate and supplementation) for 3 and 6 months. Results showed that HFD feeding induced a time-dependent aortic remodeling, demonstrated by increased vessel wall thickness, tunica cell proliferation and fibrotic responses, and inflammatory response, reflected by increased expression of inflammatory cytokines (tumor necrosis factor-α and vascular cell adhesion molecule 1). HFD feeding also caused aortic oxidative damage, reflected by 3-nitrotyrosine and 4-hydroxy-2-nonenal accumulation, and down-regulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and function, shown by down-regulation of its downstream antioxidants, catalase, NAD(P)H dehydrogenase (quinone 1), and metallothionein expression. The vascular effects of obesity-induced by HFD was exacerbated by zinc deficiency but significantly improved by zinc supplementation. In addition, down-regulation of Nrf2 function and associated antioxidants expression were also worsened by zinc deficiency but improved by zinc supplementation. These results suggest that HFD induces aortic remodeling, which can be exacerbated by zinc deficiency and improved by zinc supplementation. PMID:27370414

  17. Abnormal thallium kinetics in postoperative coarctation of the aorta: evidence for diffuse hypertension-induced vascular pathology

    SciTech Connect

    Kimball, B.P.; Shurvell, B.L.; Mildenberger, R.R.; Houle, S.; McLaughlin, P.R.

    1986-03-01

    After operative correction of congenital coarctation of the aorta, patients continue to have excess cardiovascular mortality, including manifestations of ischemic heart disease. Previous morphologic studies support the concept of direct hypertensive vascular injury in these patients. To determine whether abnormalities of myocardial perfusion were present in an asymptomatic group of patients with coarctation repair, 18 men and 9 women with a mean age of 26 years (range 19 to 41) were studied between 2 and 25 years after operative correction. Stress electrocardiography and quantitative thallium imaging by a circumferential profile technique were used. These patients were compared with a normal group, statistically defined as having a less than 1% prevalence of significant obstructive coronary artery disease. The postoperative coarctation group demonstrated a reduction in global thallium redistribution in each view analyzed. As compared with findings in the control subjects, thallium washout in the anterior view (41.9 versus 48.6%, p = 0.02) and left anterior oblique projection (40.5 versus 48.2%, p = 0.007) was significantly diminished. Although the postoperative coarctation group had a lower thallium redistribution rate in the lateral view (41.4 versus 46.3%, p = 0.09) this difference did not reach statistical significance because of the intrinsic variability of this projection. Plots of the median percent thallium washout revealed independence from circumferential profile angle, indicating global abnormalities in perfusion. No correlation between clinical variables and thallium kinetics could be established, suggesting marked individual variability in the development of this vascular lesion. The observation of abnormal thallium kinetics in patients with coarctation repair may have consequences for long-term follow-up and therapy.

  18. HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype.

    PubMed

    Shroff, Rukshana; Speer, Thimoteus; Colin, Sophie; Charakida, Marietta; Zewinger, Stephen; Staels, Bart; Chinetti-Gbaguidi, Giulia; Hettrich, Inga; Rohrer, Lucia; O'Neill, Francis; McLoughlin, Eve; Long, David; Shanahan, Catherine M; Landmesser, Ulf; Fliser, Danilo; Deanfield, John E

    2014-11-01

    Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2-5 (HDL(CKD)), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL(CKD) strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation. PMID:24854267

  19. Abnormalities of pulmonary vascular dynamics and inflammation in early progressive systemic sclerosis

    SciTech Connect

    Furst, D.E.; Davis, J.A.; Clements, P.J.; Chopra, S.K.; Theofilopoulos, A.N.; Chia, D.

    1981-11-01

    Abnormalities of pulmonary function were studied in 10 patients with progressive systemic sclerosis (PSS) and 3 control subjects. All underwent 81M krypton lung scanning and total body gallium scanning. Immune complexes were measured by Raji cell radioimmunoassay and polyethylene glycol (PEG) assay. Perfusion scans were abnormal in 7 of 9 patients, and 5 of 9 showed a decrease in pulmonary perfusion after cold challenge. Increased gallium uptake was noted in the lungs of 6 of 9 patients. Krypton scans were normal in the control group. Elevated immune complexes were noted in 8 of 10 patients by the Raji assay and in 5 of 10 with the PEG assay. Efforts to separate patients with PSS into subgroups may lead to a better understanding of and advances in therapy for PSS.

  20. Hindlimb Suspension as a Model to Study Ophthalmic Complications in Microgravity Status Report: Optimization of Rat Retina Flat Mounts Staining to Study Vascular Remodeling

    NASA Technical Reports Server (NTRS)

    Theriot, Corey A.; Zanello, Susana B.

    2014-01-01

    Preliminary data from a prior tissue-sharing experiment has suggested that early growth response protein-1 (Egr1), a transcription factor involved in various stress responses in the vasculature, is induced in the rat retina after 14 days of hindlimb suspension (HS) and may be evidence that mechanical stress is occurring secondary to the cephalad fluid shift. This mechanical stress could cause changes in oxygenation of the retina, and the subsequent ischemia- or inflammation-driven hypoxia may lead to microvascular remodeling. This microvascular remodeling process can be studied using image analysis of retinal vessels and can be then be quantified by the VESsel GENeration Analysis (VESGEN) software, a computational tool that quantifies remodeling patterns of branching vascular trees and capillary or vasculogenic networks. Our project investigates whether rodent HS is a valid model to study the effects of simulated-weightlessness on ocular structures and their relationship with intracranial pressure (ICP). One of the hypotheses to be tested is that HS-induced cephalad fluid shift is accompanied by vascular engorgement that produces changes in retinal oxygenation, leading to oxidative stress, hypoxia, microvascular remodeling, and cellular degeneration. We have optimized the procedure to obtain flat mounts of rat retina, staining of the endothelial lining in vasculature and acquisition of high quality images suitable for VESGEN analysis. Briefly, eyes were fixed in 4% paraformaldehyde for 24 hours and retinas were detached and then mounted flat on microscope slides. The microvascular staining was done with endothelial cell-specific isolectin binding, coupled to Alexa-488 fluorophore. Image acquisition at low magnification and high resolution was performed using a new Leica SP8 confocal microscope in a tile pattern across the X,Y plane and multiple sections along the Z-axis. This new confocal microscope has the added capability of dye separation using the Linear

  1. Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Mediated Redox Signaling and Vascular Remodeling by 16α-Hydroxyestrone in Human Pulmonary Artery Cells: Implications in Pulmonary Arterial Hypertension.

    PubMed

    Hood, Katie Y; Montezano, Augusto C; Harvey, Adam P; Nilsen, Margaret; MacLean, Margaret R; Touyz, Rhian M

    2016-09-01

    Estrogen and oxidative stress have been implicated in pulmonary arterial hypertension (PAH). Mechanisms linking these systems are elusive. We hypothesized that estrogen metabolite, 16α-hydroxyestrone (16αOHE1), stimulates nicotinamide adenine dinucleotide phosphate oxidase (Nox)-induced reactive oxygen species (ROS) generation and proliferative responses in human pulmonary artery smooth muscle cells (hPASMCs) and that in PAH aberrant growth signaling promotes vascular remodeling. The pathophysiological significance of estrogen-Nox-dependent processes was studied in female Nox1(-/-) and Nox4(-/-) mice with PAH. PASMCs from control subjects (control hPASMCs) and PAH patients (PAH-hPASMCs) were exposed to estrogen and 16αOHE1 in the presence/absence of inhibitors of Nox, cytochrome P450 1B1, and estrogen receptors. Estrogen, through estrogen receptor-α, increased Nox-derived ROS and redox-sensitive growth in hPASMCs, with greater effects in PAH-hPASMCs versus control hPASMCs. Estrogen effects were inhibited by cytochrome P450 1B1 blockade. 16αOHE1 stimulated transient ROS production in hPASMCs, with sustained responses in PAH-hPASMCs. Basal expression of Nox1/Nox4 was potentiated in PAH-hPASMCs. In hPASMCs, 16αOHE1 increased Nox1 expression, stimulated irreversible oxidation of protein tyrosine phosphatases, decreased nuclear factor erythroid-related factor 2 activity and expression of nuclear factor erythroid-related factor 2-regulated antioxidant genes, and promoted proliferation. This was further amplified in PAH-hPASMCs. Nox1(-/-) but not Nox4(-/-) mice were protected against PAH and vascular remodeling. Our findings demonstrate that in PAH-hPASMCs, 16αOHE1 stimulates redox-sensitive cell growth primarily through Nox1. Supporting this, in vivo studies exhibited protection against pulmonary hypertension and remodeling in Nox1(-/-) mice. This study provides new insights through Nox1/ROS and nuclear factor erythroid-related factor 2 whereby 16αOHE1 influences

  2. Nicotinamide Adenine Dinucleotide Phosphate Oxidase–Mediated Redox Signaling and Vascular Remodeling by 16α-Hydroxyestrone in Human Pulmonary Artery Cells

    PubMed Central

    Hood, Katie Y.; Montezano, Augusto C.; Harvey, Adam P.; Nilsen, Margaret; MacLean, Margaret R.

    2016-01-01

    Estrogen and oxidative stress have been implicated in pulmonary arterial hypertension (PAH). Mechanisms linking these systems are elusive. We hypothesized that estrogen metabolite, 16α-hydroxyestrone (16αOHE1), stimulates nicotinamide adenine dinucleotide phosphate oxidase (Nox)–induced reactive oxygen species (ROS) generation and proliferative responses in human pulmonary artery smooth muscle cells (hPASMCs) and that in PAH aberrant growth signaling promotes vascular remodeling. The pathophysiological significance of estrogen–Nox–dependent processes was studied in female Nox1−/− and Nox4−/− mice with PAH. PASMCs from control subjects (control hPASMCs) and PAH patients (PAH-hPASMCs) were exposed to estrogen and 16αOHE1 in the presence/absence of inhibitors of Nox, cytochrome P450 1B1, and estrogen receptors. Estrogen, through estrogen receptor-α, increased Nox-derived ROS and redox-sensitive growth in hPASMCs, with greater effects in PAH-hPASMCs versus control hPASMCs. Estrogen effects were inhibited by cytochrome P450 1B1 blockade. 16αOHE1 stimulated transient ROS production in hPASMCs, with sustained responses in PAH-hPASMCs. Basal expression of Nox1/Nox4 was potentiated in PAH-hPASMCs. In hPASMCs, 16αOHE1 increased Nox1 expression, stimulated irreversible oxidation of protein tyrosine phosphatases, decreased nuclear factor erythroid–related factor 2 activity and expression of nuclear factor erythroid–related factor 2–regulated antioxidant genes, and promoted proliferation. This was further amplified in PAH-hPASMCs. Nox1−/− but not Nox4−/− mice were protected against PAH and vascular remodeling. Our findings demonstrate that in PAH-hPASMCs, 16αOHE1 stimulates redox-sensitive cell growth primarily through Nox1. Supporting this, in vivo studies exhibited protection against pulmonary hypertension and remodeling in Nox1−/− mice. This study provides new insights through Nox1/ROS and nuclear factor erythroid–related factor 2

  3. Smooth muscle calcium and endothelium-derived relaxing factor in the abnormal vascular responses of acute renal failure.

    PubMed Central

    Conger, J D; Robinette, J B; Schrier, R W

    1988-01-01

    Abnormal renovascular reactivity, characterized by paradoxical vasoconstriction to a reduction in renal perfusion pressure (RPP) in the autoregulatory range, increased sensitivity to renal nerve stimulation (RNS), and loss of vasodilatation to acetylcholine have all been demonstrated in ischemic acute renal failure (ARF). To determine if ischemic injury alters vascular contractility by increasing smooth muscle cell calcium or calcium influx, the renal blood flow (RBF) response to reductions in RPP within the autoregulatory range and to RNS were tested before and after a 90-min intrarenal infusion of verapamil or diltiazem in 7-d ischemic ARF rats. Both calcium entry blockers, verapamil and diltiazem, blocked the aberrant vasoconstrictor response to a reduction in RPP and RNS (both P less than 0.001). In a second series of experiments the potential role of an ischemia-induced endothelial injury and of the absence of endothelium-derived relaxing factor (EDRF) production were examined to explain the lack of vasodilatation to acetylcholine. Acetylcholine, bradykinin (a second EDRF-dependent vasodilator), or prostacyclin, an EDRF-independent vasodilator, was infused intrarenally for 90 min, and RBF responses to a reduction in RPP and RNS were tested in 7-d ischemic ARF rats. Neither acetylcholine nor bradykinin caused vasodilatation or altered the slope of the relationship between RBF and RPP. By contrast, prostacyclin increased RBF (P less than 0.001), but did not change the vascular response to changes in RPP. It was concluded that the abnormal pressor sensitivity to a reduction in RPP and RNS was due to changes in renovascular smooth muscle cell calcium activity that could be blocked by calcium entry blockers. A lack of response to EDRF-dependent vasodilators, as a result of ischemic endothelial injury, may contribute to the increased pressor sensitivity of the renal vessels. PMID:3261301

  4. Key Role of ROS in the Process of 15-Lipoxygenase/15-Hydroxyeicosatetraenoiccid-Induced Pulmonary Vascular Remodeling in Hypoxia Pulmonary Hypertension

    PubMed Central

    Qiu, Yanli; Liu, Gaofeng; Sheng, Tingting; Yu, Xiufeng; Wang, Shuang; Zhu, Daling

    2016-01-01

    We previously reported that 15-lipoxygenase (15-LO) and its metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) were up-regulated in pulmonary arterial cells from both pulmonary artery hypertension patients and hypoxic rats and that these factors mediated the progression of pulmonary hypertension (PH) by affecting the proliferation and apoptosis of pulmonary arterial (PA) cells. However, the underlying mechanisms of the remodeling induced by 15-HETE have remained unclear. As reactive oxygen species (ROS) and 15-LO are both induced by hypoxia, it is possible that ROS are involved in the events of hypoxia-induced 15-LO expression that lead to PH. We employed immunohistochemistry, tube formation assays, bromodeoxyuridine (BrdU) incorporation assays, and cell cycle analyses to explore the role of ROS in the process of 15-HETE-mediated hypoxic pulmonary hypertension (HPH). We found that exogenous 15-HETE facilitated the generation of ROS and that this effect was mainly localized to mitochondria. In particular, the mitochondrial electron transport chain and nicotinamide-adenine dinucleotide phosphate oxidase 4 (Nox4) were responsible for the significant 15-HETE-stimulated increase in ROS production. Moreover, ROS induced by 15-HETE stimulated endothelial cell (EC) migration and promoted pulmonary artery smooth muscle cell (PASMC) proliferation under hypoxia via the p38 MAPK pathway. These results indicated that 15-HETE-regulated ROS mediated hypoxia-induced pulmonary vascular remodeling (PVR) via the p38 MAPK pathway. PMID:26871724

  5. Red yeast rice improves lipid pattern, high-sensitivity C-reactive protein, and vascular remodeling parameters in moderately hypercholesterolemic Italian subjects.

    PubMed

    Cicero, Arrigo F G; Derosa, Giuseppe; Parini, Angelo; Maffioli, Pamela; D'Addato, Sergio; Reggi, Alessandra; Giovannini, Marina; Borghi, Claudio

    2013-08-01

    Despite a recent health claim by the European Agency on Food Safety, the effect of high doses of dietary monacolin supplements from red yeast rice on cholesterolemia has not been tested in Italian subjects. Our aim via a crossover, double-blind, placebo-controlled randomized clinical trial was to test if a short-term treatment with 10 mg monacolins could improve lipid pattern, high-sensitivity C-reactive protein (hs-CRP), and vascular remodeling biomarkers in a small cohort of Mediterranean subjects. Thus, 25 healthy, mildly hypercholesterolemic subjects were enrolled, and after 4 weeks of a stabilization diet, subjects were randomized to the sequence placebo-washout-monacolins or monacolins-washout-placebo, with each period being 4 weeks long. At each study step, a complete lipid pattern, safety parameters, hs-CRP, and matrix metalloproteinases 2 and 9 levels were measured. When compared to the placebo group, monacolins-treated patients experienced a more favorable percent change in total cholesterol (-12.45%, 95% CI -16.19 to -8.71), low-density lipoprotein cholesterol (-21.99%, 95% CI -26.63 to -17.36), non-high-density lipoprotein cholesterol (-14.67%, 95% CI -19.22 to -10.11), matrix metalloproteinase 2 (-28.05%, 95% CI -35.18 to -20.93), matrix metalloproteinase 9 (-27.19%, 95% CI -36.21 to -18.15), and hs-CRP (-23.77%, 95% CI -30.54 to -17.01). No significant differences were observed in regards to triglycerides, high-density lipoprotein cholesterol, and safety parameters. On the basis of our data, we demonstrate that a 10-mg monacolin nutraceutical appears to safely reduce cholesterolemia, hs-CRP, and markers of vascular remodeling in Italian subjects. These results have to be confirmed in larger patient samples and longer studies. PMID:23890351

  6. Long-Term Administration of High-Fat Diet Corrects Abnormal Bone Remodeling in the Tibiae of Interleukin-6-Deficient Mice.

    PubMed

    Feng, Wei; Liu, Bo; Liu, Di; Hasegawa, Tomoka; Wang, Wei; Han, Xiuchun; Cui, Jian; Yimin; Oda, Kimimitsu; Amizuka, Norio; Li, Minqi

    2016-01-01

    In this study, we aimed to evaluate the influence of diet-induced obesity on IL-6 deficiency-induced bone remodeling abnormality. Seven-week-old IL-6(-/-) mice and their wild type (WT) littermates were fed a standard diet (SD) or high-fat diet (HFD) for 25 weeks. Lipid formation and bone metabolism in mice tibiae were investigated by histochemical analysis. Both IL-6(-/-) and WT mice fed the HFD showed notable body weight gain, thickened cortical bones, and adipose accumulation in the bone marrow. Notably, the HFD normalized the bone phenotype of IL-6(-/-) mice to that of their WT counterpart, as characterized by a decrease in bone mass and the presence of an obliquely arranged, plate-like morphology in the trabecular bone. Alkaline phosphatase and osteocalcin expressions were attenuated in both genotypes after HFD feeding, especially for the IL-6(-/-) mice. Meanwhile, tartrate-resistant acid phosphatase staining was inhibited, osteoclast apoptosis rate down-regulated (revealed by TUNEL assay), and the proportion of cathepsin K (CK)-positive osteoclasts significantly increased in IL-6(-/-) mice on a HFD as compared with IL-6(-/-) mice on standard chow. Our results demonstrate that HFD-induced obesity reverses IL-6 deficiency-associated bone metabolic disorders by suppressing osteoblast activity, upregulating osteoclastic activity, and inhibiting osteoclast apoptosis. PMID:26416243

  7. Novel application of a multiscale entropy index as a sensitive tool for detecting subtle vascular abnormalities in the aged and diabetic.

    PubMed

    Wu, Hsien-Tsai; Lo, Men-Tzung; Chen, Guan-Hong; Sun, Cheuk-Kwan; Chen, Jian-Jung

    2013-01-01

    Although previous studies have shown the successful use of pressure-induced reactive hyperemia as a tool for the assessment of endothelial function, its sensitivity remains questionable. This study aims to investigate the feasibility and sensitivity of a novel multiscale entropy index (MEI) in detecting subtle vascular abnormalities in healthy and diabetic subjects. Basic anthropometric and hemodynamic parameters, serum lipid profiles, and glycosylated hemoglobin levels were recorded. Arterial pulse wave signals were acquired from the wrist with an air pressure sensing system (APSS), followed by MEI and dilatation index (DI) analyses. MEI succeeded in detecting significant differences among the four groups of subjects: healthy young individuals, healthy middle-aged or elderly individuals, well-controlled diabetic individuals, and poorly controlled diabetic individuals. A reduction in multiscale entropy reflected age- and diabetes-related vascular changes and may serve as a more sensitive indicator of subtle vascular abnormalities compared with DI in the setting of diabetes. PMID:23509600

  8. Novel Application of a Multiscale Entropy Index as a Sensitive Tool for Detecting Subtle Vascular Abnormalities in the Aged and Diabetic

    PubMed Central

    Wu, Hsien-Tsai; Lo, Men-Tzung; Chen, Guan-Hong; Sun, Cheuk-Kwan; Chen, Jian-Jung

    2013-01-01

    Although previous studies have shown the successful use of pressure-induced reactive hyperemia as a tool for the assessment of endothelial function, its sensitivity remains questionable. This study aims to investigate the feasibility and sensitivity of a novel multiscale entropy index (MEI) in detecting subtle vascular abnormalities in healthy and diabetic subjects. Basic anthropometric and hemodynamic parameters, serum lipid profiles, and glycosylated hemoglobin levels were recorded. Arterial pulse wave signals were acquired from the wrist with an air pressure sensing system (APSS), followed by MEI and dilatation index (DI) analyses. MEI succeeded in detecting significant differences among the four groups of subjects: healthy young individuals, healthy middle-aged or elderly individuals, well-controlled diabetic individuals, and poorly controlled diabetic individuals. A reduction in multiscale entropy reflected age- and diabetes-related vascular changes and may serve as a more sensitive indicator of subtle vascular abnormalities compared with DI in the setting of diabetes. PMID:23509600

  9. Anti-vascular endothelial growth factor treatment induces blood flow recovery through vascular remodeling in high-fat diet induced diabetic mice.

    PubMed

    Xiao, Lamei; Yan, Kai; Yang, Yan; Chen, Ni; Li, Yongjie; Deng, Xin; Wang, Liqun; Liu, Yan; Mu, Lin; Li, Rong; Luo, Mao; Ren, Meiping; Wu, Jianbo

    2016-05-01

    Diabetes mellitus (DM) leads to the development of microvascular diseases and is associated with impaired angiogenesis. The presence of vascular endothelial growth factor (VEGF) can block PDGF-BB dependent regulation of neovascularization and vessel normalization. We tested the hypothesis that the inhibition of VEGF improves blood flow in a mouse hindlimb ischemia model produced by femoral artery ligation. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on blood perfusion and angiogenesis after hindlimb ischemia. We showed that bevacizumab induces functional blood flow in high fat chow (HFC)-fed diabetic mice. Treatment with bevacizumab increased the expression of platelet derived growth factor-BB (PDGF-BB) in ischemic muscle, and led to vascular normalization. It also blocked vascular leakage by improving the recruitment of pericytes associated with nascent blood vessels, but it did not affect capillary formation. Furthermore, treatment with an anti-PDGF drug significantly inhibited blood flow perfusion in diabetic mice treated with bevacizumab. These results indicate that bevacizumab improves blood flow recovery through the induction of PDGF-BB in a diabetic mouse hindlimb ischemia model, and that vessel normalization may represent a useful strategy for the prevention and treatment of diabetic peripheral arterial disease. PMID:26808210

  10. Possible involvement of PPARγ-associated eNOS signaling activation in rosuvastatin-mediated prevention of nicotine-induced experimental vascular endothelial abnormalities.

    PubMed

    Kathuria, Sonam; Mahadevan, Nanjaian; Balakumar, Pitchai

    2013-02-01

    Nicotine exposure via cigarette smoking and tobacco chewing is associated with vascular complications. The present study investigated the effect of rosuvastatin in nicotine (2 mg/kg/day, i.p., 4 weeks)-induced vascular endothelial dysfunction (VED) in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating aortic and serum nitrite/nitrate concentration. Further, scanning electron microscopy and hematoxylin-eosin staining of thoracic aorta were performed to assess the vascular endothelial integrity. Moreover, oxidative stress was assessed by estimating aortic superoxide anion generation and serum thiobarbituric acid-reactive substances. The nicotine administration produced VED by markedly reducing acetylcholine-induced endothelium-dependent relaxation, impairing the integrity of vascular endothelium, decreasing aortic and serum nitrite/nitrate concentration, increasing oxidative stress, and inducing lipid alteration. However, treatment with rosuvastatin (10 mg/kg/day, i.p., 4 weeks) markedly attenuated nicotine-induced vascular endothelial abnormalities, oxidative stress, and lipid alteration. Interestingly, the co-administration of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 (1 mg/kg/day, i.p., 2 weeks) submaximally, significantly prevented rosuvastatin-induced improvement in vascular endothelial integrity, endothelium-dependent relaxation, and nitrite/nitrate concentration in rats administered nicotine. However, GW9662 co-administration did not affect rosuvastatin-associated vascular anti-oxidant and lipid-lowering effects. The incubation of aortic ring, isolated from rosuvastatin-treated nicotine-administered rats, with L-NAME (100 μM), an inhibitor of nitric oxide synthase (NOS), significantly attenuated rosuvastatin-induced improvement in acetylcholine-induced endothelium-dependent relaxation. Rosuvastatin prevents nicotine-induced vascular endothelial abnormalities by activating

  11. Hemoglobin-induced lung vascular oxidation, inflammation, and remodeling contribute to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeated-dose haptoglobin administration.

    PubMed

    Irwin, David C; Baek, Jin Hyen; Hassell, Kathryn; Nuss, Rachelle; Eigenberger, Paul; Lisk, Christina; Loomis, Zoe; Maltzahn, Joanne; Stenmark, Kurt R; Nozik-Grayck, Eva; Buehler, Paul W

    2015-05-01

    Haptoglobin (Hp) is an approved treatment in Japan for trauma, burns, and massive transfusion-related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia-mediated PH. Rats were simultaneously exposed to chronic Hb infusion (35 mg per day) and hypobaric hypoxia for 5 weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated nonheme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right-ventricular hypertrophy, which suggests a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia and (2) suggest a novel therapy for chronic hemolysis-associated PH. PMID:25656991

  12. Hemoglobin induced lung vascular oxidation, inflammation, and remodeling contributes to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeat dose haptoglobin administration

    PubMed Central

    Baek, Jin Hyen; Hassell, Kathryn; Nuss, Rachelle; Eigenberger, Paul; Lisk, Christina; Loomis, Zoe; Maltzahn, Joanne; Stenmark, Kurt R; Nozik-Grayck, Eva

    2015-01-01

    Objective Haptoglobin (Hp) is an approved treatment in Japan with indications for trauma, burns and massive transfusion related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia mediated PH. Approach and results Rats were simultaneously exposed to chronic Hb-infusion (35 mg per day) and hypobaric hypoxia for five weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated non-heme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right ventricular hypertrophy, which suggest a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. Conclusions By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia; and (2) suggest a novel therapy for chronic hemolysis associated PH. PMID:25656991

  13. Cases of limb-body wall complex: Early amnion rupture, vascular disruption, or abnormal splitting of the embryo?

    PubMed Central

    Crespo, Frank; Pinar, Halit; Kostadinov, Stefan

    2012-01-01

    We report two cases of limb-body wall complex (LBWC), also known as body stalk anomaly, a rare form of body wall defect incompatible with life. The first case was identified during a level II ultrasound examination performed at 7 wk gestational age. The delivery was by breech extraction at 39 wk and 4 days. The second case was delivered by spontaneous vaginal delivery at 35 wk and 5 days. Karyotype analysis was normal in both fetuses. The phenotype of LBWC is variable, but commonly identified features include: exencephaly, limb defects, and either facial clefts or thoraco-abdominoschisis. The exact etiology remains uncertain, as the disorder has been regarded as sporadic with low recurrence. Vascular disruption during early embryogenesis, early amnion rupture, abnormal splitting of the embryo, and failure of amnion fusion have been implicated in the pathogenesis of LBWC. A role for possible gene mutation and maternal use of alcohol, tobacco, or illicit drugs has also been suggested. Detailed ultrasonography along with biochemical screening may allow for early detection.

  14. Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure.

    PubMed

    Rickard, Amanda J; Morgan, James; Chrissobolis, Sophocles; Miller, Alyson A; Sobey, Christopher G; Young, Morag J

    2014-05-01

    Recent studies have identified novel pathological roles for mineralocorticoid receptors (MR) in specific cell types in cardiovascular disease. The mechanisms by which MR promotes inflammation and fibrosis involve multiple cell-specific events. To identify the role of MR in endothelial cells (EC-MR), the current study explored the vascular responses to aldosterone in wild-type (WT) and EC-null mice (EC-MRKO). Nitric oxide function was impaired in the thoracic aorta and mesenteric arteries of aldosterone-treated WT mice. Although endothelial nitric oxide function was equivalently impaired in the mesenteric arteries of aldosterone-treated EC-MRKO mice, endothelial function was unaffected in the aorta, suggesting a differential role for EC-MR depending on the vascular bed. Second, the contribution of EC-MR to cardiovascular inflammation, fibrosis, and hypertension was determined in WT and EC-MRKO treated with deoxycorticosterone/salt for 8 days or 8 weeks. At 8 days, loss of EC-MR prevented macrophage infiltration and the expression of proinflammatory genes in the myocardium. Increased cardiac fibrosis was not detected in either genotype at this time, mRNA levels of profibrotic genes were significantly lower in EC-MRKO mice versus WT. At 8 weeks, deoxycorticosterone/salt treatment increased macrophage recruitment and proinflammatory gene expression in WT but not in EC-MRKO. Collagen deposition and connective tissue growth factor expression were significantly reduced in EC-MRKO versus WT. Interestingly, systolic blood pressure was equivalently elevated in deoxycorticosterone/salt treated WT and EC-MRKO. Our data demonstrate that (1) EC-MR signaling contributes to vascular nitric oxide function in large conduit arteries but not in resistance vessels and (2) an independent role for EC-MR in the inflammatory and profibrotic response to deoxycorticosterone/salt. PMID:24566081

  15. Involvement of calcium-sensing receptors in hypoxia-induced vascular remodeling and pulmonary hypertension by promoting phenotypic modulation of small pulmonary arteries.

    PubMed

    Peng, Xue; Li, Hong-Xia; Shao, Hong-Jiang; Li, Guang-Wei; Sun, Jian; Xi, Yu-Hui; Li, Hong-Zhu; Wang, Xin-Yan; Wang, Li-Na; Bai, Shu-Zhi; Zhang, Wei-Hua; Zhang, Li; Yang, Guang-Dong; Wu, Ling-Yun; Wang, Rui; Xu, Chang-Qing

    2014-11-01

    Phenotype modulation of pulmonary artery smooth muscle cells (PASMCs) plays an important role during hypoxia-induced vascular remodeling and pulmonary hypertension (PAH). We had previously shown that calcium-sensing receptor (CaSR) is expressed in rat PASMCs. However, little is known about the role of CaSR in phenotypic modulation of PASMCs in hypoxia-induced PAH as well as the underlying mechanisms. In this study, we investigated whether CaSR induces the proliferation of PASMCs in small pulmonary arteries from both rats and human with PAH. PAH was induced by exposing rats to hypoxia for 7-21 days. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVI), the percentage of medial wall thickness to the external diameter (WT %), and cross-sectional total vessel wall area to the total area (WA %) of small pulmonary arteries were determined by hematoxylin and eosin (HE), masson trichrome and Weigert's staining. The protein expressions of matrix metalloproteinase (MMP)-2 and MMP-9, the tissue inhibitors of metalloproteinase (TIMP)-3, CaSR, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated kinase (p-ERK), and smooth muscle cell (SMC) phenotype marker proteins in rat small pulmonary arteries, including calponin, SMα-actin (SMAα), and osteopontin (OPN), were analyzed by immunohistochemistry and Western blotting, respectively. In addition, immunohistochemistry was applied to paraffin-embedded human tissues from lungs of normal human and PAH patients with chronic heart failure (PAH/CHF). Compared with the control group, mPAP, RVI, WT % and WA % in PAH rats were gradually increased with the prolonged hypoxia. At the same time, the expressions of CaSR, MMP-2, MMP-9, TIMP-3, PCNA, OPN, and p-ERK were markedly increased, while the expressions of SMAα and calponin were significantly reduced in lung tissues or small pulmonary arteries of PAH rats. Neomycin (an agonist of CaSR) enhanced but NPS2390 (an

  16. Effects of early feed restriction and cold temperature on lipid peroxidation, pulmonary vascular remodelling and ascites morbidity in broilers under normal and cold temperature.

    PubMed

    Pan, J Q; Tan, X; Li, J C; Sun, W D; Wang, X L

    2005-06-01

    Two experiments were conducted to evaluate the effects of early feed restriction on lipid peroxidation, pulmonary vascular remodelling and ascites incidence in broilers under normal and low ambient temperature. In experiment 1, the restricted birds were fed 8h per day either from 7 to 14 d or from 7 to 21 d, while the controlled birds were fed ad libitum. In experiment 2, the restricted birds were fed 80 or 60% of the previous 24-h feed consumption of full-fed controls for 7 d from 7 to 14 d. On d 14, half of the birds in each treatment both in experiment 1 and experiment 2 were exposed to low ambient temperature to induce ascites. Body weight and feed conversion ratio were measured weekly. The incidences of ascites and other disease were recorded to determine ascites morbidity and total mortality. Blood samples were taken on d 14, 21, 28, 35 and 42 to measure the plasma malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). On d 42, samples were taken to determine the right/total ventricular weight ratio (RV/TV), vessel wall area/vessel total area ratio (WA/TA) and mean media thickness in pulmonary arterioles (mMTPA). Low-temperature treatment increased plasma MDA concentration. When broilers were exposed to a cool environment for 3 weeks, plasma SOD and GSH-Px activity were decreased compared with normal-temperature chicks. RV/TV, WA/TA and mMTPA on d 42 were increased in birds exposed to cold, consistent with the increased pulmonary hypertension and ascites morbidity. Early feed restriction markedly decreased plasma MDA concentration. The plasma SOD and GSH-Px activity of feed-restricted birds were markedly higher than those fed ad libitum on d 35 and d 42. All early feed restriction treatments reduced ascites morbidity and total mortality. On d 42, the RV/TV, WA/TA and mMTPA of feed-restricted broilers were lower than that of the ad libitum-fed broilers. The results suggested that early feed restriction alleviated the lipid

  17. Progressive vascular remodelling, endothelial dysfunction and stiffness in mesenteric resistance arteries in a rodent model of chronic kidney disease.

    PubMed

    Quek, K J; Boyd, R; Ameer, O Z; Zangerl, B; Butlin, M; Murphy, T V; Avolio, A P; Phillips, J K

    2016-06-01

    Chronic kidney disease (CKD) and hypertension are co-morbid conditions both associated with altered resistance artery structure, biomechanics and function. We examined these characteristics in mesenteric artery together with renal function and systolic blood pressure (SBP) changes in the Lewis polycystic kidney (LPK) rat model of CKD. Animals were studied at early (6-weeks), intermediate (12-weeks), and late (18-weeks) time-points (n=21), relative to age-matched Lewis controls (n=29). At 12 and 18-weeks, LPK arteries exhibited eutrophic and hypertrophic inward remodelling characterised by thickened medial smooth muscle, decreased lumen diameter, and unchanged or increased media cross-sectional area, respectively. At these later time points, endothelium-dependent vasorelaxation was also compromised, associated with impaired endothelium-dependent hyperpolarisation and reduced nitric oxide synthase activity. Stiffness, elastic-modulus/stress slopes and collagen/elastin ratios were increased in 6 and 18-week-old-LPK, in contrast to greater arterial compliance at 12weeks. Multiple linear regression analysis highlighted SBP as the main predictor of wall-lumen ratio (r=0.536, P<0.001 n=46 pairs). Concentration-response curves revealed increased sensitivity to phenylephrine but not potassium chloride in 18-week-LPK. Our results indicate that impairment in LPK resistance vasculature is evident at 6weeks, and worsens with hypertension and progression of renal disease. PMID:26771067

  18. Severe vitamin D deficiency in patients with Kawasaki disease: a potential role in the risk to develop heart vascular abnormalities?

    PubMed

    Stagi, Stefano; Rigante, Donato; Lepri, Gemma; Matucci Cerinic, Marco; Falcini, Fernanda

    2016-07-01

    Twenty-five-hydroxyvitamin D (25(OH)-vitamin D) is crucial in the regulation of immunologic processes, but-although its deficiency has been reported in patients with different rheumatological disorders-no data are available for Kawasaki disease (KD). The goals of this study were to assess the serum levels of 25(OH)-vitamin D in children with KD and evaluate the relationship with the eventual occurrence of KD-related vascular abnormalities. We evaluated serum 25(OH)-vitamin D levels in 79 children with KD (21 females, 58 males, median age 4.9 years, range 1.4-7.5 years) in comparison with healthy sex-/age-matched controls. A significantly higher percentage of KD patients (98.7 %) were shown to have reduced 25(OH)-vitamin D levels (<30 ng/mL) in comparison with controls (78.6 %, p < 0.0001). Furthermore, KD patients had severely low levels of 25(OH)-vitamin D than controls (9.17 ± 4.94 vs 23.3 ± 10.6 ng/mL, p < 0.0001), especially the subgroup who developed coronary artery abnormalities (4.92 ± 1.36 vs 9.41 ± 4.95 ng/mL, p < 0.0001). In addition, serum 25(OH)-vitamin D levels correlated not only with erythrosedimentation rate (p < 0.0001), C-reactive protein (p < 0.0001), hemoglobin level at KD diagnosis (p < 0.0001) but also with both coronary artery aneurysms (p = 0.005) and non-aneurysmatic cardiovascular lesions (p < 0.05). Low serum concentrations of 25(OH)-vitamin D might have a contributive role in the development of coronary artery complications observed in children with KD. PMID:25994612

  19. Assessment of Vascular Geometry for Bilateral Carotid Artery Ligation to Induce Early Basilar Terminus Aneurysmal Remodeling in Rats.

    PubMed

    Tutino, Vincent Matthew; Liaw, Nicholas; Spernyak, Joseph Andrew; Ionita, Ciprian Nicolae; Siddiqui, Adnan Hussain; Kolega, John; Meng, Hui

    2016-01-01

    Bilateral common carotid artery (CCA) ligation in rabbits is a model for basilar terminus (BT) aneurysm formation. We asked if this model could be replicated in rats. Fourteen female Sprague Dawley rats underwent bilateral CCA ligation (n=8) or sham surgery (n=6). After 7 days, 5 ligated and 3 sham rats were euthanized for histological evaluation of BT aneurysm formation, while the remaining rats were imaged with magnetic resonance angiography, euthanized, and subjected to corrosion casting of the Circle of Willis (CoW). 3D micro computed tomography images of CoW casts were used for flow simulations at the rat BT, and electron micrographs of the casts were analyzed for aneurysmal and morphological changes. Results from these analyses were compared to rabbit model data (n=10 ligated and n=6 sham). Bilateral CCA ligation did not produce aneurysmal damage at the rat BT. While the surgical manipulation increased rat basilar artery flow, fluid dynamics simulations showed that the initial hemodynamic stress at the rat BT was significantly less than in rabbits. Rats also exhibited fewer morphological and pathological changes (minor changes only occurred in the posterior CoW) than rabbits, which had drastic changes throughout the CoW. A comparison of CoW anatomies demonstrated a greater number of branching arteries at the BT, larger CoW arteries in relation to basilar artery, and a steeper BT bifurcation angle in the rat. These differences could account for the lower hemodynamic stress at the BT and in the cerebrovasculature of the rat. In conclusion, bilateral CCA ligation in rats does not recapitulate the rabbit model of early flow-induced BT aneurysm. We suspect that the different CoW morphology of the rat lessens hemodynamic insults, thereby diminishing flow-induced aneurysmal remodeling. PMID:26503026

  20. MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells

    PubMed Central

    Zeng, Yan; Zhang, Xiaoying; Kang, Kang; Chen, Jidong; Wu, Zhiqin; Huang, Jinyong; Lu, Wenju; Chen, Yuqin; Zhang, Jie; Wang, Zhiwei; Zhai, Yujia; Qu, Junle; Ramchandran, Ramaswamy; Raj, J. Usha; Wang, Jian; Gou, Deming

    2016-01-01

    There is growing evidence that microRNAs are implicated in pulmonary arterial hypertension (PAH), but underlying mechanisms remain elusive. Here, we identified that miR-223 was significantly downregulated in chronically hypoxic mouse and rat lungs, as well as in pulmonary artery and pulmonary artery smooth muscle cells (PASMC) exposed to hypoxia. Knockdown of miR-223 increased PASMC proliferation. In contrast, miR-223 overexpression abrogated cell proliferation, migration and stress fiber formation. Administering miR-223 agomir in vivo antagonized hypoxia-induced increase in pulmonary artery pressure and distal arteriole muscularization. RhoB, which was increased by hypoxia, was identified as one of the targets of miR-223. Overexpressed miR-223 suppressed RhoB and inhibited the consequent phosphorylation of myosin phosphatase target subunit (MYPT1) and the expression of myosin light chain of myosin II (MLC2), which was identified as another target of miR-223. Furthermore, serum miR-223 levels were decreased in female patients with PAH associated with congenital heart disease. Our study provides the first evidence that miR-223 can regulate PASMC proliferation, migration, and actomyosin reorganization through its novel targets, RhoB and MLC2, resulting in vascular remodeling and the development of PAH. It also highlights miR-223 as a potential circulating biomarker and a small molecule drug for diagnosis and treatment of PAH. PMID:27121304

  1. Upregulation of MicroRNA-214 Contributes to the Development of Vascular Remodeling in Hypoxia-induced Pulmonary Hypertension Via Targeting CCNL2.

    PubMed

    Liu, HaiTao; Tao, Yin; Chen, Mai; Yu, Jin; Li, Wei-Jie; Tao, Ling; Li, Yan; Li, Fei

    2016-01-01

    Hypoxia-induced pulmonary hypertension (PH), which is characterized by vascular remodeling of blood vessels, is a significant complication of chronic obstructive pulmonary disease (COPD). In this study, we screened 13 candidate miRNAs in pulmonary artery smooth muscle cells (PASMCs) harvested from COPD patients with PH (n = 18) and normal controls (n = 15) and found that the expression of miR-214 was differentially expressed between these two groups. Additionally, cyclin L2 (CCNL2) was validated as a target of miR-214 in PASMCs using a luciferase assay. Based on real-time PCR, immunohistochemistry and western blot, the expression of CCNL2 was substantially downregulated in PASMCs from COPD patients with PH compared with those from normal controls. Moreover, the relationship between miRNA and mRNA expression was confirmed using real-time PCR and western blot in PASMCs transfected with miR-214 mimics. Furthermore, the introduction of miR-214 significantly promoted the proliferation of PASMCs by suppressing cell apoptosis, and this effect was mediated by the downregulation of CCNL2. Exposure of PASMCs to hypoxia significantly increased the expression of miR-214, decreased the expression of CCNL2, and promoted cell proliferation. However, these effects were significantly attenuated by the introduction of miR-214 inhibitors, which significantly downregulated miR-214 expression and upregulated CCNL2 expression. PMID:27381447

  2. Upregulation of MicroRNA-214 Contributes to the Development of Vascular Remodeling in Hypoxia-induced Pulmonary Hypertension Via Targeting CCNL2

    PubMed Central

    Liu, HaiTao; Tao, Yin; Chen, Mai; Yu, Jin; Li, Wei-Jie; Tao, Ling; Li, Yan; Li, Fei

    2016-01-01

    Hypoxia-induced pulmonary hypertension (PH), which is characterized by vascular remodeling of blood vessels, is a significant complication of chronic obstructive pulmonary disease (COPD). In this study, we screened 13 candidate miRNAs in pulmonary artery smooth muscle cells (PASMCs) harvested from COPD patients with PH (n = 18) and normal controls (n = 15) and found that the expression of miR-214 was differentially expressed between these two groups. Additionally, cyclin L2 (CCNL2) was validated as a target of miR-214 in PASMCs using a luciferase assay. Based on real-time PCR, immunohistochemistry and western blot, the expression of CCNL2 was substantially downregulated in PASMCs from COPD patients with PH compared with those from normal controls. Moreover, the relationship between miRNA and mRNA expression was confirmed using real-time PCR and western blot in PASMCs transfected with miR-214 mimics. Furthermore, the introduction of miR-214 significantly promoted the proliferation of PASMCs by suppressing cell apoptosis, and this effect was mediated by the downregulation of CCNL2. Exposure of PASMCs to hypoxia significantly increased the expression of miR-214, decreased the expression of CCNL2, and promoted cell proliferation. However, these effects were significantly attenuated by the introduction of miR-214 inhibitors, which significantly downregulated miR-214 expression and upregulated CCNL2 expression. PMID:27381447

  3. Impairment of the accumulation of decidual T cells, NK cells, and monocytes, and the poor vascular remodeling of spiral arteries, were observed in oocyte donation cases, regardless of the presence or absence of preeclampsia.

    PubMed

    Nakabayashi, Yasushi; Nakashima, Akitoshi; Yoshino, Osamu; Shima, Tomoko; Shiozaki, Arihiro; Adachi, Tomoko; Nakabayashi, Masao; Okai, Takashi; Kushima, Miki; Saito, Shigeru

    2016-04-01

    In oocyte donation (OD) pregnancies, a fetus is a complete allograft to the maternal host and OD pregnancies are an independent risk factor for preeclampsia. Immunocompetent cells contribute to spiral artery remodeling and the failure of this process could contribute to the pathophysiology of preeclampsia. Recent data have shown that impaired autophagy of extravillous trophoblasts (EVT) may induce poor vascular remodeling in preeclampsia. We have studied the distribution of T cells, NK cells and macrophages in the decidua basalis of 14 normotensive OD pregnancies, 5 preeclamptic OD cases, 16 normotensive pregnancy cases, and 13 preeclamptic cases in natural pregnancy or autologous oocyte IVF-ET (NP/IVF). The populations of decidual CD3(+)T cells, CD8(+)T cells, CD4(+)T cells, Foxp3(+)Treg cells, CD56(+)NK cells, and CD68(+) macrophages in preeclampsia were significantly smaller than those in normal pregnancy in NP/IVF. Those frequencies in normotensive OD pregnancies or preeclamptic cases in OD pregnancies were similar to those in preeclamptic cases in NP/IVF. Impaired vascular remodeling was observed in OD pregnancies, regardless of the presence or absence of preeclampsia. The expression of p62, an impaired autophagy marker in EVT of normotensive or preeclamptic OD pregnancies, was significantly higher than that in normal pregnancies in NP/IVF. Immunological change in the decidua basalis and impairment of autophagy in EVT may induce impairment of spiral artery remodeling in OD pregnancies. PMID:26282090

  4. Feasibility of US-CT image fusion to identify the sources of abnormal vascularization in posterior sacroiliac joints of ankylosing spondylitis patients

    PubMed Central

    Hu, Zhenlong; Zhu, Jiaan; Liu, Fang; Wang, Niansong; Xue, Qin

    2015-01-01

    Ultrasound (US) can be used to evaluate the inflammatory activity of the sacroiliac joints (SIJs) in ankylosing spondylitis (AS) patients, but to precisely locate the abnormal vascularization observed on color Doppler US (CDUS) was difficult. To address this issue, we performed US and computed tomography (CT) fusion imaging of SIJs with 84 inpatients and 30 controls, and then assessed the sources of abnormal vascularization in the posterior SIJs of AS patients based on the fused images. Several possible factors impacting the fusion process were considered including the lesion classes of SIJ, the skinfold thickness of the sacral region and the cross-sectional levels of the first, second and third posterior sacral foramina. Our data showed high image fusion success rates at the 3 levels in the AS group (97.0%, 87.5% and 79.8%, respectively) and the control group (96.7%, 86.7%, and 86.7%, respectively).The skinfold thickness was identified as the main factor affecting the success rates. The successfully fused images revealed significant differences in the distribution of abnormal vascularization between 3 levels, as detected via CDUS (P = 0.011), which suggested that inflammation occurred in distinct tissues at different levels of the SIJ (intraligamentous inflammation in Regions 1 and 2; intracapsular inflammation in Region 3). PMID:26669847

  5. Progressive vascular remodeling and reduced neointimal formation after placement of a thermoelastic self-expanding nitinol stent in an experimental model.

    PubMed

    Carter, A J; Scott, D; Laird, J R; Bailey, L; Kovach, J A; Hoopes, T G; Pierce, K; Heath, K; Hess, K; Farb, A; Virmani, R

    1998-06-01

    Despite the improvements afforded by intracoronary stenting, restenosis remains a significant problem. The optimal physical properties of a stent have not been defined. We compared the vascular response to a thermoelastic self-expanding nitinol stent with a balloon-expandable tubular slotted stainless steel stent in normal porcine coronary arteries. Twenty-two stents (11 nitinol and 11 tubular slotted) were implanted in 11 miniature swine. The nitinol stents were deployed using the intrinsic thermal properties of the metal, without adjunctive balloon dilation. The tubular slotted stents were implanted using a noncompliant balloon with a mean inflation pressure of 12 atm. Intravascular ultrasound (IVUS) and histology were used to evaluate the vascular response to the stents. The mean cross-sectional area (CSA) of the nitinol stents (mm2) as measured by IVUS increased from 8.13 +/- 1.09 at implant to 9.10 +/- 0.99 after 28 days (P = 0.038), while the mean CSA of the tubular slotted stents was unchanged (7.84 +/- 1.39 mm2 vs. 7.10 +/- 1.07 mm2, P = 0.25). On histology at 3 days, the tubular slotted stents had more inflammatory cells adjacent to the stent wires (5.7 +/- 1.5 cells/0.1 mm2) than the nitinol (3.9 +/- 1.3 cells/0.1 mm2, P = 0.016). The tubular slotted also had increased thrombus thickness (83 +/- 85 microm) than the nitinol stents (43 +/- 25 microm, P = 0.0014). After 28 days, the vessel injury score was similar for the nitinol (0.6 +/- 0.3) and the tubular slotted (0.5 +/- 0.1, P = 0.73) designs. The mean neointimal area (0.97 +/- 0.46 mm2 vs. 1.96 +/- 0.34 mm2, P = 0.002) and percent area stenosis (15 +/- 7 vs. 33 +/- 7, P = 0.003) were significantly lower in the nitinol than in the tubular slotted stents, respectively. We conclude that a thermoelastic nitinol stent exerts a more favorable effect on vascular remodeling, with less neointimal formation, than a balloon-expandable design. Progressive intrinsic stent expansion after implant does not appear to

  6. Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer

    PubMed Central

    Ader, Isabelle; Golzio, Muriel; Andrieu, Guillaume; Zalvidea, Santiago; Richard, Sylvain; Sabbadini, Roger A.; Malavaud, Bernard; Cuvillier, Olivier

    2015-01-01

    Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1α (HIF-1α), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α under hypoxia. Taking advantage of a monoclonal antibody neutralizing extracellular S1P (sphingomab), we report that inhibition of S1P extracellular signaling blocks HIF-1α accumulation and activity in several cancer cell models exposed to hypoxia. In an orthotopic xenograft model of prostate cancer, we show that sphingomab reduces hypoxia and modifies vessel architecture within 5 days of treatment, leading to increased intratumoral blood perfusion. Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling. These findings validate sphingomab as a potential new normalization agent that could contribute to successful sensitization of hypoxic tumors to chemotherapy. PMID:25915662

  7. Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer.

    PubMed

    Ader, Isabelle; Gstalder, Cécile; Bouquerel, Pierre; Golzio, Muriel; Andrieu, Guillaume; Zalvidea, Santiago; Richard, Sylvain; Sabbadini, Roger A; Malavaud, Bernard; Cuvillier, Olivier

    2015-05-30

    Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1α (HIF-1α), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α under hypoxia. Taking advantage of a monoclonal antibody neutralizing extracellular S1P (sphingomab), we report that inhibition of S1P extracellular signaling blocks HIF-1α accumulation and activity in several cancer cell models exposed to hypoxia. In an orthotopic xenograft model of prostate cancer, we show that sphingomab reduces hypoxia and modifies vessel architecture within 5 days of treatment, leading to increased intratumoral blood perfusion. Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling. These findings validate sphingomab as a potential new normalization agent that could contribute to successful sensitization of hypoxic tumors to chemotherapy. PMID:25915662

  8. Reciprocal Effects of Oxidative Stress on Heme Oxygenase Expression and Activity Contributes to Reno-Vascular Abnormalities in EC-SOD Knockout Mice

    PubMed Central

    Kawakami, Tomoko; Puri, Nitin; Sodhi, Komal; Bellner, Lars; Takahashi, Toru; Morita, Kiyoshi; Rezzani, Rita; Oury, Tim D.; Abraham, Nader G.

    2012-01-01

    Heme oxygenase (HO) system is one of the key regulators of cellular redox homeostasis which responds to oxidative stress (ROS) via HO-1 induction. However, recent reports have suggested an inhibitory effect of ROS on HO activity. In light of these conflicting reports, this study was designed to evaluate effects of chronic oxidative stress on HO system and its role in contributing towards patho-physiological abnormalities observed in extracellular superoxide dismutase (EC-SOD, SOD3) KO animals. Experiments were performed in WT and EC-SOD(−/−) mice treated with and without HO inducer, cobalt protoporphyrin (CoPP). EC-SOD(−/−) mice exhibited oxidative stress, renal histopathological abnormalities, elevated blood pressure, impaired endothelial function, reduced p-eNOS, p-AKT and increased HO-1 expression; although, HO activity was significantly (P < 0.05) attenuated along with attenuation of serum adiponectin and vascular epoxide levels (P < 0.05). CoPP, in EC-SOD(−/−) mice, enhanced HO activity (P < 0.05) and reversed aforementioned pathophysiological abnormalities along with restoration of vascular EET, p-eNOS, p-AKT and serum adiponectin levels in these animals. Taken together our results implicate a causative role of insufficient activation of heme-HO-adiponectin system in pathophysiological abnormalities observed in animal models of chronic oxidative stress such as EC-SOD(−/−) mice. PMID:22292113

  9. Clinical Implications and Pathogenesis of Esophageal Remodeling in Eosinophilic Esophagitis

    PubMed Central

    Hirano, Ikuo; Aceves, Seema S.

    2014-01-01

    In eosinophilic esophagitis (EoE), remodeling changes are manifest histologically in both the epithelium as well as in the subepithelium where lamina propria (LP) fibrosis, expansion of the muscularis propria and increased vascularity occur. The major clinical symptoms and complications of EoE are largely consequences of esophageal remodeling. Important mediators of the process include IL-5, IL-13, TGFβ1, mast cells, fibroblasts and eosinophils. Methods to detect remodeling effects include upper endoscopy, histopathology, barium esophagram, endoscopic ultrasonography, esophageal manometry, and functional luminal imaging. These modalities provide evidence of organ dysfunction that include focal and diffuse esophageal strictures, expansion of the mucosa and subepithelium, esophageal motor abnormalities and reduced esophageal distensibility. Complications of food impaction and perforations of the esophageal wall have been associated with reduction in esophageal caliber and increased esophageal mural stiffness. The therapeutic benefits of topical corticosteroids and elimination diet therapy in resolving mucosal eosinophilic inflammation of the esophagus are evident. Available therapies, however, have demonstrated variable ability to reverse existing remodeling changes of the esophagus. Systemic therapies that include novel, targeted biologic agents have the potential of addressing subepithelial remodeling. Esophageal dilation remains a useful, adjunctive therapeutic maneuver in symptomatic adults with esophageal stricture. As novel treatments emerge, it is essential that therapeutic endpoints account for the fundamental contributions of esophageal remodeling to overall disease activity. PMID:24813517

  10. Albuminuria is Independently Associated with Cardiac Remodeling, Abnormal Right and Left Ventricular Function, and Worse Outcomes in Heart Failure with Preserved Ejection Fraction

    PubMed Central

    Katz, Daniel H.; Burns, Jacob A.; Aguilar, Frank G.; Beussink, Lauren; Shah, Sanjiv J.

    2014-01-01

    Objectives To determine the relationship between albuminuria and cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). Background Albuminuria, a marker of endothelial dysfunction, has been associated with adverse cardiovascular outcomes in HFpEF. However, the relationship between albuminuria and cardiac structure/function in HFpEF has not been well studied. Methods We measured urinary albumin-to-creatinine ratio (UACR) and performed comprehensive echocardiography, including tissue Doppler imaging and right ventricular (RV) evaluation, in a prospective study of 144 patients with HFpEF. Multivariable-adjusted linear regression was used to determine the association between UACR and echocardiographic parameters. Cox proportional hazards analyses were used to determine the association between UACR and outcomes. Results The mean age was 66±11 years, 62% were female, and 42% were African-American. Higher UACR was associated with greater left ventricular (LV) mass, lower preload-recruitable stroke work, and lower global longitudinal strain. Higher UACR was also significantly associated with RV remodeling (for each doubling of UACR, RV wall thickness was 0.9 mm higher [95% confidence interval (CI) 0.05–0.14 mm; P=0.001, adjusted P=0.01]) and worse RV systolic function (for each doubling of UACR, RV fractional area change was 0.56% lower [95% CI 0.14–0.98%; P=0.01, adjusted P=0.03]. The association between UACR and RV parameters persisted after excluding patients with macroalbuminuria (UACR > 300 mg/g). Increased UACR was also independently associated with worse outcomes. Conclusions In HFpEF, increased UACR is a prognostic marker and is associated with increased RV and LV remodeling, and longitudinal systolic dysfunction. PMID:25282032

  11. Prematurely Elevating Estradiol in Early Baboon Pregnancy Suppresses Uterine Artery Remodeling and Expression of Extravillous Placental Vascular Endothelial Growth Factor and α1β1 and α5β1 Integrins

    PubMed Central

    Bonagura, Thomas W.; Babischkin, Jeffery S.; Aberdeen, Graham W.; Pepe, Gerald J.

    2012-01-01

    We previously showed that advancing the increase in estradiol levels from the second to the first third of baboon pregnancy suppressed placental extravillous trophoblast (EVT) invasion and remodeling of the uterine spiral arteries. Cell culture studies show that vascular endothelial cell growth factor (VEGF) plays a central role in regulating EVT migration and remodeling of the uterine spiral arteries by increasing the expression/action of certain integrins that control extracellular matrix remodeling. To test the hypothesis that the estradiol-induced reduction in vessel remodeling in baboons is associated with an alteration in VEGF and integrin expression, extravillous placental VEGF and integrin expression was determined on d 60 of gestation (term is 184 d) in baboons in which uterine artery transformation was suppressed by maternal estradiol administration on d 25–59. EVT uterine spiral artery invasion was 5-fold lower (P < 0.01), and VEGF protein expression, quantified by in situ proximity ligation assay, was 50% lower (P < 0.05) in the placenta anchoring villi of estradiol-treated than in untreated baboons. α1β1 and α5β1 mRNA levels in cells isolated by laser capture microdissection from the anchoring villi and cytotrophoblastic shell of estradiol-treated baboons were over 2-fold (P < 0.01) and 40% (P < 0.05) lower, respectively, than in untreated animals. In contrast, placental extravillous αvβ3 mRNA expression was unaltered by estradiol treatment. In summary, extravillous placental expression of VEGF and α1β1 and α5β1 integrins was decreased in a cell- and integrin-specific manner in baboons in which EVT invasion and remodeling of the uterine spiral arteries were suppressed by prematurely elevating estradiol levels in early pregnancy. We propose that estrogen normally controls the extent to which the uterine arteries are transformed by placental EVT in primate pregnancy by regulating expression of VEGF and particular integrin extracellular

  12. Peanut witches' broom (PnWB) phytoplasma-mediated leafy flower symptoms and abnormal vascular bundles development

    PubMed Central

    Liu, Chi-Te; Huang, Hsin-Mei; Hong, Syuan-Fei; Kuo-Huang, Ling-Long; Yang, Chiao-Yin; Lin, Yen-Yu; Lin, Chan-Pin; Lin, Shih-Shun

    2015-01-01

    The peanut witches' broom (PnWB) phytoplasma causes virescence symptoms such as phyllody (leafy flower) in infected peanuts. However, the obligate nature of phytoplasma limits the study of host-pathogen interactions, and the detailed anatomy of PnWB-infected plants has yet to be reported. Here, we demonstrate that 4′,6′-diamidino-2-phenylindole (DAPI) staining can be used to track PnWB infection. The DAPI-stained phytoplasma cells were observed in phloem/internal phloem tissues, and changes in vascular bundle morphology, including increasing pith rays and thinner cell walls in the xylem, were found. We also discerned the cell types comprising PnWB in infected sieve tube members. These results suggest that the presence of PnWB in phloem tissue facilitates the transmission of phytoplasma via sap-feeding insect vectors. In addition, PnWB in sieve tube members and changes in vascular bundle morphology might strongly promote the ability of phytoplasmas to assimilate nutrients. These data will help further an understanding of the obligate life cycle and host-pathogen interactions of phytoplasma. PMID:26492318

  13. Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension

    PubMed Central

    Farha, Samar; Lichtin, Alan; Graham, Brian; George, Deepa; Aldred, Micheala; Hazen, Stanley L.; Loyd, James; Tuder, Rubin

    2012-01-01

    Hematopoietic myeloid progenitors released into the circulation are able to promote vascular remodeling through endothelium activation and injury. Endothelial injury is central to the development of pulmonary arterial hypertension (PAH), a proliferative vasculopathy of the pulmonary circulation, but the origin of vascular injury is unknown. In the present study, mice transplanted with BM-derived CD133+ progenitor cells from patients with PAH, but not from healthy controls, exhibited morbidity and/or death due to features of PAH: in situ thrombi and endothelial injury, angioproliferative remodeling, and right ventricular hypertrophy and failure. Myeloid progenitors from patients with heritable and/or idiopathic PAH all produced disease in xenografted mice. Analyses of hematopoietic transcription factors and colony formation revealed underlying abnormalities of progenitors that skewed differentiation toward the myeloid-erythroid lineage. The results of the present study suggest a causal role for hematopoietic stem cell abnormalities in vascular injury, right ventricular hypertrophy, and morbidity associated with PAH. PMID:22745307

  14. Long-lasting intestinal bleeding in an old patient with multiple mucosal vascular abnormalities and Glanzmann's thrombasthenia: 3-year pharmacological management.

    PubMed

    Coppola, A; De Stefano, V; Tufano, A; Nardone, G; Amoriello, A; Cerbone, A M; Di Minno, G

    2002-09-01

    A 75-year-old woman with Glanzmann's thrombasthenia was admitted because of persistent melaena. Endoscopic examination showed multiple angiodysplastic lesions, with active bleeding in small and large bowel. Electro-coagulation of some lesions, octreotide, conjugated oestrogens and selective embolization of jejunal vessels did not change transfusion requirements. After 8 month-transfusions, ethinylestradiol + norethisterone in association with octreotide was started, leading to no transfusion over the following 9 months. Bleeding recurred after withdrawing octreotide and substituting ethinylestradiol + norgestrel for the ethinylestradiol + norethisterone combination. Re-introduction of octreotide did not improve bleeding; however, a reduction of transfusion requirement was observed when the ethinylestradiol + norethisterone pill was re-administered. The association of octreotide and of an oestrogen-progesterone combination was helpful in the difficult management of recurrent bleeding in this patient with diffuse gastrointestinal vascular abnormalities and a severe condition predisposing to bleeding. PMID:12270009

  15. Rosiglitazone, a peroxisome proliferator-activated receptor γ stimulant, abrogates diabetes-evoked hypertension by rectifying abnormalities in vascular reactivity.

    PubMed

    El-Bassossy, Hany M; Abo-Warda, Shaymaa M; Fahmy, Ahmed

    2012-08-01

    In addition to insulin sensitization, rosiglitazone exhibits favourable circulatory effects. In the present study, we tested the hypothesis that rosiglitazone protects against hypertension and vascular derangements caused by diabetes. Diabetes was induced by a single bolus injection of streptozotocin (50 mg/kg, i.p.). After 2 weeks, rats were started on a treatment regimen of 5 mg/kg rosiglitazone daily for a period of 6 weeks. The control group consisted of rats treated with vehicle (distilled water) for the same period of time. After 6 weeks treatment, blood pressure (BP) was recorded and serum levels of glucose, advanced glycation end-products (AGE), triglycerides, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) were determined. In in vitro experiments, concentration-response curves were constructed to phenylephrine (PE), KCl and acetylcholine (ACh) in thoracic aorta rings. In addition, ACh-induced nitric oxide (NO) generation and KCl-induced intracellular Ca accumulation were determined in the aorta. Compared with values in control rats, both diastolic and systolic BP were increased in diabetic rats. Rosiglitazone treatment of diabetic rats abolished the increase in diastolic BP and significantly reduced the increased systolic BP without affecting the development of hyperglycaemia. The possibility that changes in vascular reactivity and/or lipid profile contributed to the effects of rosiglitazone on BP in diabetic rats was investigated. In aortic rings from diabetic rats, contractile responses to KCl were increased, whereas the relaxant responses to ACh were decreased. In rings from diabetic rosiglitazone-treated rats, the exaggerated response to KCl and the impaired response to ACh were abolished. Furthermore, rosiglitazone abrogated impaired ACh-stimulated NO generation in aortas isolated from diabetic rats. Diabetes in rats was accompanied by elevated levels of triglycerides, total cholesterol, LDL-C and AGE. Rosiglitazone treatment

  16. Wholemount imaging reveals abnormalities of the aqueous outflow pathway and corneal vascularity in Foxc1 and Bmp4 heterozygous mice.

    PubMed

    van der Merwe, Elizabeth L; Kidson, Susan H

    2016-05-01

    Mutations in the FOXC1/Foxc1 gene in humans and mice and Bmp4 in mice are associated with congenital anterior segment dysgenesis (ASD) and the development of the aqueous outflow structures throughout the limbus. The aim of this study was to advance our understanding of anterior segment abnormalities in mouse models of ASD using a 3-D imaging approach. Holistic imaging information combined with quantitative measurements were carried out on PECAM-1 stained individual components of the aqueous outflow vessels and corneal vasculature of Foxc1(+/-) on the C57BL/6Jx129 and ICR backgrounds, Bmp4(+/-) ICR mice, and wildtype mice from each background. In both wildtype and heterozygotes, singular, bifurcated and plexus forms of Schlemm's canal were noted. Of note, missing portions of the canal were seen in the heterozygous groups but not in wildtype animals. In general, we found the number of collector channels to be reduced in both heterozygotes. Lastly, we found a significant increase in the complexity of the corneal arcades and their penetration into the cornea in heterozygotes as compared with wild types. In conclusion, our 3-D imaging studies have revealed a more complex arrangement of both the aqueous vessels and corneal arcades in Foxc1(+/-) and Bmp4(+/-) heterozygotes, and further advance our understanding of how such abnormalities could impact on IOP and the aetiology of glaucoma. PMID:27068508

  17. Reduced Expression of the Extracellular Calcium-Sensing Receptor (CaSR) Is Associated with Activation of the Renin-Angiotensin System (RAS) to Promote Vascular Remodeling in the Pathogenesis of Essential Hypertension

    PubMed Central

    Wang, La-mei; Tang, Na; Zhong, Hua; Liu, Yong-min; Li, Zhen; Feng, Qian; He, Fang

    2016-01-01

    The proliferation of vascular smooth muscle cells (VSMCs), remodeling of the vasculature, and the renin-angiotensin system (RAS) play important roles in the development of essential hypertension (EH), which is defined as high blood pressure (BP) in which secondary causes, such as renovascular disease, are absent. The calcium-sensing receptor (CaSR) is involved in the regulation of BP. However, the underlying mechanisms by which the CaSR regulates BP are poorly understood. In the present study, the role of the CaSR in EH was investigated using male spontaneously hypertensive rats (SHRs) and rat and human plasma samples. The percentages of medial wall thickness to external diameter (WT%), total vessel wall cross-sectional area to the total area (WA%) of thoracic arteries, as well as the percentage of wall area occupied by collagen to total vessel wall area (CA%) were determined. Tissue protein expression and plasma concentrations of the CaSR, cyclic adenosine monophosphate (cAMP), renin, and angiotensin II (Ang II) were additionally assessed. WT%, WA%, and CA% were found to increase with increasing BP, whereas the plasma concentration of CaSR was found to decrease. With increasing BP, the levels of smooth muscle actin and calponin decreased, whereas those of osteopontin and proliferating cell nuclear antigen increased. The CaSR level negatively correlated with the levels of cAMP and Ang II, but positively correlated with those of renin. Our data suggest that reduced expression of the CaSR is correlated with activation of the RAS, which induces increased vascular remodeling and VSMC proliferation, and thereby associated with EH in the SHR model and in the Han Chinese population. Our findings provide new insights into the pathogenesis of EH. PMID:27391973

  18. Increased Lung Expression of Anti-Angiogenic Factors in Down Syndrome: Potential Role in Abnormal Lung Vascular Growth and the Risk for Pulmonary Hypertension

    PubMed Central

    Galambos, Csaba; Minic, Angela D.; Bush, Douglas; Nguyen, Dominique; Dodson, Blair; Seedorf, Gregory; Abman, Steven H.

    2016-01-01

    Background and Aims Infants with Down syndrome (DS) or Trisomy 21, are at high risk for developing pulmonary arterial hypertension (PAH), but mechanisms that increase susceptibility are poorly understood. Laboratory studies have shown that early disruption of angiogenesis during development impairs vascular and alveolar growth and causes PAH. Human chromosome 21 encodes known anti-angiogenic factors, including collagen18a1 (endostatin, ES), ß-amyloid peptide (BAP) and Down Syndrome Critical Region 1 (DSCR-1). Therefore, we hypothesized that fetal lungs from subjects with DS are characterized by early over-expression of anti-angiogenic factors and have abnormal lung vascular growth in utero. Methods Human fetal lung tissue from DS and non-DS subjects were obtained from a biorepository. Quantitative reverse transcriptase PCR (qRT-PCR) was performed to assay 84 angiogenesis-associated genes and individual qRT-PCR was performed for ES, amyloid protein precursor (APP) and DSCR1. Western blot analysis (WBA) was used to assay lung ES, APP and DSCR-1 protein contents. Lung vessel density and wall thickness were determined by morphometric analysis. Results The angiogenesis array identified up-regulation of three anti-angiogenic genes: COL18A1 (ES), COL4A3 (tumstatin) and TIMP3 (tissue inhibitor of metallopeptidase 3) in DS lungs. Single qRT-PCR and WBA showed striking elevations of ES and APP mRNA (p = 0.022 and p = 0.001) and protein (p = 0.040 and p = 0.002; respectively). Vessel density was reduced (p = 0.041) and vessel wall thickness was increased in DS lung tissue (p = 0.033) when compared to non-DS subjects. Conclusions We conclude that lung anti-angiogenic factors, including COL18A1 (ES), COL4A3, TIMP3 and APP are over-expressed and fetal lung vessel growth is decreased in subjects with DS. We speculate that increased fetal lung anti-angiogenic factor expression due to trisomy 21 impairs lung vascular growth and signaling, which impairs alveolarization and

  19. Negative Regulation of p21Waf1/Cip1 by Human INO80 Chromatin Remodeling Complex Is Implicated in Cell Cycle Phase G2/M Arrest and Abnormal Chromosome Stability

    PubMed Central

    Cao, Lingling; Ding, Jian; Dong, Liguo; Zhao, Jiayao; Su, Jiaming; Wang, Lingyao; Sui, Yi; Zhao, Tong; Wang, Fei; Jin, Jingji; Cai, Yong

    2015-01-01

    We previously identified an ATP-dependent human Ino80 (INO80) chromatin remodeling complex which shares a set of core subunits with yeast Ino80 complex. Although research evidence has suggested that INO80 complex functions in gene transcription and genome stability, the precise mechanism remains unclear. Herein, based on gene expression profiles from the INO80 complex-knockdown in HeLa cells, we first demonstrate that INO80 complex negatively regulates the p21Waf1/Cip1 (p21) expression in a p53-mediated mechanism. In chromatin immunoprecipitation (ChIP) and a sequential ChIP (Re-ChIP) assays, we determined that the INO80 complex and p53 can bind to the same promoter region of p21 gene (-2.2kb and -1.0kb upstream of the p21 promoter region), and p53 is required for the recruitment of the INO80 complex to the p21 promoter. RNAi knockdown strategies of INO80 not only led to prolonged progression of cell cycle phase G2/M to G1, but it also resulted in abnormal chromosome stability. Interestingly, high expression of p21 was observed in most morphologically-changed cells, suggesting that negative regulation of p21 by INO80 complex might be implicated in maintaining the cell cycle process and chromosome stability. Together, our findings will provide a theoretical basis to further elucidate the cellular mechanisms of the INO80 complex. PMID:26340092

  20. Calcitonin gene-related peptide does not mediate the abnormal vascular reactivity observed in a rat model of acute Pseudomonas pneumonia.

    PubMed

    Fox, G A; Paterson, N A; McCormack, D G

    1996-06-01

    Abnormal systemic and pulmonary vascular reactivity has been demonstrated in numerous models of sepsis and pneumonia. Furthermore, the attenuated hypoxic pulmonary pressor response observed in these animals probably is responsible for the ventilation/perfusion (V/Q) mismatching and consequent arterial hypoxemia. We hypothesized that excess release of endogenous vasodilators such as calcitonin gene-related peptide (CGRP) in pneumonia was responsible for the diminished hypoxic pressor response. Using the CGRP receptor antagonist CGRP (8-37), we examined the role of CGRP in the attenuated hypoxic pulmonary response in a rat model of acute Pseudomonas pneumonia. Sixteen Sprague-Dawley rats were instrumented for chronic hemodynamic monitoring and subsequently randomized to either Pneumonia (n = 8), induced by the instillation of 0.2 ml broth containing 2 x 10(8) colony-forming units (CFU)/ml Pseudomonas aeruginosa into the right lower lobe, or Sham (n = 8) procedure. Hemodynamic measurements and the hypoxic (FiO2 = 0.08) pulmonary pressor response were recorded at baseline, 48 h after the pneumonia or sham procedure and after the administration of 250 micrograms CGRP (8-37) (post-CGRP(8-37)). The regional distribution of pulmonary blood flow was determined by the injection of radioactive microspheres. Forty-eight hours after the instillation of Pseudomonas, Pneumonia animals had significantly increased cardiac output (CO) as compared with Sham (193 +/- 7 vs. 154 +/- 7 ml/min, p < 0.05), slightly decreased mean arterial pressure (MAP 109 +/- 4 vs. 118 +/- 3 mm Hg, p = NS), and reduced total systemic vascular resistance (TSVR 0.57 +/- 0.03 vs. 0.78 +/- 0.05 mm Hg.min.ml-1, p < 0.05). Pneumonia animals were further characterized by increased mean pulmonary artery pressure (MPAP) as compared with Sham (24 +/- 2 vs. 20 +/- 1 mm Hg, p < 0.05) animals, and an increased alveolar-arterial (A-a) oxygen gradient (31 +/- 3 vs. 20 +/- 4 mm Hg, p < 0.05). The administration of CGRP

  1. Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor

    PubMed Central

    Howangyin, Kiave-Yune; Zlatanova, Ivana; Pinto, Cristina; Ngkelo, Anta; Cochain, Clément; Rouanet, Marie; Vilar, José; Lemitre, Mathilde; Stockmann, Christian; Fleischmann, Bernd K.; Mallat, Ziad

    2016-01-01

    Background— In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. Methods and Results— We generated double-deficient mice for Mertk and Mfge8 (Mertk−/−/Mfge8−/−) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk−/−), or Mfge8-deficient (Mfge8−/−) animals, Mertk−/−/Mfge8−/− mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6CHigh and Low monocytes and macrophages. In parallel, Mertk−/−/Mfge8−/− bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6CHigh and Ly6CHow monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6CHigh/Ly6CLow monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre+/VEGFAfl/fl mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. Conclusions— After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the

  2. Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD.

    PubMed

    Pera, T; Zuidhof, A; Valadas, J; Smit, M; Schoemaker, R G; Gosens, R; Maarsingh, H; Zaagsma, J; Meurs, H

    2011-10-01

    Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease. PMID:21349917

  3. Lipidomics and H2(18)O labeling techniques reveal increased remodeling of DHA-containing membrane phospholipids associated with abnormal locomotor responses in α-tocopherol deficient zebrafish (danio rerio) embryos.

    PubMed

    McDougall, Melissa Q; Choi, Jaewoo; Stevens, Jan F; Truong, Lisa; Tanguay, Robert L; Traber, Maret G

    2016-08-01

    We hypothesized that vitamin E (α-tocopherol) is required by the developing embryonic brain to prevent depletion of highly polyunsaturated fatty acids, especially docosahexaenoic acid (DHA, 22:6), the loss of which we predicted would underlie abnormal morphological and behavioral outcomes. Therefore, we fed adult 5D zebrafish (Danio rerio) defined diets without (E-) or with added α-tocopherol (E+, 500mg RRR-α-tocopheryl acetate/kg diet) for a minimum of 80 days, and then spawned them to obtain E- and E+ embryos. The E- compared with E+ embryos were 82% less responsive (p<0.01) to a light/dark stimulus at 96h post-fertilization (hpf), demonstrating impaired locomotor behavior, even in the absence of gross morphological defects. Evaluation of phospholipid (PL) and lysophospholipid (lyso-PL) composition using untargeted lipidomics in E- compared with E+ embryos at 24, 48, 72, and 120hpf showed that four PLs and three lyso-PLs containing docosahexaenoic acid (DHA), including lysophosphatidylcholine (LPC 22:6, required for transport of DHA into the brain, p<0.001), were at lower concentrations in E- at all time-points. Additionally, H2(18)O labeling experiments revealed enhanced turnover of LPC 22:6 (p<0.001) and three other DHA-containing PLs in the E- compared with the E+ embryos, suggesting that increased membrane remodeling is a result of PL depletion. Together, these data indicate that α-tocopherol deficiency in the zebrafish embryo causes the specific depletion and increased turnover of DHA-containing PL and lyso-PLs, which may compromise DHA delivery to the brain and thereby contribute to the functional impairments observed in E- embryos. PMID:26774753

  4. Lipidomics and H218O labeling techniques reveal increased remodeling of DHA-containing membrane phospholipids associated with abnormal locomotor responses in α-tocopherol deficient zebrafish (danio rerio) embryos

    PubMed Central

    McDougall, Melissa Q.; Choi, Jaewoo; Stevens, Jan F.; Truong, Lisa; Tanguay, Robert L.; Traber, Maret G.

    2016-01-01

    We hypothesized that vitamin E (α-tocopherol) is required by the developing embryonic brain to prevent depletion of highly polyunsaturated fatty acids, especially docosahexaenoic acid (DHA, 22:6), the loss of which we predicted would underlie abnormal morphological and behavioral outcomes. Therefore, we fed adult 5D zebrafish (Danio rerio) defined diets without (E−) or with added α-tocopherol (E+, 500 mg RRR-α-tocopheryl acetate/kg diet) for a minimum of 80 days, and then spawned them to obtain E− and E+ embryos. The E− compared with E+ embryos were 82% less responsive (p<0.01) to a light/dark stimulus at 96 h post-fertilization (hpf), demonstrating impaired locomotor behavior, even in the absence of gross morphological defects. Evaluation of phospholipid (PL) and lysophospholipid (lyso-PL) composition using untargeted lipidomics in E− compared with E+ embryos at 24, 48, 72, and 120 hpf showed that four PLs and three lyso-PLs containing docosahexaenoic acid (DHA), including lysophosphatidylcholine (LPC 22:6, required for transport of DHA into the brain, p<0.001), were at lower concentrations in E− at all time-points. Additionally, H218O labeling experiments revealed enhanced turnover of LPC 22:6 (p<0.001) and three other DHA-containing PLs in the E− compared with the E+ embryos, suggesting that increased membrane remodeling is a result of PL depletion. Together, these data indicate that α-tocopherol deficiency in the zebrafish embryo causes the specific depletion and increased turnover of DHA-containing PL and lyso-PLs, which may compromise DHA delivery to the brain and thereby contribute to the functional impairments observed in E− embryos. PMID:26774753

  5. Composition of connective tissues and morphometry of vascular smooth muscle in arterial wall of DOCA-salt hypertensive rats - In relation with arterial remodeling.

    PubMed

    Hayashi, Kozaburo; Shimizu, Emiko

    2016-05-01

    Hypertension (HT) was induced in Wistar rats aged 16 and 48 weeks by a deoxycortico-sterone acetate (DOCA)-salt procedure. Common carotid arteries were resected 16 weeks after, and their histological specimens were selectively stained for observations of collagen, elastin, and vascular smooth muscle (VSM) cells. Then, the fractions of collagen and elastin and their radial distributions, and the size and number of VSM cells were determined with an image analyzer. These results were compared with the results from age-matched, non-treated, normotensive (NT) animals and also with those from our previous biomechanical studies. In both age groups, there were no significant differences in the fractions of collagen and elastin, and the ratio of collagen to elastin content between HT and NT arteries. These results correspond well with our previous biomechanical results, which showed no significant difference in wall elasticity between HT and NT vessels. Moreover, in the innermost layer out of 4 layers bordered with thick elastic lamellae, the fraction of collagen was significantly greater in HT arteries than in NT ones, which is attributable to HT-related stress concentration in the layer. VSM cells were significantly hypertrophied and their content was increased by HT, although their total number in the media remained unchanged. The increased size and content of cells correspond to the enhancement of vascular tone and contractility in HT arteries. PMID:26987272

  6. Niflumic Acid Attenuated Pulmonary Artery Tone and Vascular Structural Remodeling of Pulmonary Arterial Hypertension Induced by High Pulmonary Blood Flow In Vivo.

    PubMed

    Wang, Kai; Ma, Jianfa; Pang, Yusheng; Lao, Jinquan; Pan, Xuanren; Tang, Qiaoyun; Zhang, Feng; Su, Danyan; Qin, Suyuan; Shrestha, Arnav Prasad

    2015-10-01

    Calcium-activated chloride channels (CaCCs) play a vital role in regulating pulmonary artery tone during pulmonary arterial hypertension (PAH) induced by high blood flow. The role of CaCCs inhibitor niflumic acid (NFA) in vivo during this process requires further investigation. We established the PAH model by abdominal shunt surgery and treated with NFA in vivo. Fifty rats were randomly divided into normal, sham, shunt, NFA group 1 (0.2 mg/kg), and NFA group 2 (0.4 mg/kg). Pathological changes, right ventricle hypertrophy index, arterial wall area/vessel area, and arterial wall thickness/vessel external diameter were analyzed. Then contraction reactions of pulmonary arteries were measured. Finally, the electrophysiological characteristics of pulmonary arterial smooth muscle cells were investigated using patch-clamp technology. After 11 weeks of shunting, PAH developed, accompanied with increased right ventricle hypertrophy index, arterial wall area/vessel area, and arterial wall thickness/vessel external diameter. In the NFA treatment groups, the pressure and pathological changes were alleviated. The pulmonary artery tone in the shunt group increased, whereas it decreased after NFA treatment. The current density of CaCC was higher in the shunt group, and it was decreased in the NFA treatment groups. In conclusion, NFA attenuated pulmonary artery tone and structural remodeling in PAH induced by high pulmonary blood flow in vivo. CaCCs were involved and the augmented current density was alleviated by NFA treatment. PMID:26132368

  7. In Brief: Picturing the complex world of chromatin remodelling families.

    PubMed

    Witkowski, Leora; Foulkes, William D

    2015-12-01

    Over the past decade, chromatin remodelling emerged as one of the most important causes of both abnormal development and cancer. Although much has been written about one or another of the complexes, no recent concise summary of the chromatin remodelling families as a whole is available. In this short review, we introduce the family members, briefly summarize their role in developmental abnormalities and neoplasia, and outline the different ways in which these families remodel chromatin. PMID:26174723

  8. Cyclic nucleotide phosphodiesterase 1 and vascular aging.

    PubMed

    Yan, Chen

    2015-12-01

    VSMCs (vascular smooth muscle cells) play critical roles in arterial remodelling with aging, hypertension and atherosclerosis. VSMCs exist in diverse phenotypes and exhibit phenotypic plasticity, e.g. changing from a quiescent/contractile phenotype to an active myofibroblast-like, often called 'synthetic', phenotype. Synthetic VSMCs are able to proliferate, migrate and secrete ECM (extracellular matrix) proteinases and ECM proteins. In addition, they produce pro-inflammatory molecules, providing an inflammatory microenvironment for leucocyte penetration, accumulation and activation. The aging VSMCs have also shown changes in cellular phenotype, responsiveness to contracting and relaxing mediators, replicating potential, matrix synthesis, inflammatory mediators and intracellular signalling. VSMC dysfunction plays a key role in age-associated vascular remodelling. Cyclic nucleotide PDEs (phosphodiesterases), by catalysing cyclic nucleotide hydrolysis, play a critical role in regulating the amplitude, duration and compartmentalization of cyclic nucleotide signalling. Abnormal alterations of PDEs and subsequent changes in cyclic nucleotide homoeostasis have been implicated in a number of different diseases. In the study published in the latest issue of Clinical Science, Bautista Niño and colleagues have shown that, in cultured senescent human VSMCs, PDE1A and PDE1C mRNA levels are significantly up-regulated and inhibition of PDE1 activity with vinpocetine reduced cellular senescent makers in senescent VSMCs. Moreover, in the premature aging mice with genomic instability (Ercc1(d/-)), impaired aortic ring relaxation in response to SNP (sodium nitroprusside), an NO (nitric oxide) donor, was also largely improved by vinpocetine. More interestingly, using data from human GWAS (genome-wide association studies), it has been found that PDE1A single nucleotide polymorphisms is significantly associated with diastolic blood pressure and carotid intima-media thickening, two

  9. Mechanotransduction in Embryonic Vascular Development

    PubMed Central

    Roman, Beth L.; Pekkan, Kerem

    2015-01-01

    A plethora of biochemical signals provides spatial and temporal cues that carefully orchestrate the complex process of vertebrate embryonic development. The embryonic vasculature develops not only in the context of these biochemical cues, but also in the context of the biomechanical forces imparted by blood flow. In the mature vasculature, different blood flow regimes induce distinct genetic programs, and significant progress has been made toward understanding how these forces are perceived by endothelial cells and transduced into biochemical signals. However, it cannot be assumed that paradigms that govern the mature vasculature are pertinent to the developing embryonic vasculature. The embryonic vasculature can respond to the mechanical forces of blood flow, and these responses are critical in vascular remodeling, certain aspects of sprouting angiogenesis, and maintenance of arterial-venous identity. Here, we review data regarding mechanistic aspects of endothelial cell mechanotransduction, with a focus on the response to shear stress, and elaborate upon the multifarious effects of shear stress on the embryonic vasculature. In addition, we discuss emerging predictive vascular growth models and highlight the prospect of combining signaling pathway information with computational modeling. We assert that correlation of precise measurements of hemodynamic parameters with effects on endothelial cell gene expression and cell behavior is required for fully understanding how blood flow-induced loading governs normal vascular development and shapes congenital cardiovascular abnormalities. PMID:22744845

  10. 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

  11. Reconciling paradigms of abnormal pulmonary blood flow and quasi-malignant cellular alterations in pulmonary arterial hypertension.

    PubMed

    Happé, C M; Szulcek, R; Voelkel, N F; Bogaard, H J

    2016-08-01

    In pulmonary arterial hypertension (PAH) structural and functional abnormalities of the small lung vessels interact and lead to a progressive increase in pulmonary vascular resistance and right heart failure. A current pathobiological concept characterizes PAH as a 'quasi-malignant' disease focusing on cancer-like alterations in endothelial cells (EC) and the importance of their acquired apoptosis-resistant, hyper-proliferative phenotype in the process of vascular remodeling. While changes in pulmonary blood flow (PBF) have been long-since recognized and linked to the development of PAH, little is known about a possible relationship between an altered PBF and the quasi-malignant cell phenotype in the pulmonary vascular wall. This review summarizes recognized and hypothetical effects of an abnormal PBF on the pulmonary vascular bed and links these to quasi-malignant changes found in the pulmonary endothelium. Here we describe that abnormal PBF does not only trigger a pulmonary vascular cell growth program, but may also maintain the cancer-like phenotype of the endothelium. Consequently, normalization of PBF and EC response to abnormal PBF may represent a treatment strategy in patients with established PAH. PMID:26804008

  12. For Application to Human Spaceflight and ISS Experiments: VESGEN Mapping of Microvascular Network Remodeling during Intestinal Inflammation.

    PubMed

    Parsons-Wingerter, Patricia; Reinecker, Hans-Christian

    2012-10-01

    Challenges to long-duration space exploration and colonization in microgravity and cosmic radiation environments by humans include poorly understood risks for gastrointestinal function and cancer. Nonetheless, constant remodeling of the intestinal microvasculature is critical for tissue viability, healthy wound healing, and successful prevention or recovery from vascular-mediated inflammatory or ischemic diseases such as cancer. Currently no automated image analysis programs provide quantitative assessments of the complex structure of the mucosal vascular system that are necessary for tracking disease development and tissue recovery. Increasing abnormalities to the microvascular network geometry were therefore mapped with VESsel GENeration Analysis (VESGEN) software from 3D tissue reconstructions of developing intestinal inflammation in a dextran sulfate sodium (DSS) mouse model. By several VESGEN parameters and a novel vascular network linking analysis, inflammation strongly disrupted the regular, lattice-like geometry that defines the normal microvascular network, correlating positively with the increased recruitment of dendritic cells during mucosal defense responses. PMID:25143705

  13. 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. PMID:24099797

  14. 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

  15. Vascular wall extracellular matrix proteins and vascular diseases

    PubMed Central

    Xu, Junyan; Shi, Guo-Ping

    2014-01-01

    Extracellular matrix proteins form the basic structure of blood vessels. Along with providing basic structural support to blood vessels, matrix proteins interact with different sets of vascular cells via cell surface integrin or non-integrin receptors. Such interactions induce vascular cell de novo synthesis of new matrix proteins during blood vessel development or remodeling. Under pathological conditions, vascular matrix proteins undergo proteolytic processing, yielding bioactive fragments to influence vascular wall matrix remodeling. Vascular cells also produce alternatively spliced variants that induce vascular cell production of different matrix proteins to interrupt matrix homeostasis, leading to increased blood vessel stiffness; vascular cell migration, proliferation, or death; or vascular wall leakage and rupture. Destruction of vascular matrix proteins leads to vascular cell or blood-borne leukocyte accumulation, proliferation, and neointima formation within the vascular wall; blood vessels prone to uncontrolled enlargement during blood flow diastole; tortuous vein development; and neovascularization from existing pathological tissue microvessels. Here we summarize discoveries related to blood vessel matrix proteins within the past decade from basic and clinical studies in humans and animals — from expression to cross-linking, assembly, and degradation under physiological and vascular pathological conditions, including atherosclerosis, aortic aneurysms, varicose veins, and hypertension. PMID:25045854

  16. Intracranial pressure and skull remodeling

    PubMed Central

    McCulley, Timothy J.; Jordan Piluek, W.; Chang, Jessica

    2014-01-01

    In this article we review bony changes resulting from alterations in intracranial pressure (ICP) and the implications for ophthalmologists and the patients for whom we care. Before addressing ophthalmic implications, we will begin with a brief overview of bone remodeling. Bony changes seen with chronic intracranial hypotension and hypertension will be discussed. The primary objective of this review was to bring attention to bony changes seen with chronic intracranial hypotension. Intracranial hypotension skull remodeling can result in enophthalmos. In advanced disease enophthalmos develops to a degree that is truly disfiguring. The most common finding for which subjects are referred is ocular surface disease, related to loss of contact between the eyelids and the cornea. Other abnormalities seen include abnormal ocular motility and optic atrophy. Recognition of such changes is important to allow for diagnosis and treatment prior to advanced clinical deterioration. Routine radiographic assessment of bony changes may allow for the identification of patient with abnormal ICP prior to the development of clinically significant disease. PMID:25859141

  17. Mice That Lack Thrombospondin 2 Display Connective Tissue Abnormalities That Are Associated with Disordered Collagen Fibrillogenesis, an Increased Vascular Density, and a Bleeding Diathesis

    PubMed Central

    Kyriakides, Themis R.; Zhu, Yu-Hong; Smith, Lynne T.; Bain, Steven D.; Yang, Zhantao; Lin, Ming T.; Danielson, Keith G.; Iozzo, Renato V.; LaMarca, Mary; McKinney, Cindy E.; Ginns, Edward I.; Bornstein, Paul

    1998-01-01

    Thrombospondin (TSP) 2, and its close relative TSP1, are extracellular proteins whose functions are complex, poorly understood, and controversial. In an attempt to determine the function of TSP2, we disrupted the Thbs2 gene by homologous recombination in embryonic stem cells, and generated TSP2-null mice by blastocyst injection and appropriate breeding of mutant animals. Thbs2−/− mice were produced with the expected Mendelian frequency, appeared overtly normal, and were fertile. However, on closer examination, these mice displayed a wide variety of abnormalities. Collagen fiber patterns in skin were disordered, and abnormally large fibrils with irregular contours were observed by electron microscopy in both skin and tendon. As a functional correlate of these findings, the skin was fragile and had reduced tensile strength, and the tail was unusually flexible. Mutant skin fibroblasts were defective in attachment to a substratum. An increase in total density and in cortical thickness of long bones was documented by histology and quantitative computer tomography. Mutant mice also manifested an abnormal bleeding time, and histologic surveys of mouse tissues, stained with an antibody to von Willebrand factor, showed a significant increase in blood vessels. The basis for the unusual phenotype of the TSP2-null mouse could derive from the structural role that TSP2 might play in collagen fibrillogenesis in skin and tendon. However, it seems likely that some of the diverse manifestations of this genetic disorder result from the ability of TSP2 to modulate the cell surface properties of mesenchymal cells, and thus, to affect cell functions such as adhesion and migration. PMID:9442117

  18. Inner Ear Conductive Hearing Loss and Unilateral Pulsatile Tinnitus Associated with a Dural Arteriovenous Fistula: Case Based Review and Analysis of Relationship between Intracranial Vascular Abnormalities and Inner Ear Fluids

    PubMed Central

    Cassandro, Ettore; Cassandro, Claudia; Sequino, Giuliano; Scarpa, Alfonso; Petrolo, Claudio; Chiarella, Giuseppe

    2015-01-01

    While pulsatile tinnitus (PT) and dural arteriovenous fistula (DAVF) are not rarely associated, the finding of a conductive hearing loss (CHL) in this clinical picture is unusual. Starting from a case of CHL and PT, diagnosed to be due to a DAVF, we analyzed relationship between intracranial vascular abnormalities and inner ear fluids. DAVF was treated with endovascular embolization. Following this, there was a dramatic recovery of PT and of CHL, confirming their cause-effect link with DAVF. We critically evaluated the papers reporting this association. This is the first case of CHL associated with PT and DAVF. We describe the most significant experiences and theories reported in literature, with a personal analysis about the possible relationship between vascular intracranial system and labyrinthine fluids. In conclusion, we believe that this association may be a challenge for otolaryngologists. So we suggest to consider the possibility of a DAVF or other AVMs when PT is associated with CHL, without alterations of tympanic membrane and middle ear tests. PMID:26693371

  19. Arterial remodeling of basilar atherosclerosis in isolated pontine infarction.

    PubMed

    Feng, Chao; Hua, Ting; Xu, Yu; Liu, Xue-Yuan; Huang, Jing

    2015-04-01

    Isolated pontine infarctions are usually classified as paramedian pontine infarction (PPI) and lacunar pontine infarction (LPI). Although they have different shapes and locations, some recent studies proved that they might both be associated with basilar artery atherosclerosis in pathogenesis. This study aimed to explore the difference of basilar artery remodeling between two subtypes of pontine infarctions. Patients with PPI or LPI were scanned by High-resolution MRI (HR-MRI). The MR images of patients with basilar artery atherosclerosis were further analyzed to measure the vessel, lumen and wall areas at different segments of basilar arteries. Stenosis rate and remodeling index were calculated according to which arterial remodeling was divided into positive, intermediate and negative remodeling. Vascular risk factors and remodeling-related features were compared between PPI and LPI, and also between patients with and without positive remodeling. 34 patients with PPI and 21 patients with LPI had basilar artery atherosclerosis identified by HR-MRI. Positive remodeling was dominant in LPI group while in PPI group, three subtypes of remodeling were equal. Patients with positive remodeling had higher levels of low-density lipoprotein and homocysteine. Positive remodeling of basilar artery might reflect the low stability of basilar atherosclerotic plaques, which was more closely associated with LPI than PPI. PMID:25367406

  20. Mechanism of chromatin remodeling.

    PubMed

    Lorch, Yahli; Maier-Davis, Barbara; Kornberg, Roger D

    2010-02-23

    Results from biochemical and structural studies of the RSC chromatin-remodeling complex prompt a proposal for the remodeling mechanism: RSC binding to the nucleosome releases the DNA from the histone surface and initiates DNA translocation (through one or a small number of DNA base pairs); ATP binding completes translocation, and ATP hydrolysis resets the system. Binding energy thus plays a central role in the remodeling process. RSC may disrupt histone-DNA contacts by affecting histone octamer conformation and through extensive interaction with the DNA. Bulging of the DNA from the octamer surface is possible, and twisting is unavoidable, but neither is the basis of remodeling. PMID:20142505

  1. The Role of Reactive Oxygen Species in Microvascular Remodeling

    PubMed Central

    Staiculescu, Marius C.; Foote, Christopher; Meininger, Gerald A.; Martinez-Lemus, Luis A.

    2014-01-01

    The microcirculation is a portion of the vascular circulatory system that consists of resistance arteries, arterioles, capillaries and venules. It is the place where gases and nutrients are exchanged between blood and tissues. In addition the microcirculation is the major contributor to blood flow resistance and consequently to regulation of blood pressure. Therefore, structural remodeling of this section of the vascular tree has profound implications on cardiovascular pathophysiology. This review is focused on the role that reactive oxygen species (ROS) play on changing the structural characteristics of vessels within the microcirculation. Particular attention is given to the resistance arteries and the functional pathways that are affected by ROS in these vessels and subsequently induce vascular remodeling. The primary sources of ROS in the microcirculation are identified and the effects of ROS on other microcirculatory remodeling phenomena such as rarefaction and collateralization are briefly reviewed. PMID:25535075

  2. Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation Impairs Trophoblast Invasion and Spiral Artery Remodelling during Pregnancy in Mice.

    PubMed

    Winship, Amy; Correia, Jeanne; Zhang, Jian-Guo; Nicola, Nicos A; Dimitriadis, Evdokia

    2015-01-01

    The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Trophoblast cell proliferation, migration and invasion into the endometrium are fundamental events in the initiation of placentation. Leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasion in vitro, however its precise role in trophoblast invasion in vivo is unknown. We hypothesized that LIF would be required for normal trophoblast invasion and spiral artery remodeling in mice. Both LIF and its receptor (LIFRα) co-localized with cytokeratin-positive invasive endovascular extravillous trophoblasts (EVT) in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via administration of our unique LIFRα antagonist, PEGLA, resulted in abnormal trophoblast invasion and impaired spiral artery remodeling compared to PEG control. PEGLA-treated mouse decidual vessels were characterized by retention of α-smooth muscle actin (αSMA)-positive vascular smooth muscle cells (VSMCs), while PEG control decidual vessels were remodelled by cytokeratin-positive trophoblasts. LIF blockade did not alter F4/80-positive decidual macrophage numbers between treatment groups, but resulted in down-regulation of decidual transcript levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10), which are important immune cell activation factors that promote spiral artery remodeling during pregnancy. Our data suggest that LIF plays an important role in trophoblast invasion in vivo and may facilitate trophoblast-decidual-immune cell cross talk to enable adequate spiral artery remodeling. PMID:26479247

  3. Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation Impairs Trophoblast Invasion and Spiral Artery Remodelling during Pregnancy in Mice

    PubMed Central

    Winship, Amy; Correia, Jeanne; Zhang, Jian-Guo; Nicola, Nicos A.; Dimitriadis, Evdokia

    2015-01-01

    The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Trophoblast cell proliferation, migration and invasion into the endometrium are fundamental events in the initiation of placentation. Leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasion in vitro, however its precise role in trophoblast invasion in vivo is unknown. We hypothesized that LIF would be required for normal trophoblast invasion and spiral artery remodeling in mice. Both LIF and its receptor (LIFRα) co-localized with cytokeratin-positive invasive endovascular extravillous trophoblasts (EVT) in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via administration of our unique LIFRα antagonist, PEGLA, resulted in abnormal trophoblast invasion and impaired spiral artery remodeling compared to PEG control. PEGLA-treated mouse decidual vessels were characterized by retention of α-smooth muscle actin (αSMA)-positive vascular smooth muscle cells (VSMCs), while PEG control decidual vessels were remodelled by cytokeratin-positive trophoblasts. LIF blockade did not alter F4/80-positive decidual macrophage numbers between treatment groups, but resulted in down-regulation of decidual transcript levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10), which are important immune cell activation factors that promote spiral artery remodeling during pregnancy. Our data suggest that LIF plays an important role in trophoblast invasion in vivo and may facilitate trophoblast-decidual-immune cell cross talk to enable adequate spiral artery remodeling. PMID:26479247

  4. Sinapic Acid Prevents Hypertension and Cardiovascular Remodeling in Pharmacological Model of Nitric Oxide Inhibited Rats

    PubMed Central

    Silambarasan, Thangarasu; Manivannan, Jeganathan; Krishna Priya, Mani; Suganya, Natarajan; Chatterjee, Suvro; Raja, Boobalan

    2014-01-01

    Objectives Hypertensive heart disease is a constellation of abnormalities that includes cardiac fibrosis in response to elevated blood pressure, systolic and diastolic dysfunction. The present study was undertaken to examine the effect of sinapic acid on high blood pressure and cardiovascular remodeling. Methods An experimental hypertensive animal model was induced by L-NAME intake on rats. Sinapic acid (SA) was orally administered at a dose of 10, 20 and 40 mg/kg body weight (b.w.). Blood pressure was measured by tail cuff plethysmography system. Cardiac and vascular function was evaluated by Langendorff isolated heart system and organ bath studies, respectively. Fibrotic remodeling of heart and aorta was assessed by histopathologic analyses. Oxidative stress was measured by biochemical assays. mRNA and protein expressions were assessed by RT-qPCR and western blot, respectively. In order to confirm the protective role of SA on endothelial cells through its antioxidant property, we have utilized the in vitro model of H2O2-induced oxidative stress in EA.hy926 endothelial cells. Results Rats with hypertension showed elevated blood pressure, declined myocardial performance associated with myocardial hypertrophy and fibrosis, diminished vascular response, nitric oxide (NO) metabolites level, elevated markers of oxidative stress (TBARS, LOOH), ACE activity, depleted antioxidant system (SOD, CAT, GPx, reduced GSH), aberrant expression of TGF-β, β-MHC, eNOS mRNAs and eNOS protein. Remarkably, SA attenuated high blood pressure, myocardial, vascular dysfunction, cardiac fibrosis, oxidative stress and ACE activity. Level of NO metabolites, antioxidant system, and altered gene expression were also repaired by SA treatment. Results of in vitro study showed that, SA protects endothelial cells from oxidative stress and enhance the production of NO in a concentration dependent manner. Conclusions Taken together, these results suggest that SA may have beneficial role in the

  5. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  6. Differentiation of Multipotent Vascular Stem Cells Contributes to Vascular Diseases

    PubMed Central

    Tang, Zhenyu; Wang, Aijun; Yuan, Falei; Yan, Zhiqiang; Liu, Bo; Chu, Julia S.; Helms, Jill A.

    2012-01-01

    It is generally accepted that the de-differentiation of smooth muscle cells (SMCs) from contractile to proliferative/synthetic phenotype has an important role during vascular remodeling and diseases. Here we provide evidence that challenges this theory. We identify a new type of multipotent vascular stem cell (MVSC) in blood vessel wall. MVSCs express markers including Sox17, Sox10 and S100β, are cloneable, have telomerase activity, and can differentiate into neural cells and mesenchymal stem cell (MSC)-like cells that subsequently differentiate into SMCs. On the other hand, we use lineage tracing with smooth muscle myosin heavy chain as a marker to show that MVSCs and proliferative or synthetic SMCs do not arise from the de-differentiation of mature SMCs. Upon vascular injuries, MVSCs, instead of SMCs, become proliferative, and MVSCs can differentiate into SMCs and chondrogenic cells, thus contributing to vascular remodeling and neointimal hyperplasia. These findings support a new hypothesis that the differentiation of MVSCs, rather than the de-differentiation of SMCs, contributes to vascular remodeling and diseases. PMID:22673902

  7. Vascular Biomarkers in Asthma and COPD.

    PubMed

    Bakakos, Petros; Patentalakis, George; Papi, Alberto

    2016-01-01

    Bronchial asthma and chronic obstructive pulmonary disease (COPD) remain a global health problem with significant morbidity and mortality. The changes in bronchial microvasculature that occurin asthma and COPD contribute to airway wall remodeling. Angiogenesis seems to be more prevalent in asthma and vasodilatation seemsmore relevant in COPD while vascular leak is present in both diseases. Recently, there has been increased interest in the vascular component of airway remodeling in chronic bronchial inflammation of asthma and COPD although its role in the progression of the diseases has not been fully elucidated. Various cells andmediators are involved in the vascular remodeling in asthma and COPD while proinflammatory cytokines and growth factors exert angiogenic and antiangiogenic effects. Vascular endothelial growth factor (VEGF) is a key regulator of blood vessel growth mainly in asthma but also in COPD. In asthmatic airways VEGF promotes proliferation and differentiation of endothelial cells and induces vascular leakage and permeability. It has also been involved in enhanced allergic sensitization, upregulated subsequent T-helper-2 type inflammatory responses, chemotaxis for monocytes and eosinophils, and airway oedema. Impaired VEGF signaling has been associated with emphysema in animal models. Studies on lung biopsies have shown a decreasing effect of anti-asthma drugs to the vascular component of airway remodeling. There is less available evidence on the effect of the currently used drugs on airway microvascular network in COPD. This review article explores the current knowledge regarding vascular biomarkers in asthma and COPD as well as the therapeutic implications of these mediators. PMID:26420364

  8. Vascular Lesions.

    PubMed

    Jahnke, Marla N

    2016-08-01

    Vascular lesions in childhood are comprised of vascular tumors and vascular malformations. Vascular tumors encompass neoplasms of the vascular system, of which infantile hemangiomas (IHs) are the most common. Vascular malformations, on the other hand, consist of lesions due to anomalous development of the vascular system, including the capillary, venous, arterial, and lymphatic systems. Capillary malformations represent the most frequent type of vascular malformation. IHs and vascular malformations tend to follow relatively predictable growth patterns in that IHs grow then involute during early childhood, whereas vascular malformations tend to exhibit little change. Both vascular tumors and vascular malformations can demonstrate a wide range of severity and potential associated complications necessitating specialist intervention when appropriate. Evaluation and treatment of the most common types of vascular lesions are discussed in this article. [Pediatr Ann. 2016;45(8):e299-e305.]. PMID:27517358

  9. Congenital Abnormalities

    MedlinePlus

    ... serious health problems (e.g. Down syndrome ). Single-Gene Abnormalities Sometimes the chromosomes are normal in number, ... blood flow to the fetus impair fetal growth. Alcohol consumption and certain drugs during pregnancy significantly increase ...

  10. Craniofacial Abnormalities

    MedlinePlus

    ... of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft ... palate, are among the most common of all birth defects. Others are very rare. Most of them affect ...

  11. Walking abnormalities

    MedlinePlus

    ... include: Arthritis of the leg or foot joints Conversion disorder (a psychological disorder) Foot problems (such as a ... injuries. For an abnormal gait that occurs with conversion disorder, counseling and support from family members are strongly ...

  12. Chromosome Abnormalities

    MedlinePlus

    ... decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal abnormalities without using a microscope. These newer methods compare the patient's DNA to a normal DNA ...

  13. Nail abnormalities

    MedlinePlus

    Nail abnormalities are problems with the color, shape, texture, or thickness of the fingernails or toenails. ... Fungus or yeast cause changes in the color, texture, and shape of the nails. Bacterial infection may ...

  14. The role of microRNAs in arterial remodelling.

    PubMed

    Nazari-Jahantigh, M; Wei, Y; Schober, A

    2012-04-01

    Adaptive alterations of the vessel wall architecture, called vascular remodelling, can be found in arterial hypertension, during the formation of aneurysms, in restenosis after vascular interventions, and in atherosclerosis. MicroRNAs (miR) critically affect the main cellular players in arterial remodelling and may either promote or inhibit the structural changes in the vessel wall. They regulate the phenotype of smooth muscle cells (SMCs) and control the inflammatory response in endothelial cells and macrophages. In SMCs, different sets of miRs induce either a synthetic or contractile phenotype, respectively. The conversion into a synthetic SMC phenotype is a crucial event in arterial remodelling. Therefore, reprogramming of the SMC phenotype by miR targeting can modulate the remodelling process. Furthermore, the effects of stimuli that induce remodelling, such as shear stress, angiotensin II, oxidised low-density lipoprotein, or apoptosis, on endothelial cells are mediated by miRs. The endothelial cell-specific miR-126, for example, is transferred in microvesicles from apoptotic endothelial cells and plays a protective role in atherogenesis. The inflammatory response of the innate immune system, especially through macrophages, promotes arterial remodelling. miR-155 induces the expression of inflammatory cytokines, whereas miR-146a and miR-147 are involved in the resolution phase of inflammation. However, in vivo data on the role of miRs in vascular remodelling are still scarce, which are required to test the therapeutic potential of the available, highly effective miR inhibitors. PMID:22371089

  15. 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

  16. In vivo laser speckle imaging reveals microvascular remodeling and hemodynamic changes during wound healing angiogenesis

    PubMed Central

    Rege, Abhishek; Thakor, Nitish V.; Rhie, Kevin

    2015-01-01

    Laser speckle contrast imaging (LSCI) is a high-resolution and high contrast optical imaging technique often used to characterize hemodynamic changes in short-term physiological experiments. In this study, we demonstrate the utility of LSCI for characterizing microvascular remodeling and hemodynamic changes during wound healing angiogenesis in vivo. A 2 mm diameter hole was made in the mouse ear and the periphery of the wound imaged in vivo using LSCI over 12 days. We were able to visualize and quantify the vascular and perfusion changes that accompanied wound healing in the microenvironment proximal to the wound, and validated these changes with histology. We found that consistent with the stages of wound healing, microvessel density increased during the initial inflammatory phase (i.e., day 0–3), stayed elevated through the tissue formation phase (i.e., until day 7) and returned to baseline during the tissue remodeling phase (i.e., by day 12). Concomitant ‘‘wide area mapping’’ of blood flow revealed that tissue perfusion in the wound periphery initially decreased, gradually increased from day 3–7, and subsided as healing completed. Interestingly, some regions exhibited a reestablishment of tissue perfusion approximately 6 days earlier than the ∼ 18 days usually reported for the long term remodeling phase. The results from this study demonstrate that LSCI is an ideal platform for elucidating in vivo changes in microvascular hemodynamics and angiogenesis, and has the potential to offer invaluable insights in a range of disease models involving abnormal hemodynamics, such as diabetes and tumors. PMID:22198198

  17. Photoreceptor degeneration, structural remodeling and glial activation: a morphological study on a genetic mouse model for pericyte deficiency.

    PubMed

    Genové, G; Mollick, T; Johansson, K

    2014-10-24

    Interaction between pericytes and endothelial cells via platelet-derived growth factor B (PDGF-B) signaling is critical for the development of the retinal microvasculature. The PDGF-B retention motif controls the spatial distribution range of the growth factor in the vicinity of its producing endothelial cells allowing its recognition by PDGF receptor beta-(PDGFR-β)-carrying pericytes; this promotes recruitment of pericytes to the vascular basement membrane. Impairment of the PDGF-B signaling mechanism causes development of vascular abnormalities, and in the retina this consequently leads to defects in the neurological circuitry. The vascular pathology in the pdgf-b(ret/ret) (PDGF-B retention motif knockout) mouse retina has been previously reported; our study investigates the progressive neuronal defects and changes in the retinal morphology of this pericyte-deficient mouse model. Immunohistochemical analysis revealed retinal injuries to occur as early as postnatal day (P) 10 with substantial damage progressing from P15 and onward. Vascular abnormalities were apparent from P10, however, prominent neuronal defects were mostly observed from P15, beginning with the compromised integrity of the laminated retinal structure characterized by the presence of rosettes and focally distorted regions. Photoreceptor degeneration was observed by loss of both rod and cone cells, including the disassembly and altered structure of their synaptic terminals. Significant shortening of cone outer segments was observed from P10 and later stages; however, decrease in cone density was only observed at P28. Disorganization and dendrite remodeling of rod bipolar cells also added to the diminished neural and synaptic integrity. Moreover, in response to retinal injuries, Müller and microglial cells were observed to be in the reactive phenotype from P15 and onward. Such a sequence of events indicates that the pdgf-b(ret/ret) mouse model displays a short time frame between P10 and P15

  18. Dealing with vascular conundrums with MR imaging.

    PubMed

    Angthong, Wirana; Semelka, Richard C

    2014-07-01

    Magnetic resonance (MR) imaging is a robust imaging modality for evaluation of vascular diseases. Technological advances have made MR imaging widely available for accurate and time-efficient vascular assessment. In this article the clinical usefulness of MR imaging techniques and their application are reviewed, using examples of vascular abnormalities commonly encountered in clinical practice, including abdominal, pelvic, and thoracic vessels. Common pitfalls and problem solving in interpretation of vascular findings in body MR imaging are also discussed. PMID:24889175

  19. Bioactive Factors in Uteroplacental and Systemic Circulation Link Placental Ischemia to Generalized Vascular Dysfunction in Hypertensive Pregnancy and Preeclampsia

    PubMed Central

    Shah, Dania A.; Khalil, Raouf A.

    2015-01-01

    Preeclampsia is a pregnancy-associated disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality; however, the pathophysiological mechanisms involved are unclear. Predisposing demographic, genetic and environmental risk factors could cause localized abnormalities in uteroplacental cytoactive factors such as integrins, matrix metalloproteinases, cytokines and major histocompatibility complex molecules leading to decreased vascular remodeling, uteroplacental vasoconstriction, trophoblast cells apoptosis, and abnormal development of the placenta. Defective placentation and decreased trophoblast invasion of the myometrium cause reduction in uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia, an important event in preeclampsia. RUPP could stimulate the release of circulating bioactive factors such as the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin that cause imbalance with the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or cause the release of inflammatory cytokines, reactive oxygen species, hypoxia-induced factor-1 and AT1 angiotensin receptor agonistic autoantibodies. The circulating bioactive factors target endothelial cells causing generalized endotheliosis, endothelial dysfunction, decreased vasodilators such as nitric oxide and prostacyclin and increased vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction. The bioactive factors also stimulate the mechanisms of VSM contraction including Ca2+, protein kinase C, and Rho-kinase and induce extracellular matrix remodeling leading to further vasoconstriction and hypertension. While therapeutic options are currently limited, understanding the underlying mechanisms could help design new interventions for management of preeclampsia. PMID:25916268

  20. Vascular parkinsonism: Deconstructing a syndrome

    PubMed Central

    Vizcarra, Joaquin A.; Lang, Anthony E.; Sethi, Kapil D; Espay, Alberto J.

    2015-01-01

    Progressive ambulatory impairment and abnormal white matter signal on neuroimaging come together under the diagnostic umbrella of vascular parkinsonism. A critical appraisal of the literature, however, suggests that (1) no abnormal structural imaging pattern is specific to vascular parkinsonism; (2) there is poor correlation between brain magnetic resonance imaging hyperintensities and microangiopathic brain disease and parkinsonism from available clinicopathologic data; (3) pure parkinsonism from vascular injury (“definite” vascular parkinsonism) consistently results from ischemic or hemorrhagic strokes involving the substantia nigra and/or nigrostriatal pathway but sparing the striatum itself, the cortex, and the intervening white matter; and (4) many cases reported as vascular parkinsonism may represent pseudovascular parkinsonism (e.g., Parkinson disease or another neurodegenerative parkinsonism such as progressive supranuclear palsy with non-specific neuroimaging signal abnormalities), vascular pseudoparkinsonism (e.g., akinetic mutism due to bilateral mesial frontal strokes or apathetic depression from bilateral striatal lacunar strokes), or pseudovascular pseudoparkinsonism (e.g., higher-level gait disorders, including normal pressure hydrocephalus with transependimal exudate). These syndromic designations are preferable over vascular parkinsonism until pathology or validated biomarkers confirm the underlying nature and relevance of the leukoaraiosis. PMID:25997420

  1. Pulmonary arterial remodeling revealed by microfocal x-ray tomography

    NASA Astrophysics Data System (ADS)

    Karau, Kelly L.; Molthen, Robert C.; Johnson, Roger H.; Dhyani, Anita H.; Haworth, Steven T.; Dawson, Christopher A.

    2001-05-01

    Animal models and micro-CT imaging are useful for understanding the functional consequences of, and identifying the genes involved in, the remodeling of vascular structures that accompanies pulmonary vascular disease. Using a micro-CT scanner to image contrast-enhanced arteries in excised lungs from fawn hooded rats (a strain genetically susceptible to hypoxia induced pulmonary hypertension), we found that portions of the pulmonary arterial tree downstream from a given diameter were morphometrically indistinguishable. This 'self-consistency' property provided a means for summarizing the pulmonary arterial tree architecture and mechanical properties using a parameter vector obtained from measurements of the contiguous set of vessel segments comprising the longest (principal) pathway and its branches over a range of vascular pressures. This parameter vector was used to characterize the pulmonary vascular remodeling that occurred in rats exposed to a hypoxic (11.5% oxygen) environment and provided the input to a hemodynamic model relating structure to function. The major effect of the remodeling was a longitudinally (pulmonary artery to arterioles) uniform decrease in vessel distensibility that resulted in a 90% increase in arterial resistance. Despite the almost uniform change in vessel distensibility, over 50% of the resistance increase was attributable to vessels with unstressed diameters less than 125 microns.

  2. Vascular ring

    MedlinePlus

    ... with aberrant subclavian and left ligamentum ateriosus; Congenital heart defect - vascular ring; Birth defect heart - vascular ring ... accounts for less than 1% of all congenital heart problems. The condition occurs as often in males ...

  3. Immunoregulation of bone remodelling

    PubMed Central

    Singh, Ajai; Mehdi, Abbass A; Srivastava, Rajeshwer N; Verma, Nar Singh

    2012-01-01

    Remodeling, a continuous physiological process maintains the strength of the bones, which maintains a delicate balance between bone formation and resorption process. This review gives an insight to the complex interaction and correlation between the bone remodeling and the corresponding changes in host immunological environment and also summarises the most recent developments occuring in the understanding of this complex field. T cells, both directly and indirectly increase the expression of receptor activator of nuclear factor kB ligand (RANKL); a vital step in the activation of osteoclasts, thus positively regulates the osteoclastogenesis. Though various cytokines, chemikines, transcription factors and co-stimulatory molecules are shared by both skeletal and immune systems, but researches are being conducted to establish and analyse their role and / or control on this complex but vital process. The understanding of this part of research may open new horizons in the management of inflammatory and autoimmune diseases, resulting into bone loss and that of osteoporosis also. PMID:22837895

  4. Synaptic circuit remodelling by matrix metalloproteinases in health and disease

    PubMed Central

    Huntley, George W.

    2016-01-01

    Matrix metalloproteinases (MMPs) are extracellularly acting enzymes that have long been known to have deleterious roles in brain injury and disease. In particular, widespread and protracted MMP activity can contribute to neuronal loss and synaptic dysfunction. However, recent studies show that rapid and focal MMP-mediated proteolysis proactively drives synaptic structural and functional remodelling that is crucial for ongoing cognitive processes. Deficits in synaptic remodelling are associated with psychiatric and neurological disorders, and aberrant MMP expression or function may contribute to the molecular mechanisms underlying these deficits. This Review explores the paradigm shift in our understanding of the contribution of MMPs to normal and abnormal synaptic plasticity and function. PMID:23047773

  5. Radiologic atlas of pulmonary abnormalities in children

    SciTech Connect

    Singleton, E.B.; Wagner, M.L.; Dutton, R.V.

    1988-01-01

    This book is an atlas about thoracic abnormalities in infants and children. The authors include computed tomographic, digital subtraction angiographic, ultrasonographic, and a few magnetic resonance (MR) images. They recognize and discuss how changes in the medical treatment of premature infants and the management of infection and pediatric tumors have altered some of the appearances and considerations in these diseases. Oriented toward all aspects of pulmonary abnormalities, the book starts with radiographic techniques and then discusses the normal chest, the newborn, infections, tumors, and pulmonary vascular diseases. There is comprehensive treatment of mediastinal abnormalities and a discussion of airway abnormalities.

  6. Remodeling and Shuttling

    PubMed Central

    Rodrigueza, Wendi V.; Williams, Kevin Jon; Rothblat, George H.; Phillips, Michael C.

    2016-01-01

    In normal physiology, cells are exposed to cholesterol acceptors of different sizes simultaneously. The current study examined the possible interactions between two different classes of acceptors, one large (large unilamellar phospholipid vesicles, LUVs) and one small (HDL or other small acceptors), added separately or in combination to Fu5AH rat hepatoma cells. During a 24-hour incubation, LUVs of palmitoyl-oleoyl phosphatidylcholine at 1 mg phospholipid (PL) per milliliter extracted ≈20% of cellular unesterified cholesterol (UC) label and mass in a slow, continuous fashion (half-time [t½] for UC efflux was ≈50 hours) and human HDL3 at 25 μg PL per milliliter extracted ≈15% cellular UC label with no change in cellular cholesterol mass (t½ of ≈8 hours). In contrast, the combination of LUVs and HDL3 extracted over 90% of UC label (t½ of ≈4 hours) and ≈50% of the UC mass, indicating synergy. To explain this synergy, specific particle interactions were examined, namely, remodeling, in which the two acceptors alter each other’s composition and thus the ability to mobilize cellular cholesterol, and shuttling, in which the small acceptor ferries cholesterol from cells to the large acceptor. To examine remodeling, LUVs and HDL were coincubated and reisolated before application to cells. This HDL became UC depleted, PL enriched, and lost a small amount of apolipoprotein A-I. Compared with equivalent numbers of control HDL particles, remodeled HDL caused faster efflux (t½ ≈4 hours) and exhibited a greater capacity to sequester cellular cholesterol over 24 hours (≈38% versus ≈15% for control HDL), consistent with their enrichment in PL. Remodeled LUVs still extracted ≈20% of cellular UC. Thus, remodeling accounted for some but not all of the synergy between LUVs and HDL. To examine shuttling, several approaches were used. First, reisolation of particles after an 8-hour exposure to cells revealed that HDL contained very little of the cellular UC

  7. Vascular smooth muscle in hypertension.

    PubMed

    Winquist, R J; Webb, R C; Bohr, D F

    1982-06-01

    The cause of the elevated arterial pressure in most forms of hypertension is an increase in total peripheral resistance. This brief review is directed toward an assessment of recent investigations contributing information about the factors responsible for this increased vascular resistance. Structural abnormalities in the vasculature that characterize the hypertensive process are 1) changes in the vascular media, 2) rarefication of the resistance vessels, and 3) lesions of the intimal vascular surface. These abnormalities are mainly the result of an adaptive process and are secondary to the increase in wall stress and/or to pathological damage to cellular components in the vessel wall. Functional alterations in the vascular smooth muscle are described as changes in agonist-smooth muscle interaction or plasma membrane permeability. These types of changes appear to play a primary, initiating role in the elevation of vascular resistance of hypertension. These alterations are not the result of an increase in wall stress and they often precede the development of high blood pressure. The functional changes are initiated by abnormal function of neurogenic, humoral, and/or myogenic changes that alter vascular smooth muscle activity. PMID:6282652

  8. Remodeling with the sun

    SciTech Connect

    Bodzin, S.

    1997-05-01

    Remodeling is the perfect time to improve daylighting, direct gain heating and shading with passive solar techniques. It can also provide the best opportunity to add solar water heating or even photoboltaics to a home. This article describes addition of such energy efficient plans to a home in terms of what is needed and what the benefits are: adding windows, North glass, east and west glass, south glass, daylighting, the roof, shingles and roofing tiles, walls and floors, solar hot water, photovoltaics. Two side bars discuss the sunplace: a passive solar room and angles and overhangs.

  9. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling.

    PubMed

    Hu, Ming Chang; Shi, Mingjun; Cho, Han Jun; Adams-Huet, Beverley; Paek, Jean; Hill, Kathy; Shelton, John; Amaral, Ansel P; Faul, Christian; Taniguchi, Masatomo; Wolf, Myles; Brand, Markus; Takahashi, Masaya; Kuro-O, Makoto; Hill, Joseph A; Moe, Orson W

    2015-06-01

    Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiency-genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-β1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-β1- or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging. PMID:25326585

  10. Apelin Is Required for Non-Neovascular Remodeling in the Retina

    PubMed Central

    McKenzie, Jenny A.G.; Fruttiger, Marcus; Abraham, Sabu; Lange, Clemens A.K.; Stone, Jay; Gandhi, Pranita; Wang, Xiaomeng; Bainbridge, James; Moss, Stephen E.; Greenwood, John

    2012-01-01

    Retinal pathologies are frequently accompanied by retinal vascular responses, including the formation of new vessels by angiogenesis (neovascularization). Pathological vascular changes may also include less well characterized traits of vascular remodeling that are non-neovascular, such as vessel pruning and the emergence of dilated and tortuous vessel phenotypes (telangiectasis). The molecular mechanisms underlying neovascular growth versus non-neovascular remodeling are poorly understood. We therefore undertook to identify novel regulators of non-neovascular remodeling in the retina by using the dystrophic Royal College of Surgeons (RCS) rat and the retinal dystrophy 1 (RD1) mouse, both of which display pronounced non-neovascular remodeling. Gene expression profiling of isolated retinal vessels from these mutant rodent models and wild-type controls revealed 60 differentially expressed genes. These included the genes for apelin (Apln) and for its receptor (Aplnr), both of which were strongly up-regulated in the mutants. Crossing RD1 mice into an Apln-null background substantially reduced vascular telangiectasia. In contrast, Apln gene deletion had no effect in two models of neovascular pathology [laser-induced choroidal neovascularization and the very low density lipoprotein receptor (Vldlr)-knockout mouse]. These findings suggest that in these models apelin has minimal effect on sprouting retinal angiogenesis, but contributes significantly to pathogenic non-neovascular remodeling. PMID:22067912

  11. Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling

    PubMed Central

    Chow, Kelsey; Fessel, Joshua P.; KaoriIhida-Stansbury; Schmidt, Eric P.; Gaskill, Christa; Alvarez, Diego; Graham, Brian; Harrison, David G.; Wagner, David H.; Nozik-Grayck, Eva; West, James D.; Klemm, Dwight J.; Majka, Susan M.

    2013-01-01

    Pulmonary vascular remodeling and oxidative stress are common to many adult lung diseases. However, little is known about the relevance of lung mesenchymal stem cells (MSCs) in these processes. We tested the hypothesis that dysfunctional lung MSCs directly participate in remodeling of the microcirculation. We employed a genetic model to deplete extracellular superoxide dismutase (EC-SOD) in lung MSCs coupled with lineage tracing analysis. We crossed floxpsod3 and mT/mG reporter mice to a strain expressing Cre recombinase under the control of the ABCG2 promoter. We demonstrated In vivo that depletion of EC-SOD in lung MSCs resulted in their contribution to microvascular remodeling in the smooth muscle actin positive layer. We further characterized lung MSCs to be multipotent vascular precursors, capable of myofibroblast, endothelial and pericyte differentiation in vitro. EC-SOD deficiency in cultured lung MSCs accelerated proliferation and apoptosis, restricted colony-forming ability, multilineage differentiation potential and promoted the transition to a contractile phenotype. Further studies correlated cell dysfunction to alterations in canonical Wnt/β-catenin signaling, which were more evident under conditions of oxidative stress. Our data establish that lung MSCs are a multipotent vascular precursor population, a population which has the capacity to participate in vascular remodeling and their function is likely regulated in part by the Wnt/β-catenin signaling pathway. These studies highlight an important role for microenviromental regulation of multipotent MSC function as well as their potential to contribute to tissue remodeling. PMID:23662173

  12. To Remodel or To Build?

    ERIC Educational Resources Information Center

    Rosenblum, Todd

    2009-01-01

    The question of remodeling an existing house to make it wheelchair accessible or building a new barrier-free house is a difficult decision. This article presents some initial questions and considerations followed by a list of pros and cons for remodeling an existing house vs. building a new house.

  13. No-Regrets Remodeling, 2nd Edition

    SciTech Connect

    2013-12-01

    No-Regrets Remodeling, sponsored by Oak Ridge National Laboratory, is an informative publication that walks homeowners and/or remodelers through various home remodeling projects. In addition to remodeling information, the publication provides instruction on how to incorporate energy efficiency into the remodeling process. The goal of the publication is to improve homeowner satisfaction after completing a remodeling project and to provide the homeowner with a home that saves energy and is comfortable and healthy.

  14. Vascular stiffness in insulin resistance and obesity

    PubMed Central

    Jia, Guanghong; Aroor, Annayya R.; DeMarco, Vincent G.; Martinez-Lemus, Luis A.; Meininger, Gerald A.; Sowers, James R.

    2015-01-01

    Obesity, insulin resistance, and type 2 diabetes are associated with a substantially increased prevalence of vascular fibrosis and stiffness, with attendant increased risk of cardiovascular and chronic kidney disease. Although the underlying mechanisms and mediators of vascular stiffness are not well understood, accumulating evidence supports the role of metabolic and immune dysregulation related to increased adiposity, activation of the renin angiotensin aldosterone system, reduced bioavailable nitric oxide, increased vascular extracellular matrix (ECM) and ECM remodeling in the pathogenesis of vascular stiffness. This review will give a brief overview of the relationship between obesity, insulin resistance and increased vascular stiffness to provide a contemporary understanding of the proposed underlying mechanisms and potential therapeutic strategies. PMID:26321962

  15. Engineering clinically relevant volumes of vascularized bone

    PubMed Central

    Roux, Brianna M; Cheng, Ming-Huei; Brey, Eric M

    2015-01-01

    Vascularization remains one of the most important challenges that must be overcome for tissue engineering to be consistently implemented for reconstruction of large volume bone defects. An extensive vascular network is needed for transport of nutrients, waste and progenitor cells required for remodelling and repair. A variety of tissue engineering strategies have been investigated in an attempt to vascularize tissues, including those applying cells, soluble factor delivery strategies, novel design and optimization of bio-active materials, vascular assembly pre-implantation and surgical techniques. However, many of these strategies face substantial barriers that must be overcome prior to their ultimate translation into clinical application. In this review recent progress in engineering vascularized bone will be presented with an emphasis on clinical feasibility. PMID:25877690

  16. 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. PMID:26178373

  17. Vascular rings.

    PubMed

    Backer, Carl L; Mongé, Michael C; Popescu, Andrada R; Eltayeb, Osama M; Rastatter, Jeffrey C; Rigsby, Cynthia K

    2016-06-01

    The term vascular ring refers to congenital vascular anomalies of the aortic arch system that compress the esophagus and trachea, causing symptoms related to those two structures. The most common vascular rings are double aortic arch and right aortic arch with left ligamentum. Pulmonary artery sling is rare and these patients need to be carefully evaluated for frequently associated tracheal stenosis. Another cause of tracheal compression occurring only in infants is the innominate artery compression syndrome. In the current era, the diagnosis of a vascular ring is best established by CT imaging that can accurately delineate the anatomy of the vascular ring and associated tracheal pathology. For patients with a right aortic arch there recently has been an increased recognition of a structure called a Kommerell diverticulum which may require resection and transfer of the left subclavian artery to the left carotid artery. A very rare vascular ring is the circumflex aorta that is now treated with the aortic uncrossing operation. Patients with vascular rings should all have an echocardiogram because of the incidence of associated congenital heart disease. We also recommend bronchoscopy to assess for additional tracheal pathology and provide an assessment of the degree of tracheomalacia and bronchomalacia. The outcomes of surgical intervention are excellent and most patients have complete resolution of symptoms over a period of time. PMID:27301603

  18. Chromatin remodeling in cardiovascular development and physiology

    PubMed Central

    Han, Pei; Hang, Calvin T.; Yang, Jin; Chang, Ching-Pin

    2010-01-01

    Chromatin regulation provides an important means of controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various transcription factors in the fine regulation of gene expression, essential for all aspects of cardiovascular biology. Aberrant cardiac gene expression, triggered by a variety of pathological insults, can cause heart diseases in both animals and humans. The severity of cardiomyopathy and heart failure correlates strongly with abnormal cardiac gene expression. Therefore, controlling cardiac gene expression presents a promising approach to the treatment of human cardiomyopathy. This review focuses on the roles of ATP-dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression during cardiovascular development and disease. PMID:21293009

  19. Vascular Tumors

    PubMed Central

    Sepulveda, Abel; Buchanan, Edward P.

    2014-01-01

    Vascular anomalies are divided into two main groups: tumors and malformations. Vascular tumors are a large and complex group of lesions, especially for clinicians with none or little experience in this field. In the past, these lesions caused a great deal of confusion because many appear analogous to the naked eye. Thankfully, recent advances in diagnostic techniques have helped the medical community to enhance our comprehension, accurately label, diagnose, and treat these lesions. In this article, we will review the most frequent vascular tumors and provide the reader with the tools to properly label, diagnose, and manage these complex lesions. PMID:25045329

  20. A Novel Algorithm to Quantify Coronary Remodeling Using Inferred Normal Dimensions

    PubMed Central

    Falcão, Breno A. A.; Falcão, João Luiz A. A.; Morais, Gustavo R.; Silva, Rafael C.; Lopes, Augusto C.; Soares, Paulo R.; Mariani Jr, José; Kalil-Filho, Roberto; Edelman, Elazer R.; Lemos, Pedro A.

    2015-01-01

    Background Vascular remodeling, the dynamic dimensional change in face of stress, can assume different directions as well as magnitudes in atherosclerotic disease. Classical measurements rely on reference to segments at a distance, risking inappropriate comparison between dislike vessel portions. Objective to explore a new method for quantifying vessel remodeling, based on the comparison between a given target segment and its inferred normal dimensions. Methods Geometric parameters and plaque composition were determined in 67 patients using three-vessel intravascular ultrasound with virtual histology (IVUS-VH). Coronary vessel remodeling at cross-section (n = 27.639) and lesion (n = 618) levels was assessed using classical metrics and a novel analytic algorithm based on the fractional vessel remodeling index (FVRI), which quantifies the total change in arterial wall dimensions related to the estimated normal dimension of the vessel. A prediction model was built to estimate the normal dimension of the vessel for calculation of FVRI. Results According to the new algorithm, “Ectatic” remodeling pattern was least common, “Complete compensatory” remodeling was present in approximately half of the instances, and “Negative” and “Incomplete compensatory” remodeling types were detected in the remaining. Compared to a traditional diagnostic scheme, FVRI-based classification seemed to better discriminate plaque composition by IVUS-VH. Conclusion Quantitative assessment of coronary remodeling using target segment dimensions offers a promising approach to evaluate the vessel response to plaque growth/regression. PMID:26559986

  1. Measuring Vascular Permeability In Vivo.

    PubMed

    Meijer, Eelco F J; Baish, James W; Padera, Timothy P; Fukumura, Dai

    2016-01-01

    Over the past decades, in vivo vascular permeability measurements have provided significant insight into vascular functions in physiological and pathophysiological conditions such as the response to pro- and anti-angiogenic signaling, abnormality of tumor vasculature and its normalization, and delivery and efficacy of therapeutic agents. Different approaches for vascular permeability measurements have been established. Here, we describe and discuss a conventional 2D imaging method to measure vascular permeability, which was originally documented by Gerlowski and Jain in 1986 (Microvasc Res 31:288-305, 1986) and further developed by Yuan et al. in the early 1990s (Microvasc Res 45:269-289, 1993; Cancer Res 54:352-3356, 1994), and our recently developed 3D imaging method, which advances the approach originally described by Brown et al. in 2001 (Nat Med 7:864-868, 2001). PMID:27581015

  2. Diabetes and Retinal Vascular Dysfunction

    PubMed Central

    Shin, Eui Seok; Sorenson, Christine M.; Sheibani, Nader

    2014-01-01

    Diabetes predominantly affects the microvascular circulation of the retina resulting in a range of structural changes unique to this tissue. These changes ultimately lead to altered permeability, hyperproliferation of endothelial cells and edema, and abnormal vascularization of the retina with resulting loss of vision. Enhanced production of inflammatory mediators and oxidative stress are primary insults with significant contribution to the pathogenesis of diabetic retinopathy (DR). We have determined the identity of the retinal vascular cells affected by hyperglycemia, and have delineated the cell autonomous impact of high glucose on function of these cells. We discuss some of the high glucose specific changes in retinal vascular cells and their contribution to retinal vascular dysfunction. This knowledge provides novel insight into the molecular and cellular defects contributing to the development and progression of diabetic retinopathy, and will aid in the development of innovative, as well as target specific therapeutic approaches for prevention and treatment of DR. PMID:25667739

  3. Vascular Diseases

    MedlinePlus

    ... heart and blood vessels, such as diabetes or high cholesterol Smoking Obesity Losing weight, eating healthy foods, being active and not smoking can help vascular disease. Other treatments include medicines and surgery.

  4. Tribbles 3: A potential player in diabetic aortic remodelling.

    PubMed

    Ti, Yun; Xie, Guo-lu; Wang, Zhi-hao; Ding, Wen-yuan; Zhang, Yun; Zhong, Ming; Zhang, Wei

    2016-01-01

    Tribbles 3, whose expression is up-regulated by insulin resistance, was confirmed to be involved in diabetic cardiomyopathy in our previous study. However, it is not known whether Tribbles 3 has a role on conduit arteries such as the aorta in diabetes. Type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of diabetic rats by serial ultrasonography and histopathologic analyses of aortic wall architecture. Diabetic rats displayed increased aortic medial thickness, excessive collagen deposition, diminished elastic fibres and reduced vascular compliance together with Tribbles 3 overexpression. To further investigate the role of Tribbles 3 in aortic remodelling, we used Tribbles 3 gene silencing in vivo 12 weeks after onset of diabetes. Silence of Tribbles 3 significantly reversed pathological aortic remodelling without blood pressure modification. In Tribbles 3-small interfering RNA group, medial thickness and perivascular fibrosis were markedly decreased; moreover, there were prominent reductions in collagen content and collagen/elastin ratio, resulting in an improved arterial compliance. Additionally, with Tribbles 3 silencing, the diminished phosphorylation of PI3K/Akt was restored, and increased activation of MKK4/JNK was decreased. Silence of Tribbles 3 is potent in mediating reversal of aortic remodelling, implicating that Tribbles 3 is proposed to be a potential therapeutic target for vascular complication in diabetes. PMID:26410836

  5. Plant cell remodeling by autophagy

    PubMed Central

    Kim, Jimi; Lee, Han Nim; Chung, Taijoon

    2014-01-01

    Plant seedlings are not photoautotrophs until they are equipped with photosynthetic machinery. Some plant cells are remodeled after being exposed to light, and a group of peroxisomal proteins are degraded during the remodeling. Autophagy was proposed as one of the mechanisms for the degradation of peroxisomal proteins. We recently showed that ATG7-dependent autophagy is partially responsible for the degradation of obsolete peroxisomal proteins during Arabidopsis seedling growth. PMID:24492493

  6. Relationship between self-reported residential indoor remodeling and semen quality: a case-control study

    PubMed Central

    Miao, Mao-Hua; Li, Zheng; Li, De-Kun; Yan, Bei; Liang, Hong; Zhi, Er-Lei; Du, Hong-Wei; Yuan, Wei

    2015-01-01

    The present study examined the association between residential indoor remodeling and poor semen quality. Sperm donors aged 18–45 years old were recruited in Shanghai, China. Semen specimens were collected and analyzed. An in-person interview was conducted to obtain information on the history of indoor remodeling and potential confounders. A total of 70 participants with abnormal semen quality (case group) and 68 controls were examined. A total of 20 subjects reported indoor remodeling in the recent 24 months, and among them 17 subjects reported indoor remodeling in the recent 12 months. Compared with participants with no history of indoor remodeling, participants with a history of indoor remodeling in the recent 24 months were more than three times as likely to have poor sperm quality (adjusted odds ratio = 3.8, 95% confidence interval: 1.3–12.0) after controlling for potential confounders. The association was strengthened when the analysis was restricted to those who had indoor remodeling in the recent 12 months. Our findings provide preliminary evidence that indoor remodeling has an adverse effect on semen quality. PMID:25432500

  7. 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. PMID:25937473

  8. Sonic hedgehog is required for the assembly and remodeling of branchial arch blood vessels.

    PubMed

    Kolesová, Hana; Roelink, Henk; Grim, Milos

    2008-07-01

    Sonic hedgehog (Shh) is a morphogen involved in many developmental processes. Injection of cells (5E1) that produce a Shh-blocking antibody causes an attenuation of the Shh response, and this causes vascular malformations and impaired remodeling characterized by hemorrhages and protrusions of the anterior cardinal vein and outflow tract, delayed fusion of the dorsal aortae, impaired branching of the internal carotid artery, and delayed remodeling of the aortic arches. Distribution of smooth muscle cells in the vessel wall is unchanged. In 5E1-injected embryos, we also observed impaired assembly of endothelial cells into vascular tubes, particularly in the sixth branchial arch, around the anterior cardinal vein and around the dorsal aorta. In 5E1-treated embryos, increased numbers of macrophage-like cells, apoptotic cells, and a decreased level of proliferation were observed in head mesenchyme. Together, these observations show that Shh signaling is required at multiple stages for proper vessel formation and remodeling. PMID:18570256

  9. Pathogenic arterial remodeling: the good and bad of microRNAs.

    PubMed

    Wei, Yuanyuan; Schober, Andreas; Weber, Christian

    2013-04-15

    A number of cardiovascular diseases, such as restenosis, aneurysm, and atherosclerosis, lead to vascular remodeling associated with complex adaptive reactions of different cell populations. These reactions include growth of smooth muscle cells, proliferation of endothelial cells, and the inflammatory response of macrophages. MicroRNAs (miRNAs), a class of short RNAs, play key roles in various biological processes and in the development of human disease by post-transcriptional regulation of gene expression. Here, we review the molecular mechanisms of a subset of miRNAs involved in vascular remodeling, including miR-143/145, miR-221/222, miR-126, miR-21, and miR-155. Some of these miRNAs, such as miR-143/145 and miR-126, have been shown to be protective during vascular remodeling, whereas others, such as miR-21, may promote the cellular response that leads to neointima formation. The increasing knowledge regarding the roles of miRNAs in vascular remodeling opens novel avenues for the treatment of various cardiovascular diseases. However, more in vivo studies on the functional roles of these miRNAs are required in the future. PMID:23396454

  10. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

    PubMed Central

    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula

    2016-01-01

    Background Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. Objective The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Methods Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. Results TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. Conclusion TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis. PMID:27096523

  11. Remodeling Components of the Tumor Microenvironment to Enhance Cancer Therapy

    PubMed Central

    Gkretsi, Vasiliki; Stylianou, Andreas; Papageorgis, Panagiotis; Polydorou, Christiana; Stylianopoulos, Triantafyllos

    2015-01-01

    Solid tumor pathophysiology is characterized by an abnormal microenvironment that guides tumor progression and poses barriers to the efficacy of cancer therapies. Most common among tumor types are abnormalities in the structure of the tumor vasculature and stroma. Remodeling the tumor microenvironment with the aim to normalize any aberrant properties has the potential to improve therapy. In this review, we discuss structural abnormalities of the tumor microenvironment and summarize the therapeutic strategies that have been developed to normalize tumors as well as their potential to enhance therapy. Finally, we present different in vitro models that have been developed to analyze and better understand the effects of the tumor microenvironment on cancer cell behavior. PMID:26528429

  12. Characterization of vascular tree architecture using the Tokunaga taxonomy

    NASA Astrophysics Data System (ADS)

    Galarreta-Valverde, Miguel A.; Zoghbi, Jihan M.; Pereira, Fabricio; Beregi, Jean-Paul; Mekkaoui, Choukri; Jackowski, Marcel P.

    2015-03-01

    The diagnosis of cardiovascular disease is usually assisted by resonance angiography (MRA) or computed tomography angiography (CTA) imaging. The identification of abnormal vascular architecture from angiographic three-dimensional images is therefore crucial to the diagnosis of cardiovascular disease. Automated detection and quantification of vascular structure and architecture thus holds significant clinical value. In this work, we employ a Lindenmayer system to represent vascular trees from angiographic images and describe a quantitative measure based on the Tokunaga taxonomy to differentiate vascular architectures. Synthetic vessel architectures with varying bifurcation patterns were compared and results showed that this architectural measure is proportional to the level of branching. In real MRA images, this measure was able to differentiate between normal and abnormal intracerebral vasculature containing an aneurysm. Hence, this methodology not only allows for compact representation of vascular architectures but also provides a quantitative metric of bifurcation complexity, which has the potential to characterize different types of vascular abnormalities.

  13. Dimethylfumarate attenuates restenosis after acute vascular injury by cell-specific and Nrf2-dependent mechanisms

    PubMed Central

    Oh, Chang Joo; Park, Sungmi; Kim, Joon-Young; Kim, Han-Jong; Jeoung, Nam Ho; Choi, Young-Keun; Go, Younghoon; Park, Keun-Gyu; Lee, In-Kyu

    2014-01-01

    Excessive proliferation of vascular smooth muscle cells (VSMCs) and incomplete re-endothelialization is a major clinical problem limiting the long-term efficacy of percutaneous coronary angioplasty. We tested if dimethylfumarate (DMF), an anti-psoriasis drug, could inhibit abnormal vascular remodeling via NF−E2-related factor 2 (Nrf2)-NAD(P)H quinone oxidoreductase 1 (NQO1) activity. DMF significantly attenuated neointimal hyperplasia induced by balloon injury in rat carotid arteries via suppression of the G1 to S phase transition resulting from induction of p21 protein in VSMCs. Initially, DMF increased p21 protein stability through an enhancement in Nrf2 activity without an increase in p21 mRNA. Later on, DMF stimulated p21 mRNA expression through a process dependent on p53 activity. However, heme oxygenase-1 (HO-1) or NQO1 activity, well-known target genes induced by Nrf2, were dispensable for the DMF induction of p21 protein and the effect on the VSMC proliferation. Likewise, DMF protected endothelial cells from TNF-α-induced apoptosis and the dysfunction characterized by decreased eNOS expression. With knock-down of Nrf2 or NQO1, DMF failed to prevent TNF-α-induced cell apoptosis and decreased eNOS expression. Also, CD31 expression, an endothelial specific marker, was restored in vivo by DMF. In conclusion, DMF prevented abnormal proliferation in VSMCs by G1 cell cycle arrest via p21 upregulation driven by Nrf2 and p53 activity, and had a beneficial effect on TNF-α-induced apoptosis and dysfunction in endothelial cells through Nrf2–NQO1 activity suggesting that DMF might be a therapeutic drug for patients with vascular disease. PMID:25009787

  14. Two-photon imaging of collagen remodeling in RAFT tissue cultures

    NASA Astrophysics Data System (ADS)

    Wallace, Vincent P.; Coleno, Mariah L.; Yomo, Tatsuro; Sun, Chung-Ho; Tromberg, Bruce J.

    2001-04-01

    Tissue remodeling is associated with both normal and abnormal processes including wound healing, fibrosis and cancer. In skin, abnormal remodeling causes permanent structural changes that can lead to hypertropic scarring and keloid formation. Normal remodeling, although fast and efficient in skin, is still imperfect, and a connective tissue scar remains at the wound site1. As a result, methods are needed to optimize tissue remodeling in vivo in all cases of wound repair. Since fibroblast-mediated contraction of engineered 3-D collagen based tissues (RAFTs) represents an in vitro model of the tissue contraction and collagen remodeling that occurs in vivo, RAFT tissue contraction studies combined with two-photon microscopy (TPM) studies are used to provide information on ways to improve tissue remodeling in vivo. In the RAFT models discussed here, tissue contraction is modulated either by application of exogenous growth factors or photodynamic therapy. During tissue contraction, TPM is used to image changes in Collagen Type I fibers in the RAFT skin models. Tissues are imaged at depth at day 15 after modulation. TPM signal analysis shows that RAFT tissues having the highest collagen density have the fastest rate of decay of fluorescent signal with depth.

  15. A gene-centric study of common carotid artery remodelling

    PubMed Central

    Harrison, Seamus C.; Zabaneh, Delilah; Asselbergs, Folkert W.; Drenos, Fotios; Jones, Gregory T.; Shah, Sonia; Gertow, Karl; Sennblad, Bengt; Strawbridge, Rona J.; Gigante, Bruna; Holewijn, Suzanne; De Graaf, Jacqueline; Vermeulen, Sita; Folkersen, Lasse; van Rij, Andre M.; Baldassarre, Damiano; Veglia, Fabrizio; Talmud, Philippa J.; Deanfield, John E.; Agu, Obi; Kivimaki, Mika; Kumari, Meena; Bown, Matthew J.; Nyyssönen, Kristiina; Rauramaa, Rainer; Smit, Andries J.; Franco-Cereceda, Anders; Giral, Philippe; Mannarino, Elmo; Silveira, Angela; Syvänen, Ann-Christine; de Borst, Gert J.; van der Graaf, Yolanda; de Faire, Ulf; Baas, Annette F.; Blankensteijn, Jan D.; Wareham, Nicholas J.; Fowkes, Gerry; Tzoulaki, Ionna; Price, Jacqueline F.; Tremoli, Elena; Hingorani, Aroon D.; Eriksson, Per; Hamsten, Anders; Humphries, Steve E.

    2013-01-01

    Background Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development. PMID:23246012

  16. The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice

    PubMed Central

    YU, YING; CAI, ZHAOHUA; CUI, MINGLI; NIE, PENG; SUN, ZHE; SUN, SHIQUN; CHU, SHICHUN; WANG, XIAOLEI; HU, LIUHUA; YI, JING; SHEN, LINGHONG; HE, BEN

    2015-01-01

    Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77-deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77

  17. Synaptic remodeling of neuronal circuits in early retinal degeneration

    PubMed Central

    Soto, Florentina; Kerschensteiner, Daniel

    2015-01-01

    Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies. PMID:26500497

  18. The Notch Ligand Delta-Like 4 Regulates Multiple Stages of Early Hemato-Vascular Development

    PubMed Central

    Neves, Hélia; Gomes, Andreia C.; Saavedra, Pedro; Carvalho, Catarina C.; Duarte, António; Cidadão, António; Parreira, Leonor

    2012-01-01

    Background In mouse embryos, homozygous or heterozygous deletions of the gene encoding the Notch ligand Dll4 result in early embryonic death due to major defects in endothelial remodeling in the yolk sac and embryo. Considering the close developmental relationship between endothelial and hematopoietic cell lineages, which share a common mesoderm-derived precursor, the hemangioblast, and many key regulatory molecules, we investigated whether Dll4 is also involved in the regulation of early embryonic hematopoiesis. Methodology/Principal Findings Using Embryoid Bodies (EBs) derived from embryonic stem cells harboring hetero- or homozygous Dll4 deletions, we observed that EBs from both genotypes exhibit an abnormal endothelial remodeling in the vascular sprouts that arise late during EB differentiation, indicating that this in vitro system recapitulates the angiogenic phenotype of Dll4 mutant embryos. However, analysis of EB development at early time points revealed that the absence of Dll4 delays the emergence of mesoderm and severely reduces the number of blast-colony forming cells (BL-CFCs), the in vitro counterpart of the hemangioblast, and of endothelial cells. Analysis of colony forming units (CFU) in EBs and yolk sacs from Dll4+/− and Dll4−/− embryos, showed that primitive erythropoiesis is specifically affected by Dll4 insufficiency. In Dll4 mutant EBs, smooth muscle cells (SMCs) were seemingly unaffected and cardiomyocyte differentiation was increased, indicating that SMC specification is Dll4-independent while a normal dose of this Notch ligand is essential for the quantitative regulation of cardiomyogenesis. Conclusions/Significance This study highlights a previously unnoticed role for Dll4 in the quantitative regulation of early hemato-vascular precursors, further indicating that it is also involved on the timely emergence of mesoderm in early embryogenesis. PMID:22514637

  19. Scar remodeling after strabismus surgery.

    PubMed Central

    Ludwig, I H

    1999-01-01

    limitation of versions, less separation of the tendons from sclera, and thicker appearance of the scar segments. The use of nonabsorbable sutures in the repair procedure reduced the recurrence rate. Histologic examination of the clinical stretched scar specimens showed dense connective tissue that was less well organized compared with normal tendon. In the tissue culture studies, cells cultured from the stretched scar specimens grew rapidly and were irregularly shaped. A high-molecular-weight protein was identified in the culture medium. By contrast, cells cultured from normal tendon (controls) grew more slowly and regularly, stopped growing at 4 days, and produced less total protein than cultured stretched scar specimens. In the animal model studies, the collagenase-treated sites showed elongated scars with increased collagen between the muscle and the sclera, as well as increased collagen creep rates, compared with the saline-treated controls. The use of nonabsorbable sutures in collagenase-treated animal model surgery sites was associated with shorter, thicker scars compared with similar sites sutured with absorbable sutures. CONCLUSIONS: A lengthened or stretched, remodeled scar between an operated muscle tendon and sclera is a common occurrence and is a factor contributing to the variability of outcome after strabismus repair, even years later. This abnormality may be revealed by careful exploration of previously operated muscles. Definitive repair requires firm reattachment of tendon to sclera with nonabsorbable suture support. Images FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 9 FIGURE 10 FIGURE 11 FIGURE 12 FIGURE 13 FIGURE 14 FIGURE 15 FIGURE 16 FIGURE 17 FIGURE 18 FIGURE 19 FIGURE 20 FIGURE 21 FIGURE 22 FIGURE 23 FIGURE 24 FIGURE 25 FIGURE 26 FIGURE 27 FIGURE 28 FIGURE 29 FIGURE 30 FIGURE 31 FIGURE 32 FIGURE 33 FIGURE 34 FIGURE 35 FIGURE 36 FIGURE 37 FIGURE 38 FIGURE 39 FIGURE 40 FIGURE 41 FIGURE 42 FIGURE 43 FIGURE 44 FIGURE 45 FIGURE 46 FIGURE 52

  20. 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.

  1. Abnormal Head Position

    MedlinePlus

    ... cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal head posture could cause permanent ... occipitocervical synostosis and unilateral hearing loss. Are there any ... postures? Yes. Abnormal head postures can usually be improved depending ...

  2. Urine - abnormal color

    MedlinePlus

    ... straw-yellow. Abnormally colored urine may be cloudy, dark, or blood-colored. Causes Abnormal urine color may ... red blood cells, or mucus in the urine. Dark brown but clear urine is a sign of ...

  3. [Vascular parkinsonism].

    PubMed

    Yamanouchi, H

    1997-01-01

    Critchley speculated that multiple vascular lesions of the basal ganglia must have an etiological connection to the symptoms of so-called vascular parkinsonism (VP), but without neuropathological confirmation. Some had doubts about its existence because of the lack of the pathologically confirmed case with adequate clinical correlation. At present, VP is characterized clinically by the short-stepped or frozen gait, lead-pipe rigidity, the symmetry of findings, absence of resting tremor, and negative response to levodopa in elderly patients with cerebrovascular lesions on CT/MRI. Pseudobulbar palsies, pyramidal tract findings, and/or multi-infarct dementia coexist in some of the cases. Most of clinically suspected VP patients have cerebral white matter lesions as well as basal ganglia lesions. PMID:9014431

  4. Mechanisms of Cardiovascular Remodeling in Hyperhomocysteinemia

    PubMed Central

    Steed, Mesia M.

    2011-01-01

    Abstract In hypertension, an increase in arterial wall thickness and loss of elasticity over time result in an increase in pulse wave velocity, a direct measure of arterial stiffness. This change is reflected in gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers in the media that occurs independently of atherosclerosis. Similar results are seen with an elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), which increases vascular thickness, elastin fragmentation, and arterial blood pressure. Studies from our laboratory have demonstrated a decrease in elasticity and an increase in pulse wave velocity in HHcy cystathionine β synthase heterozygote knockout (CBS−/+) mice. Nitric oxide (NO) is a potential regulator of matrix metalloproteinase (MMP) activity in MMP-NO-TIMP (tissue inhibitor of metalloproteinase) inhibitory tertiary complex. We have demonstrated the contribustion of the NO synthase (NOS) isoforms, endothelial NOS and inducible NOS, in the activation of latent MMP. The differential production of NO contributes to oxidative stress and increased oxidative/nitrative activation of MMP resulting in vascular remodeling in response to HHcy. The contribution of the NOS isoforms, endothelial and inducible in the collagen/elastin switch, has been demonstrated. We have showed that an increase in inducible NOS activity is a key contributor to HHcy-mediated collagen/elastin switch and resulting decline in aortic compliance. In addition, increased levels of Hcy compete and suppress the γ-amino butyric acid-receptor, N-methyl-d-aspartame-receptor, and peroxisome proliferator-activated receptor. The HHcy causes oxidative stress by generating nitrotyrosine, activating the latent MMPs and decreasing the endothelial NO concentration. The HHcy causes elastinolysis and decrease elastic complicance of the vessel wall. The treatment with γ-amino butyric acid-receptor agonist (muscimol), N

  5. The inter-connection between fibrosis and microvascular remodeling in idiopathic pulmonary fibrosis: Reality or just a phenomenon

    PubMed Central

    Mlika, Mona; Bacha, Saoussen; Braham, Emna; El Mezni, Faouzi

    2015-01-01

    Background Idiopathic pulmonary fibrosis is the most frequent interstitial disease with the worst prognosis. It is characterized by an uncontrolled fibrosis which is difficult to manage. The pathogenesis of this disease remains unclear with many theories resulting in multiple target therapies. The relation between fibrosis and vascular remodeling has been debated in the literature with different results that may seem contradictory. Aim We target to evaluate the connection between fibrosis and vascular remodeling in usual interstitial pneumonia. Material and methods 26 cases of idiopathic pulmonary fibrosis were reviewed by 2 pathologists and the diagnosis of UIP was retained according to the American Thoracic Society's criteria. Fibrotic changes and vascular remodeling were evaluated blindly. The fibrotic changes were classified as severe, intermediate and mild. Vascular occlusion was graded in 4 grades extending from medial hypertrophy (grade 1) to plexiform lesions of the vascular wall (grade 4). Results We noticed that severe degrees of fibrosis were correlated with severe grades of vascular obstruction. In fact, our 26 cases were classified as severe fibrosis in 11 cases with grade IV vascular lesions in 6 cases, intermediate fibrosis in 12 cases with grade II vascular lesions in 8 cases and mild fibrosis in 3 cases with grade I vascular lesions in all cases. Conclusion Many theories have been reported concerning the UIP's pathogenesis. Recently, many authors reported that the primum movens of these lesions was an epithelial/endothelial injury which induces uncontrolled fibrosis and microvascular remodeling using different pathways. This puts emphasis on the necessity of multi-target therapies in order to improve the management of this fatal disease. PMID:27222781

  6. Rho Kinases and Cardiac Remodeling.

    PubMed

    Shimizu, Toru; Liao, James K

    2016-06-24

    Hypertensive cardiac remodeling is characterized by left ventricular hypertrophy and interstitial fibrosis, which can lead to heart failure with preserved ejection fraction. The Rho-associated coiled-coil containing kinases (ROCKs) are members of the serine/threonine protein kinase family, which mediates the downstream effects of the small GTP-binding protein RhoA. There are 2 isoforms: ROCK1 and ROCK2. They have different functions in different types of cells and tissues. There is growing evidence that ROCKs contribute to the development of cardiovascular diseases, including cardiac fibrosis, hypertrophy, and subsequent heart failure. Recent experimental studies using ROCK inhibitors, such as fasudil, have shown the benefits of ROCK inhibition in cardiac remodeling. Mice lacking each ROCK isoform also exhibit reduced myocardial fibrosis in a variety of pathological models of cardiac remodeling. Indeed, clinical studies with fasudil have suggested that ROCKs could be potential novel therapeutic targets for cardiovascular diseases. In this review, we summarize the current understanding of the roles of ROCKs in the development of cardiac fibrosis and hypertrophy and discuss their therapeutic potential for deleterious cardiac remodeling. (Circ J 2016; 80: 1491-1498). PMID:27251065

  7. Vascular biology of ageing—Implications in hypertension

    PubMed Central

    Harvey, Adam; Montezano, Augusto C.; Touyz, Rhian M.

    2015-01-01

    Ageing is associated with functional, structural and mechanical changes in arteries that closely resemble the vascular alterations in hypertension. Characteristic features of large and small arteries that occur with ageing and during the development of hypertension include endothelial dysfunction, vascular remodelling, inflammation, calcification and increased stiffness. Arterial changes in young hypertensive patients mimic those in old normotensive individuals. Hypertension accelerates and augments age-related vascular remodelling and dysfunction, and ageing may impact on the severity of vascular damage in hypertension, indicating close interactions between biological ageing and blood pressure elevation. Molecular and cellular mechanisms underlying vascular alterations in ageing and hypertension are common and include aberrant signal transduction, oxidative stress and activation of pro-inflammatory and pro-fibrotic transcription factors. Strategies to suppress age-associated vascular changes could ameliorate vascular damage associated with hypertension. An overview on the vascular biology of ageing and hypertension is presented and novel molecular mechanisms contributing to these processes are discussed. The complex interaction between biological ageing and blood pressure elevation on the vasculature is highlighted. This article is part of a Special Issue entitled: CV Ageing. PMID:25896391

  8. Vascular sphingolipids in physiological and pathological adaptation.

    PubMed

    Bao, Jun-Xiang; Su, Yu-Ting; Cheng, Yao-Ping; Zhang, Hai-Jun; Xie, Xiao-Ping; Chang, Yao-Ming

    2016-01-01

    Sphingolipids (SLs) are compounds containing a long-chain fatty alcohol amine called sphingosine which exists in cellular membranes, cytoplasm, nucleus, interstitial fluid, blood and lymphatic circulation. SLs act as essential constituents of membranes of eukaryotic cells, so the seesaw of SLs will lead to structural alteration of membranes instigating cellular functional change. SLs also act as crucial signaling molecules taking effect intracellularly or extracellularly which regulates activity of downstream molecules determining cellular adaptation to numerous stimulus. This review aims to highlight the contribution of SLs to physiological and pathophysiological remodeling of vasculature. We will first provide a short overview on metabolism, trafficking and compartmentalization of SLs. Then the regulation of SLs on reactive oxygen species (ROS) formation, vascular tone modulation, endothelial barrier integrity, apoptosis and autophagy are summarized. Finally, we will discuss how the SLs are modulated contributing to vascular development, angiogenesis and vascular remodeling in pathological situations as hypertension, atherosclerosis, and aging. The compellingly regulative actions of SLs bring about copious therapeutic targets for potential pharmacological intervention on the diseases involving vascular maladaptation. PMID:27100498

  9. Brain Arterial Diameters as a Risk Factor for Vascular Events

    PubMed Central

    Gutierrez, Jose; Cheung, Ken; Bagci, Ahmet; Rundek, Tatjana; Alperin, Noam; Sacco, Ralph L; Wright, Clinton B; Elkind, Mitchell S V

    2015-01-01

    Background Arterial luminal diameters are routinely used to assess for vascular disease. Although small diameters are typically considered pathological, arterial dilatation has also been associated with disease. We hypothesize that extreme arterial diameters are biomarkers of the risk of vascular events. Methods and Results Participants in the Northern Manhattan Study who had a time-of-flight magnetic resonance angiography were included in this analysis (N=1034). A global arterial Z-score, called the brain arterial remodeling (BAR) score, was obtained by averaging the measured diameters within each individual. Individuals with a BAR score <−2 SDs were considered to have the smallest diameters, individuals with a BAR score >−2 and <2 SDs had average diameters, and individuals with a BAR score >2 SDs had the largest diameters. All vascular events were recorded prospectively after the brain magnetic resonance imaging. Spline curves and incidence rates were used to test our hypothesis. The association of the BAR score with death (P=0.001), vascular death (P=0.02), any vascular event (P=0.05), and myocardial infarction (P=0.10) was U-shaped except for ischemic stroke (P=0.74). Consequently, incidence rates for death, vascular death, myocardial infarction, and any vascular event were higher in individuals with the largest diameters, whereas individuals with the smallest diameters had a higher incidence of death, vascular death, any vascular event, and ischemic stroke compared with individuals with average diameters. Conclusions The risk of death, vascular death, and any vascular event increased at both extremes of brain arterial diameters. The pathophysiology linking brain arterial remodeling to systemic vascular events needs further research. PMID:26251284

  10. The human tri-peptide GHK and tissue remodeling.

    PubMed

    Pickart, Loren

    2008-01-01

    Tissue remodeling follows the initial phase of wound healing and stops inflammatory and scar-forming processes, then restores the normal tissue morphology. The human peptide Gly-(L-His)-(L-Lys) or GHK, has a copper 2+ (Cu(2+)) affinity similar to the copper transport site on albumin and forms GHK-Cu, a complex with Cu(2+). These two molecules activate a plethora of remodeling related processes: (1) chemoattraction of repair cells such as macrophages, mast cells, capillary cells; (2) anti-inflammatory actions (suppression of free radicals, thromboxane formation, release of oxidizing iron, transforming growth factor beta-1, tumor necrosis factor alpha and protein glycation while increasing superoxide dismutase, vessel vasodilation, blocking ultraviolet damage to skin keratinocytes and improving fibroblast recovery after X-ray treatments); (3) increases protein synthesis of collagen, elastin, metalloproteinases, anti-proteases, vascular endothelial growth factor, fibroblast growth factor 2, nerve growth factor, neutrotropins 3 and 4, and erythropoietin; (4) increases the proliferation of fibroblasts and keratinocytes; nerve outgrowth, angiogenesis, and hair follicle size. GHK-Cu stimulates wound healing in numerous models and in humans. Controlled studies on aged skin demonstrated that it tightens skin, improves elasticity and firmness, reduces fine lines, wrinkles, photodamage and hyperpigmentation. GHK-Cu also improves hair transplant success, protects hepatic tissue from tetrachloromethane poisoning, blocks stomach ulcer development, and heals intestinal ulcers and bone tissue. These results are beginning to define the complex biochemical processes that regulate tissue remodeling. PMID:18644225

  11. [Disodium cromoglycate--mast cell degranulation blocker in the process of tissue remodelation].

    PubMed

    Maxová, H; Vasilková, M; Tkaczyk, J; Vízek, M

    2010-01-01

    Disodium cromoglycate (DSCG) is a compound commonly used in the treatment of allergic diseases. The effect of DSCG is due to its ability to stabilize the mast cell membrane and to prevent release of histamine and inflammatory mediators. Mast cells are also an abundant source of tissue metalloproteinases, serine proteases and growth factors, which play an important role in the processes of the tissue remodeling. In this view the DSCG is a substance which allows us to study the mechanisms of the pulmonary vascular bed remodeling in the experimental animals exposed to chronic hypoxia and in a phase of the recovery from hypoxia. PMID:21254664

  12. Obstructive sleep apnea and vascular disease

    PubMed Central

    Lanfranchi, Paola; Somers, Virend A

    2001-01-01

    There is emerging evidence linking obstructive sleep apnea (OSA) to vascular disease, including hypertension. This relationship may be independent of co-morbidity, such as obesity. Even apparently healthy OSA patients have evidence of subtle functional vascular abnormalities that are known to occur in patients with hypertension and atherosclerosis. Untreated OSA may possibly contribute to the initiation and/or progression of pathophysiologic mechanisms involved in hypertension, heart failure, cardiac ischemia and stroke. This brief commentary will examine the evidence and mechanisms linking OSA to vascular disease. PMID:11737928

  13. Actin remodeling by Nck regulates endothelial lumen formation.

    PubMed

    Chaki, Sankar P; Barhoumi, Rola; Rivera, Gonzalo M

    2015-09-01

    Multiple angiogenic cues modulate phosphotyrosine signaling to promote vasculogenesis and angiogenesis. Despite its functional and clinical importance, how vascular cells integrate phosphotyrosine-dependent signaling to elicit cytoskeletal changes required for endothelial morphogenesis remains poorly understood. The family of Nck adaptors couples phosphotyrosine signals with actin dynamics and therefore is well positioned to orchestrate cellular processes required in vascular formation and remodeling. Culture of endothelial cells in three-dimensional collagen matrices in the presence of VEGF stimulation was combined with molecular genetics, optical imaging, and biochemistry to show that Nck-dependent actin remodeling promotes endothelial cell elongation and proper organization of VE-cadherin intercellular junctions. Major morphogenetic defects caused by abrogation of Nck signaling included loss of endothelial apical-basal polarity and impaired lumenization. Time-lapse imaging using a Förster resonance energy transfer biosensor, immunostaining with phospho-specific antibodies, and GST pull-down assays showed that Nck determines spatiotemporal patterns of Cdc42/aPKC activation during endothelial morphogenesis. Our results demonstrate that Nck acts as an important hub integrating angiogenic cues with cytoskeletal changes that enable endothelial apical-basal polarization and lumen formation. These findings point to Nck as an emergent target for effective antiangiogenic therapy. PMID:26157164

  14. Actin remodeling by Nck regulates endothelial lumen formation

    PubMed Central

    Chaki, Sankar P.; Barhoumi, Rola; Rivera, Gonzalo M.

    2015-01-01

    Multiple angiogenic cues modulate phosphotyrosine signaling to promote vasculogenesis and angiogenesis. Despite its functional and clinical importance, how vascular cells integrate phosphotyrosine-dependent signaling to elicit cytoskeletal changes required for endothelial morphogenesis remains poorly understood. The family of Nck adaptors couples phosphotyrosine signals with actin dynamics and therefore is well positioned to orchestrate cellular processes required in vascular formation and remodeling. Culture of endothelial cells in three-dimensional collagen matrices in the presence of VEGF stimulation was combined with molecular genetics, optical imaging, and biochemistry to show that Nck-dependent actin remodeling promotes endothelial cell elongation and proper organization of VE-cadherin intercellular junctions. Major morphogenetic defects caused by abrogation of Nck signaling included loss of endothelial apical-basal polarity and impaired lumenization. Time-lapse imaging using a Förster resonance energy transfer biosensor, immunostaining with phospho-specific antibodies, and GST pull-down assays showed that Nck determines spatiotemporal patterns of Cdc42/aPKC activation during endothelial morphogenesis. Our results demonstrate that Nck acts as an important hub integrating angiogenic cues with cytoskeletal changes that enable endothelial apical-basal polarization and lumen formation. These findings point to Nck as an emergent target for effective antiangiogenic therapy. PMID:26157164

  15. Endothelial Msx1 transduces hemodynamic changes into an arteriogenic remodeling response

    PubMed Central

    Vandersmissen, Ine; Craps, Sander; Depypere, Maarten; Coppiello, Giulia; van Gastel, Nick; Maes, Frederik; Carmeliet, Geert; Schrooten, Jan; Jones, Elizabeth A.V.; Umans, Lieve; Devlieger, Roland; Koole, Michel; Gheysens, Olivier; Zwijsen, An; Aranguren, Xabier L.

    2015-01-01

    Collateral remodeling is critical for blood flow restoration in peripheral arterial disease and is triggered by increasing fluid shear stress in preexisting collateral arteries. So far, no arterial-specific mediators of this mechanotransduction response have been identified. We show that muscle segment homeobox 1 (MSX1) acts exclusively in collateral arterial endothelium to transduce the extrinsic shear stimulus into an arteriogenic remodeling response. MSX1 was specifically up-regulated in remodeling collateral arteries. MSX1 induction in collateral endothelial cells (ECs) was shear stress driven and downstream of canonical bone morphogenetic protein–SMAD signaling. Flow recovery and collateral remodeling were significantly blunted in EC-specific Msx1/2 knockout mice. Mechanistically, MSX1 linked the arterial shear stimulus to arteriogenic remodeling by activating the endothelial but not medial layer to a proinflammatory state because EC but not smooth muscle cellMsx1/2 knockout mice had reduced leukocyte recruitment to remodeling collateral arteries. This reduced leukocyte infiltration in EC Msx1/2 knockout mice originated from decreased levels of intercellular adhesion molecule 1 (ICAM1)/vascular cell adhesion molecule 1 (VCAM1), whose expression was also in vitro driven by promoter binding of MSX1. PMID:26391659

  16. VEGF receptors mediate hypoxic remodeling of adult ovine carotid arteries.

    PubMed

    Adeoye, Olayemi O; Bouthors, Vincent; Hubbell, Margaret C; Williams, James M; Pearce, William J

    2014-10-01

    Recent studies suggest that VEGF contributes to hypoxic remodeling of arterial smooth muscle, although hypoxia produces only transient increases in VEGF that return to normoxic levels despite sustained changes in arterial structure and function. To explore how VEGF might contribute to long-term hypoxic vascular remodeling, this study explores the hypothesis that chronic hypoxia produces sustained increases in smooth muscle VEGF receptor density that mediate long-term vascular effects of hypoxia. Carotid arteries from adult sheep maintained at sea level or altitude (3,820 m) for 110 days were harvested and denuded of endothelium. VEGF levels were similar in chronically hypoxic and normoxic arteries, as determined by immunoblotting. In contrast, VEGF receptor levels were significantly increased by 107% (VEGF-R1) and 156% (VEGF-R2) in hypoxic compared with normoxic arteries. In arteries that were organ cultured 24 h with 3 nM VEGF, VEGF replicated effects of hypoxia on abundances of smooth muscle α actin (SMαA), myosin light chain kinase (MLCK), and MLC20 and the effects of hypoxia on colocalization of MLC20 with SMαA, as measured via confocal microscopy. VEGF did not replicate the effects of chronic hypoxia on colocalization of MLCK with SMαA or MLCK with MLC20, suggesting that VEGF's role in hypoxic remodeling is highly protein specific, particularly for contractile protein organization. VEGF effects in organ culture were inhibited by VEGF receptor blockers vatalinib (240 nM) and dasatinib (6.3 nM). These findings support the hypothesis that long-term upregulation of VEGF receptors help mediate sustained effects of hypoxia on the abundance and colocalization of contractile proteins in arterial smooth muscle. PMID:25038104

  17. Are MPNs vascular diseases?

    PubMed

    Finazzi, Guido; De Stefano, Valerio; Barbui, Tiziano

    2013-12-01

    A high risk of arterial and venous thrombosis is the hallmark of chronic myeloproliferative neoplasms (MPNs), particularly polycythemia vera (PV) and essential thrombocythemia (ET). Clinical aspects, pathogenesis and management of thrombosis in MPN resemble those of other paradigmatic vascular diseases. The occurrence of venous thrombosis in atypical sites, such as the splanchnic district, and the involvement of plasmatic prothrombotic factors, including an acquired resistance to activated protein C, both link MPN to inherited thrombophilia. Anticoagulants are the drugs of choice for these complications. The pathogenic role of leukocytes and inflammation, and the high mortality rate from arterial occlusions are common features of MPN and atherosclerosis. The efficacy and safety of aspirin in reducing deaths and major thrombosis in PV have been demonstrated in a randomized clinical trial. Finally, the Virchow's triad of impaired blood cells, endothelium and blood flow is shared both by MPN and thrombosis in solid cancer. Phlebotomy and myelosuppressive agents are the current therapeutic options for correcting these abnormalities and reducing thrombosis in this special vascular disease represented by MPN. PMID:24037420

  18. [Research in Austria - the Ludwig Boltzmann Institute for Lung Vascular Research].

    PubMed

    Kovacs, G; Kleinschek, D; Kwapiszewska, G; Bálint, Z; Olschewski, H; Olschewski, A

    2016-05-01

    The Ludwig Boltzmann Institute for Lung Vascular Research was founded in 2010 and performs basic and clinical research on the field of chronic pulmonary vascular diseases. The major projects of the institute focus on the investigation of the pathomechanisms of pulmonary vascular remodeling, the development of novel non-invasive diagnostic techniques of pulmonary hypertension and the early detection of pulmonary vascular diseases. The institute closely cooperates with patient organizations and aims to contribute to the development of improved diagnostic and therapeutic approaches for patients with pulmonary vascular diseases. In this short overview the most important results of the first six years of the institute will be summarized. PMID:27168041

  19. Vascular dementia

    PubMed Central

    Korczyn, Amos D; Vakhapova, Veronika; Grinberg, Lea T

    2012-01-01

    The epidemic grow of dementia causes great concern for the society. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, followed by vascular dementia (VaD). This dichotomous view of a neurodegenerative disease as opposed to brain damage caused by extrinsic factors led to separate lines of research in these two entities. Indeed, accumulated data suggest that the two disorders have additive effects and probably interact; however it is still unknown to what degree. Furthermore, epidemiological studies have shown “vascular” risk factors to be associated with AD. Therefore, a clear distinction between AD and VaD cannot be made in most cases, and is furthermore unhelpful. In the absence of efficacious treatment for the neurodegenerative process, special attention must be given to vascular component, even in patients with presumed mixed pathology. Symptomatic treatment of VaD and AD are similar, although the former is less effective. For prevention of dementia it is important to treat aggressively all factors, even in stroke survivors who do not show evidence of cognitive decline,. In this review, we will give a clinical and pathological picture of the processes leading to VaD and discuss it interaction with AD. PMID:22575403

  20. Bone tissue remodeling and development: focus on matrix metalloproteinase functions.

    PubMed

    Paiva, Katiucia Batista Silva; Granjeiro, José Mauro

    2014-11-01

    Bone-forming cells originate from distinct embryological layers, mesoderm (axial and appendicular bones) and ectoderm (precursor of neural crest cells, which mainly form facial bones). These cells will develop bones by two principal mechanisms: intramembranous and endochondral ossification. In both cases, condensation of multipotent mesenchymal cells occurs, at the site of the future bone, which differentiate into bone and cartilage-forming cells. During long bone development, an initial cartilaginous template is formed and replaced by bone in a coordinated and refined program involving chondrocyte proliferation and maturation, vascular invasion, recruitment of adult stem cells and intense remodeling of cartilage and bone matrix. Matrix metalloproteinases (MMPs) are the most important enzymes for cleaving structural components of the extracellular matrix (ECM), as well as other non-ECM molecules in the ECM space, pericellular perimeter and intracellularly. Thus, the bioactive molecules generated act on several biological events, such as development, tissue remodeling and homeostasis. Since the discovery of collagenase in bone cells, more than half of the MMP members have been detected in bone tissues under both physiological and pathological conditions. Pivotal functions of MMPs during development and bone regeneration have been revealed by knockout mouse models, such as chondrocyte proliferation and differentiation, osteoclast recruitment and function, bone modeling, coupling of bone resorption and formation (bone remodeling), osteoblast recruitment and survival, angiogenesis, osteocyte viability and function (biomechanical properties); as such alterations in MMP function may alter bone quality. In this review, we look at the principal properties of MMPs and their inhibitors (TIMPs and RECK), provide an up-date on their known functions in bone development and remodeling and discuss their potential application to Bone Bioengineering. PMID:25157440

  1. Frontiers in growth and remodeling.

    PubMed

    Menzel, Andreas; Kuhl, Ellen

    2012-06-01

    Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID:22919118

  2. Frontiers in growth and remodeling

    PubMed Central

    Menzel, Andreas; Kuhl, Ellen

    2012-01-01

    Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID:22919118

  3. Advances in understanding cartilage remodeling

    PubMed Central

    Li, Yefu; Xu, Lin

    2015-01-01

    Cartilage remodeling is currently among the most popular topics in osteoarthritis research. Remodeling includes removal of the existing cartilage and replacement by neo-cartilage. As a loss of balance between removal and replacement of articular cartilage develops (particularly, the rate of removal surpasses the rate of replacement), joints will begin to degrade. In the last few years, significant progress in molecular understanding of the cartilage remodeling process has been made. In this brief review, we focus on the discussion of some current “controversial” observations in articular cartilage degeneration: (1) the biological effect of transforming growth factor-beta 1 on developing and mature articular cartilages, (2) the question of whether aggrecanase 1 (ADAMTS4) and aggrecanase 2 (ADAMTS5) are key enzymes in articular cartilage destruction, and (3) chondrocytes versus chondron in the development of osteoarthritis. It is hoped that continued discussion and investigation will follow to better clarify these topics. Clarification will be critical for those in search of novel therapeutic targets for the treatment of osteoarthritis. PMID:26380073

  4. Induction of Thoracic Aortic Remodeling by Endothelial-Specific Deletion of MicroRNA-21 in Mice

    PubMed Central

    Zhang, Xing-Yi; Shen, Bao-Rong; Zhang, Yu-Cheng; Wan, Xue-Jiao; Yao, Qing-Ping; Wu, Guang-Liang; Wang, Ji-Yao; Chen, Si-Guo; Yan, Zhi-Qiang; Jiang, Zong-Lai

    2013-01-01

    MicroRNAs (miRs) are known to have an important role in modulating vascular biology. MiR21 was found to be involved in the pathogenesis of proliferative vascular disease. The role of miR21 in endothelial cells (ECs) has well studied in vitro, but the study in vivo remains to be elucidated. In this study, miR21 endothelial-specific knockout mice were generated by Cre/LoxP system. Compared with wild-type mice, the miR21 deletion in ECs resulted in structural and functional remodeling of aorta significantly, such as diastolic pressure dropping, maximal tension depression, endothelium-dependent relaxation impairment, an increase of opening angles and wall-thickness/inner diameter ratio, and compliance decrease, in the miR21 endothelial-specific knockout mice. Furthermore, the miR21 deletion in ECs induced down-regulation of collagen I, collagen III and elastin mRNA and proteins, as well as up-regulation of Smad7 and down-regulation of Smad2/5 in the aorta of miR21 endothelial-specific knockout mice. CTGF and downstream MMP/TIMP changes were also identified to mediate vascular remodeling. The results showed that miR21 is identified as a critical molecule to modulate vascular remodeling, which will help to understand the role of miR21 in vascular biology and the pathogenesis of vascular diseases. PMID:23527070

  5. Internal associations and dynamic expression of c-kit and nanog genes in ventricular remodelling induced by adriamycin

    PubMed Central

    Liu, Zhen; Li, Shuo; Liu, Lingling; Guo, Zhikun; Wang, Pengfei

    2016-01-01

    The present study aimed to investigate the dynamic expression of the c-kit and nanog genes in rats with left ventricular remodelling induced by adriamycin (ADR), and explore its internal association and mechanism of action. Sprague-Dawley male rats were randomly divided into a normal control group and a heart failure model group. Heart failure was induced by a single intraperitoneal injection of ADR (4 mg/kg) weekly for six weeks. The normal control group was given the same amount of saline. At the eighth week, rat cardiac function was examined to demonstrate the formation of heart failure. The rat hearts were harvested frozen and sectioned, and the expression levels of the nanog and c-kit genes in the myocardial tissue samples were detected using immunohistochemistry, immunofluorescence and reverse transcription-polymerase chain reaction (RT-PCR). Hematoxylin and eosin staining demonstrated various pathological changes in the myocardial cells in the heart failure model group, whereas myocardial infarction was not observed in the normal control group. Immunohistochemistry and immunofluorescence demonstrated that nanog-positive cells were predominantly expressed in the vascular endothelium, with a few myocardial cells and stem cells in normal myocardium. The expression levels of c-kit and nanog in the myocardium of the rats with heart failure decreased significantly. c-kit-positive cells clustered together in the epicardium and its vicinity, and c-kit expression significantly decreased in the myocardium of rats with heart failure, as compared with normal rats. In both groups, some cells co-expressed both the c-kit and nanog genes. The RT-PCR results demonstrated that the expression levels of the two genes in the heart failure model group were significantly lower compared with those in the normal control group (P<0.05). In conclusion, the c-kit- and nanog-positive stem cells decreased in the myocardium of the rats with left ventricular remodelling induced by ADR

  6. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... The appearance of normal teeth varies, especially the molars. ... conditions. Specific diseases can affect tooth shape, tooth ...

  7. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... from many different conditions. Specific diseases can affect tooth shape, tooth color, time of appearance, or absence ...

  8. Imperatorin derivative OW1 inhibits the upregulation of TGF-β and MMP-2 in renovascular hypertension-induced cardiac remodeling

    PubMed Central

    ZHOU, NAN; ZHU, YANING; ZHANG, PENG; ZHANG, YU; ZHOU, MINGYAO; WANG, TAO; HE, LANGCHONG

    2016-01-01

    Chronic hypertension induces vascular and cardiac remodeling. OW1 is a novel imperatorin derivative that was previously reported to inhibit vascular remodeling and improve kidney function affected by hypertension. In the present study, the effect of OW1 on the cardiac remodeling induced by hypertension was investigated. OW1 inhibited vascular smooth muscle cell (VSMC) proliferation and the phenotypic modulation of VSMCs induced by angiotensin II (Ang II). The OW1-induced vasodilatation of rat cardiac arteries was evaluated in vitro. Renovascular hypertensive rats were developed using the two-kidney one-clip method and treated with OW1 (40 or 80 mg/kg/day) or nifedipine (30 mg/kg per day) for 5 weeks. OW1 markedly reduced the systolic and diastolic blood pressure compared with that in the hypertension group or the respective baseline value during the first week. OW1 also reduced cardiac weight, and the concentrations of Ang II, aldosterone and transforming growth factor-β1 (TGF-β1). Histological examination demonstrated that OW1 exerted an inhibitory effect on vascular and cardiac remodeling. These inhibitory effects were associated with decreased cardiac levels of Ang II, matrix metalloproteinase-2 and TGF-β1 in the hypertensive rats. In summary, OW1 exhibited a clear antihypertensive effect. More importantly, it inhibited vascular and cardiovascular remodeling, which may reduce the risk of hypertension-induced cardiovascular diseases. These results have potential implications in the development of new antihypertensive drugs. PMID:27168797

  9. A review on the vascular features of the hyperimmunoglobulin E syndrome

    PubMed Central

    Yavuz, H; Chee, R

    2010-01-01

    Autosomal recessive, autosomal dominant and the sporadic forms of hyperimmunoglobulin E syndrome (HIES) are multi-system disorders. Although HIES patients may present with cold abscesses, the vascular features of HIES are not well recognized. The objective of this review is to characterize the nature and spectrum of vascular abnormalities in HIES patients. Vascular abnormalities in HIES patients were reviewed with Medline and Google Scholar-based searches. In brief, the searches combined terms related to HIES with the terms related to vasculature. Furthermore, reference lists from the original studies and review papers identified were screened. There were vascular abnormalities in 25 patients with HIES. These abnormalities were identified as aneurysms (coronary, aortic, carotid and cerebral), pseudoaneurysms, congenital patent ductus venosus, superior vena cava syndrome, vasculitides, vascular ectasia, thrombosis and others. They may be congenital or acquired, in the veins and arteries, affecting both sexes. These abnormalities can be seen in all subtypes of HIES. They could be also fatal in children and adults. Limited pathological investigations revealed the presence of vasculitis. Three of the patients were found to have overlap diseases. In this review, the spectrum of vascular abnormalities in HIES are documented and discussed in detail for the first time. They highlight a previously under-recognized and potentially devastating complication of these disorders. These vascular abnormalities constitute one of the major clinical characteristics in HIES. The presence of hypereosinophilia, vasculitis and defective angiogenesis in HIES may contribute to the formation of vascular abnormalities in HIES. PMID:19912258

  10. Pulsatile Fluid Shear in Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Frangos, John A.

    1997-01-01

    The objective of this investigation was to elucidate the sensitivity to transients in fluid shear stress in bone remodeling. Bone remodeling is clearly a function of the local mechanical environment which includes interstitial fluid flow. Traditionally, load-induced remodeling has been associated with low frequency (1-2 Hz) signals attributed to normal locomotion. McLeod and Rubin, however, demonstrated in vivo remodeling events associated with high frequency (15-30 Hz) loading. Likewise, other in vivo studies demonstrated that slowly applied strains did not trigger remodeling events. We therefore hypothesized that the mechanosensitive pathways which control bone maintenance and remodeling are differentially sensitive to varying rates of applied fluid shear stress.

  11. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  12. Circulating and Vascular Bioactive Factors during Hypertension in Pregnancy

    PubMed Central

    Tanbe, Alain F.; Khalil, Raouf A.

    2010-01-01

    Normal pregnancy is associated with significant vascular remodeling in the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. The pregnancy-associated vascular changes are largely due to alterations in the amount/activity of vascular mediators released from the endothelium, vascular smooth muscle and extracellular matrix. The endothelium releases vasodilator substances such as nitric oxide, prostacyclin and hyperpolarizing factor as well as vasoconstrictor factors such as endothelin, angiotensin II and thromboxane A2. Vascular smooth muscle contraction is mediated by intracellular free Ca2+ concentration ([Ca2+]i), and [Ca2+]i sensitization pathways such as protein kinase C, Rho-kinase and mitogen-activated protein kinase. Extracellular matrix and vascular remodeling are regulated by matrix metalloproteases. Hypertension in pregnancy and preeclampsia are major complications and life threatening conditions to both the mother and fetus, precipitated by various genetic, dietary and environmental factors. The initiating mechanism of preeclampsia and hypertension in pregnancy is unclear; however, most studies have implicated inadequate invasion of cytotrophoblasts into the uterine artery, leading to reduction in the uteroplacental perfusion pressure and placental ischemia/hypoxia. This placental hypoxic state is thought to induce the release of several circulating bioactive factors such as growth factor inhibitors, anti-angiogenic proteins, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and vascular receptor antibodies. Increases in the plasma levels and vascular content of these factors during pregnancy could cause an imbalance in the vascular mediators released from the endothelium, smooth muscle and extracellular matrix, and lead to severe vasoconstriction and hypertension. This review will discuss the interactions between the various circulating bioactive factors and the vascular

  13. The AMPLATZER Vascular Plug 4: Preliminary Experience

    SciTech Connect

    Ferro, Carlo; Rossi, Umberto G. Bovio, Giulio; Petrocelli, Francesco; Seitun, Sara

    2010-08-15

    The purpose of this communication is to describe our preliminary experience with the AMPLATZER Vascular Plug 4 (AVP 4) in peripheral vascular embolization. The AVP 4 was used for peripheral vascular embolization in five patients with renal pseudoaneurysm (n = 2), postsurgical peritoneal bleeding (n = 1), posttraumatic gluteal hemorrhage (n = 1), and intercostal pseudoaneurysm (n = 1). Occlusion time was recorded. Patients were followed up clinically and by imaging for 1 month after the procedure. All treated vessels or vascular abnormalities were successfully occluded within 3 min for low-flow circulation and over 8 min for high-flow circulation. At 1-month follow-up, all patients were symptom-free. All deployed devices remained in the original locations and desirable configurations. In conclusion, the AVP 4 seems to be safe and effective for occluding peripheral vessels and vascular abnormalities. Because of its compatibility with 0.038-in. catheters, it can be deployed through a diagnostic catheter following angiography without exchanging a sheath or guiding catheter. Compared with the previous generation of vascular plugs, the AVP 4 allows for faster procedure times and decreased exposure to radiation.

  14. Emerging translational approaches to target STAT3 signalling and its impact on vascular disease

    PubMed Central

    Dutzmann, Jochen; Daniel, Jan-Marcus; Bauersachs, Johann; Hilfiker-Kleiner, Denise; Sedding, Daniel G.

    2015-01-01

    Acute and chronic inflammation responses characterize the vascular remodelling processes in atherosclerosis, restenosis, pulmonary arterial hypertension, and angiogenesis. The functional and phenotypic changes in diverse vascular cell types are mediated by complex signalling cascades that initiate and control genetic reprogramming. The signalling molecule's signal transducer and activator of transcription 3 (STAT3) plays a key role in the initiation and continuation of these pathophysiological changes. This review highlights the pivotal involvement of STAT3 in pathological vascular remodelling processes and discusses potential translational therapies, which target STAT3 signalling, to prevent and treat cardiovascular diseases. Moreover, current clinical trials using highly effective and selective inhibitors of STAT3 signalling for distinct diseases, such as myelofibrosis and rheumatoid arthritis, are discussed with regard to their vascular (side-) effects and their potential to pave the way for a direct use of these molecules for the prevention or treatment of vascular diseases. PMID:25784694

  15. Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels.

    PubMed

    Pennisi, P; Signorelli, S S; Riccobene, S; Celotta, G; Di Pino, L; La Malfa, T; Fiore, C E

    2004-05-01

    Patients with vascular calcifications often have low bone mineral density (BMD), but it is still uncertain if osteoporosis and peripheral vascular disease (VD) are interrelated and linked by a common pathomechanism. Moreover, data on bone turnover in patients with advanced atherosclerosis are lacking. We measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative bone ultrasound (QUS), as well as the serum levels of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPG) and its ligand RANKL, and the urinary concentration of the C-terminal telopeptides of type I collagen (CrossLaps), in 36 patient (20 male and 16 female) with serious atherosclerotic involvement of the carotid and/or femoral artery to investigate the underlying mechanism of vascular and osseous disorders. Thirty age-matched and gender matched healthy individuals served as controls. After adjustment for age, BMD was significantly reduced at the lumbar spine in 23/36 (63%) patients (mean T score -1.71+/-1.42) and at the proximal femur in 34/36 (93%) patients (neck mean T score -2.5+/-0.88). Ten patients (27%) had abnormal QUS parameters. Gender and diabetes had no effect on the relationship between vascular calcification and bone density at any site measured. VD subjects had OC and BAP serum levels lower than controls (13.3+/-3.1 vs 27.7+/-3.3 ng/ml, P<0.01, and 8.4+/-2.3 vs 12.5+/-1.4 microg/l, P<0.01, respectively). Urinary CrossLaps excretion was not significantly different in patients with VD and in controls (257.9+/-138.9 vs 272.2+/-79.4 micro g/mmol Cr, respectively). Serum OPG and RANKL levels were similar in patients and in controls (3.5+/-1.07 vs 3.4+/-1.05 pmol/l, and 0.37+/-0.07 vs 0.36+/-0.06 pmol/l, respectively). We proved high occurrence of osteoporosis in VD, with evidence of age and gender independence. Negative bone remodelling balance would be a consequence of reduced bone formation, with no apparent increased activation of the OPG-RANKL system

  16. Compartment-specific remodeling of splenic micro-architecture during experimental visceral leishmaniasis.

    PubMed

    Yurdakul, Pinar; Dalton, Jane; Beattie, Lynette; Brown, Najmeeyah; Erguven, Sibel; Maroof, Asher; Kaye, Paul M

    2011-07-01

    Progressive splenomegaly is a hallmark of visceral leishmaniasis in humans, canids, and rodents. In experimental murine visceral leishmaniasis, splenomegaly is accompanied by pronounced changes in microarchitecture, including expansion of the red pulp vascular system, neovascularization of the white pulp, and remodeling of the stromal cell populations that define the B-cell and T-cell compartments. Here, we show that Ly6C/G(+) (Gr-1(+)) cells, including neutrophils and inflammatory monocytes, accumulate in the splenic red pulp during infection. Cell depletion using monoclonal antibody against either Ly6C/G(+) (Gr-1; RB6) or Ly6G(+) (1A8) cells increased parasite burden. In contrast, depletion of Ly6C/G(+) cells, but not Ly6G(+) cells, halted the progressive remodeling of Meca-32(+) and CD31(+) red pulp vasculature. Strikingly, neither treatment affected white pulp neovascularization or the remodeling of the fibroblastic reticular cell and follicular dendritic cell networks. These findings demonstrate a previously unrecognized compartment-dependent selectivity to the process of splenic vascular remodeling during experimental murine visceral leishmaniasis, attributable to Ly6C(+) inflammatory monocytes. PMID:21703391

  17. Insulin-like growth factor I is required for vessel remodeling in the adult brain

    PubMed Central

    Lopez-Lopez, C.; LeRoith, D.; Torres-Aleman, I.

    2004-01-01

    Although vascular dysfunction is a major suspect in the etiology of several important neurodegenerative diseases, the signals involved in vessel homeostasis in the brain are still poorly understood. We have determined whether insulin-like growth factor I (IGF-I), a wide-spectrum growth factor with angiogenic actions, participates in vascular remodeling in the adult brain. IGF-I induces the growth of cultured brain endothelial cells through hypoxiainducible factor 1α and vascular endothelial growth factor, a canonical angiogenic pathway. Furthermore, the systemic injection of IGF-I in adult mice increases brain vessel density. Physical exercise that stimulates widespread brain vessel growth in normal mice fails to do so in mice with low serum IGF-I. Brain injury that stimulates angiogenesis at the injury site also requires IGF-I to promote perilesion vessel growth, because blockade of IGF-I input by an anti-IGF-I abrogates vascular growth at the injury site. Thus, IGF-I participates in vessel remodeling in the adult brain. Low serum/brain IGF-I levels that are associated with old age and with several neurodegenerative diseases may be related to an increased risk of vascular dysfunction. PMID:15210967

  18. Congenital anomalies and vascular birthmarks of the lower extremities.

    PubMed

    Laor, T; Burrows, P E

    1998-08-01

    MR imaging is an invaluable tool for the evaluation of congenital abnormalities and vascular birthmarks of the extremities in children. These abnormalities of the immature musculoskeletal system are often underestimated by radiography. MR imaging is useful for diagnosis, assisting in therapy, showing response to treatment, and determining prognosis. Localized and generalized abnormalities of the lower extremities and issues pertinent to their MR imaging are illustrated in this article. PMID:9654582

  19. Dynamin, a membrane remodelling GTPase

    PubMed Central

    Ferguson, Shawn M.; De Camilli, Pietro

    2012-01-01

    Dynamin, the founding member of a family of dynamin-like GTPases (DLPs) implicated in membrane remodelling, has a critical role in endocytic membrane fission events. The use of complementary approaches, including live cell imaging, cell free-studies, X-ray crystallography and genetic studies in mice has greatly advanced our understanding of the mechanisms by which dynamin acts, its essential roles in cell physiology and the specific function of different dynamin isoforms. In addition, several connections between dynamin and human disease have also emerged that highlight specific contributions of this GTPase to the physiology of different tissues. PMID:22233676

  20. Remodeling of alveolar septa after murine pneumonectomy.

    PubMed

    Ysasi, Alexandra B; Wagner, Willi L; Bennett, Robert D; Ackermann, Maximilian; Valenzuela, Cristian D; Belle, Janeil; Tsuda, Akira; Konerding, Moritz A; Mentzer, Steven J

    2015-06-15

    In most mammals, removing one lung (pneumonectomy) results in the compensatory growth of the remaining lung. In mice, stereological observations have demonstrated an increase in the number of mature alveoli; however, anatomic evidence of the early phases of alveolar growth has remained elusive. To identify changes in the lung microstructure associated with neoalveolarization, we used tissue histology, electron microscopy, and synchrotron imaging to examine the configuration of the alveolar duct after murine pneumonectomy. Systematic histological examination of the cardiac lobe demonstrated no change in the relative frequency of dihedral angle components (Ends, Bends, and Junctions) (P > 0.05), but a significant decrease in the length of a subset of septal ends ("E"). Septal retraction, observed in 20-30% of the alveolar ducts, was maximal on day 3 after pneumonectomy (P < 0.01) and returned to baseline levels within 3 wk. Consistent with septal retraction, the postpneumonectomy alveolar duct diameter ratio (Dout:Din) was significantly lower 3 days after pneumonectomy compared to all controls except for the detergent-treated lung (P < 0.001). To identify clumped capillaries predicted by septal retraction, vascular casting, analyzed by both scanning electron microscopy and synchrotron imaging, demonstrated matted capillaries that were most prominent 3 days after pneumonectomy. Numerical simulations suggested that septal retraction could reflect increased surface tension within the alveolar duct, resulting in a new equilibrium at a higher total energy and lower surface area. The spatial and temporal association of these microstructural changes with postpneumonectomy lung growth suggests that these changes represent an early phase of alveolar duct remodeling. PMID:26078396

  1. Vascular permeability, vascular hyperpermeability and angiogenesis

    PubMed Central

    Nagy, Janice A.; Benjamin, Laura; Zeng, Huiyan; Dvorak, Ann M.

    2008-01-01

    The vascular system has the critical function of supplying tissues with nutrients and clearing waste products. To accomplish these goals, the vasculature must be sufficiently permeable to allow the free, bidirectional passage of small molecules and gases and, to a lesser extent, of plasma proteins. Physiologists and many vascular biologists differ as to the definition of vascular permeability and the proper methodology for its measurement. We review these conflicting views, finding that both provide useful but complementary information. Vascular permeability by any measure is dramatically increased in acute and chronic inflammation, cancer, and wound healing. This hyperpermeability is mediated by acute or chronic exposure to vascular permeabilizing agents, particularly vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A). We demonstrate that three distinctly different types of vascular permeability can be distinguished, based on the different types of microvessels involved, the composition of the extravasate, and the anatomic pathways by which molecules of different size cross-vascular endothelium. These are the basal vascular permeability (BVP) of normal tissues, the acute vascular hyperpermeability (AVH) that occurs in response to a single, brief exposure to VEGF-A or other vascular permeabilizing agents, and the chronic vascular hyperpermeability (CVH) that characterizes pathological angiogenesis. Finally, we list the numerous (at least 25) gene products that different authors have found to affect vascular permeability in variously engineered mice and classify them with respect to their participation, as far as possible, in BVP, AVH and CVH. Further work will be required to elucidate the signaling pathways by which each of these molecules, and others likely to be discovered, mediate the different types of vascular permeability. PMID:18293091

  2. Origin and differentiation of vascular smooth muscle cells

    PubMed Central

    Wang, Gang; Jacquet, Laureen; Karamariti, Eirini; Xu, Qingbo

    2015-01-01

    Vascular smooth muscle cells (SMCs), a major structural component of the vessel wall, not only play a key role in maintaining vascular structure but also perform various functions. During embryogenesis, SMC recruitment from their progenitors is an important step in the formation of the embryonic vascular system. SMCs in the arterial wall are mostly quiescent but can display a contractile phenotype in adults. Under pathophysiological conditions, i.e. vascular remodelling after endothelial dysfunction or damage, contractile SMCs found in the media switch to a secretory type, which will facilitate their ability to migrate to the intima and proliferate to contribute to neointimal lesions. However, recent evidence suggests that the mobilization and recruitment of abundant stem/progenitor cells present in the vessel wall are largely responsible for SMC accumulation in the intima during vascular remodelling such as neointimal hyperplasia and arteriosclerosis. Therefore, understanding the regulatory mechanisms that control SMC differentiation from vascular progenitors is essential for exploring therapeutic targets for potential clinical applications. In this article, we review the origin and differentiation of SMCs from stem/progenitor cells during cardiovascular development and in the adult, highlighting the environmental cues and signalling pathways that control phenotypic modulation within the vasculature. PMID:25952975

  3. Uterine distension differentially affects remodelling and distensibility of the uterine vasculature in non-pregnant rats.

    PubMed

    Osol, George; Barron, Carolyn; Mandalà, Maurizio

    2012-01-01

    During pregnancy the mammalian uterine circulation undergoes significant expansive remodelling necessary for normal pregnancy outcome. The underlying mechanisms are poorly defined. The goal of this study was to test the hypothesis that myometrial stretch actively stimulates uterine vascular remodelling by developing a new surgical approach to induce unilateral uterine distension in non-pregnant rats. Three weeks after surgery, which consisted of an infusion of medical-grade silicone into the uterine lumen, main and mesometrial uterine artery and vein length, diameter and distensibility were recorded. Radial artery diameter, distensibility and vascular smooth muscle mitotic rate (Ki67 staining) were also measured. Unilateral uterine distension resulted in significant increases in the length of main uterine artery and vein and mesometrial segments but had no effect on vessel diameter or distensibility. In contrast, there were significant increases in the diameter of the radial arteries associated with the distended uterus. These changes were accompanied by reduced arterial distensibility and increased vascular muscle hyperplasia. In summary, this is the first report to show that myometrial stretch is a sufficient stimulus to induce significant remodelling of uterine vessels in non-pregnant rats. Moreover, the results indicate differential regulation of these growth processes as a function of vessel size and type. PMID:22781934

  4. Dilating venous disease: Pathophysiology and a systematic aspect to different vascular territories.

    PubMed

    Yetkin, Ertan; Ileri, Mehmet

    2016-06-01

    Venous disease is a common but overlooked clinical problem and is an important mortality and morbidity factor depending on the effected vascular territory. Different contributing factors play role on the clinical manifestation of the disease. Peripheral varices of lower extremities, hemorrhoids, varicoceles, pelvic varicose veins are the vasculopathy of veins running toward heart but against gravity. We hypothesize that all these clinical entities share common pathophysiologic steps in terms of vascular wall remodeling and vessel wall damage. A systematic approaches to both arterial and venous dilating disease in further studies and research would increase our understanding on the pathophysiology of dilating vascular disease and would provoke to find out new treatment modalities. Varicose remodeling of veins occurs by a complex interplay of various factors including both physical forces and extracellular matrix remodeling mechanisms. This article focuses on the systematic aspects of dilating venous disease with a focus on pathophysiology under the term of "Dilating Venous Disease". PMID:27142148

  5. Osteocyte-Driven Bone Remodeling

    PubMed Central

    Bellido, Teresita

    2013-01-01

    Osteocytes, the most abundant cells in bone, have been long postulated to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. The discovery that the inhibitor of bone formation sclerostin is primarily expressed in osteocytes in bone and it is downregulated by anabolic stimuli provided a mechanism by which osteocytes influence the activity of osteoblasts. Advances of the last few years provided experimental evidence demonstrating that osteocytes also participate in the recruitment of osteoclasts and the initiation of bone remodeling. Apoptotic osteocytes trigger yet to be identified signals that attract osteoclast precursors to specific areas of bone, which in turn differentiate to mature, bone resorbing osteoclasts. Osteocytes are also the source of molecules that regulate generation and activity of osteoclasts, such as OPG and RANKL; and genetic manipulations of the mouse genome leading to loss or gain of function, or to altered expression of either molecule in osteocytes, markedly affect bone resorption. This review highlights these investigations and discusses how the novel concept of osteocyte-driven bone resorption and formation impacts our understanding of the mechanisms by which current therapies control bone remodeling. PMID:24002178

  6. HDL biogenesis, remodeling, and catabolism.

    PubMed

    Zannis, Vassilis I; Fotakis, Panagiotis; Koukos, Georgios; Kardassis, Dimitris; Ehnholm, Christian; Jauhiainen, Matti; Chroni, Angeliki

    2015-01-01

    In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR-BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research. PMID:25522986

  7. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders.

    PubMed

    Choe, Sung Sik; Huh, Jin Young; Hwang, In Jae; Kim, Jong In; Kim, Jae Bum

    2016-01-01

    The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue functions as a key energy reservoir for other organs, whereas the brown adipose tissue accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secrete various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue-resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic overnutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response. PMID:27148161

  8. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders

    PubMed Central

    Choe, Sung Sik; Huh, Jin Young; Hwang, In Jae; Kim, Jong In; Kim, Jae Bum

    2016-01-01

    The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue functions as a key energy reservoir for other organs, whereas the brown adipose tissue accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secrete various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue-resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic overnutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response. PMID:27148161

  9. The Three A's in Asthma - Airway Smooth Muscle, Airway Remodeling & Angiogenesis.

    PubMed

    Keglowich, L F; Borger, P

    2015-01-01

    Asthma affects more than 300 million people worldwide and its prevalence is still rising. Acute asthma attacks are characterized by severe symptoms such as breathlessness, wheezing, tightness of the chest, and coughing, which may lead to hospitalization or death. Besides the acute symptoms, asthma is characterized by persistent airway inflammation and airway wall remodeling. The term airway wall remodeling summarizes the structural changes in the airway wall: epithelial cell shedding, goblet cell hyperplasia, hyperplasia and hypertrophy of the airway smooth muscle (ASM) bundles, basement membrane thickening and increased vascular density. Airway wall remodeling starts early in the pathogenesis of asthma and today it is suggested that remodeling is a prerequisite for other asthma pathologies. The beneficial effect of bronchial thermoplasty in reducing asthma symptoms, together with the increased potential of ASM cells of asthmatics to produce inflammatory and angiogenic factors, indicate that the ASM cell is a major effector cell in the pathology of asthma. In the present review we discuss the ASM cell and its role in airway wall remodeling and angiogenesis. PMID:26106455

  10. The Three A’s in Asthma – Airway Smooth Muscle, Airway Remodeling & Angiogenesis

    PubMed Central

    Keglowich, L.F; Borger, P

    2015-01-01

    Asthma affects more than 300 million people worldwide and its prevalence is still rising. Acute asthma attacks are characterized by severe symptoms such as breathlessness, wheezing, tightness of the chest, and coughing, which may lead to hospitalization or death. Besides the acute symptoms, asthma is characterized by persistent airway inflammation and airway wall remodeling. The term airway wall remodeling summarizes the structural changes in the airway wall: epithelial cell shedding, goblet cell hyperplasia, hyperplasia and hypertrophy of the airway smooth muscle (ASM) bundles, basement membrane thickening and increased vascular density. Airway wall remodeling starts early in the pathogenesis of asthma and today it is suggested that remodeling is a prerequisite for other asthma pathologies. The beneficial effect of bronchial thermoplasty in reducing asthma symptoms, together with the increased potential of ASM cells of asthmatics to produce inflammatory and angiogenic factors, indicate that the ASM cell is a major effector cell in the pathology of asthma. In the present review we discuss the ASM cell and its role in airway wall remodeling and angiogenesis. PMID:26106455

  11. Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2

    PubMed Central

    Lieu, Shirley; Hansen, Erik; Dedini, Russell; Behonick, Danielle; Werb, Zena; Miclau, Theodore; Marcucio, Ralph; Colnot, Céline

    2011-01-01

    SUMMARY The matrix metalloproteinase (MMP) family of extracellular proteases performs crucial roles in development and repair of the skeleton owing to their ability to remodel the extracellular matrix (ECM) and release bioactive molecules. Most MMP-null skeletal phenotypes that have been previously described are mild, thus permitting the assessment of their functions during bone repair in the adult. In humans and mice, MMP2 deficiency causes a musculoskeletal phenotype. In this study, we assessed the role of MMP2 during mouse fracture repair and compared it with the roles of MMP9 and MMP13. Mmp2 was expressed at low levels in the normal skeleton and was broadly expressed in the fracture callus. Treatment of wild-type mice with a general MMP inhibitor, GM6001, caused delayed cartilage remodeling and bone formation during fracture repair, which resembles the defect observed in Mmp9–/– mice. Unlike Mmp9- and Mmp13-null mutations, which affect both cartilage and bone in the callus, the Mmp2-null mutation delayed bone remodeling but not cartilage remodeling. This remodeling defect occurred without changes in either osteoclast recruitment or vascular invasion of the fracture callus compared with wild type. However, we did not detect changes in expression of Mmp9, Mmp13 or Mt1-Mmp (Mmp14) in the calluses of Mmp2-null mice compared with wild type by in situ hybridization, but we observed decreased expression of Timp2 in the calluses of Mmp2-, Mmp9- and Mmp13-null mice. In keeping with the skeletal phenotype of Mmp2-null mice, MMP2 plays a role in the remodeling of new bone within the fracture callus and impacts later stages of bone repair compared with MMP9 and MMP13. Taken together, our results indicate that MMPs play unique and distinct roles in regulating skeletal tissue deposition and remodeling during fracture repair. PMID:21135056

  12. Fast degrading elastomer enables rapid remodeling of a cell-free synthetic graft into a neo-artery

    PubMed Central

    Wu, Wei; Allen, Robert A.; Wang, Yadong

    2011-01-01

    Host remodeling is important for the success of medical implants including vascular substitutes. Synthetic and tissue-engineered grafts have yet to show clinical effectiveness in arteries smaller than 5 mm. We designed cell-free biodegradable elastomeric grafts that degrade rapidly to yield neo-arteries nearly free of foreign materials 3 months after interposition grafting in rat abdominal aorta. This design focuses on enabling rapid host remodeling. Three months post-implantation, the neo-arteries resemble native arteries in the following aspects: regular, strong and synchronous pulsation, a confluent endothelium and contractile smooth muscle layers, co-expression of elastin, collagen and glycosaminoglycan, and tough and compliant mechanical properties. Therefore, future study employing large animal models more representative of human vascular regeneration is warranted before clinical translation. This cell-free approach represents a philosophical shift from the prevailing focus on cells in vascular tissue engineering, and may impact regenerative medicine in general. PMID:22729285

  13. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  14. Abnormal Uterine Bleeding

    MedlinePlus

    ... Abnormal uterine bleeding is any bleeding from the uterus (through your vagina) other than your normal monthly ... or fibroids (small and large growths) in the uterus can also cause bleeding. Rarely, a thyroid problem, ...

  15. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... as cancer of the uterus, cervix, or vagina • Polycystic ovary syndrome How is abnormal bleeding diagnosed? Your health care ... before the fetus can survive outside the uterus. Polycystic Ovary Syndrome: A condition characterized by two of the following ...

  16. An Analysis of the Residential Remodeling Occupation.

    ERIC Educational Resources Information Center

    Scruggs, Kenneth

    The general purpose of the occupational analysis is to provide workable, basic information dealing with the many and varied duties performed in the residential remodeling occupation. The analysis only briefly covers the many areas of residential remodeling. The document opens with a brief introduction followed by a job description. The bulk of the…

  17. Bone remodeling and silicon deficiency in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alveolar bone undergoes continuous remodeling to meet physiologic and functional demands. The aim of the present work was to evaluate histologically and histomorphometrically the effect of silicon deficiency on bone modeling and remodeling in the periodontal cortical plate. Two groups of weaning mal...

  18. Chromatin Remodelers: From Function to Dysfunction

    PubMed Central

    Längst, Gernot; Manelyte, Laura

    2015-01-01

    Chromatin remodelers are key players in the regulation of chromatin accessibility and nucleosome positioning on the eukaryotic DNA, thereby essential for all DNA dependent biological processes. Thus, it is not surprising that upon of deregulation of those molecular machines healthy cells can turn into cancerous cells. Even though the remodeling enzymes are very abundant and a multitude of different enzymes and chromatin remodeling complexes exist in the cell, the particular remodeling complex with its specific nucleosome positioning features must be at the right place at the right time in order to ensure the proper regulation of the DNA dependent processes. To achieve this, chromatin remodeling complexes harbor protein domains that specifically read chromatin targeting signals, such as histone modifications, DNA sequence/structure, non-coding RNAs, histone variants or DNA bound interacting proteins. Recent studies reveal the interaction between non-coding RNAs and chromatin remodeling complexes showing importance of RNA in remodeling enzyme targeting, scaffolding and regulation. In this review, we summarize current understanding of chromatin remodeling enzyme targeting to chromatin and their role in cancer development. PMID:26075616

  19. Multiscale Simulation of Protein Mediated Membrane Remodeling

    PubMed Central

    Ayton, Gary S.; Voth, Gregory A.

    2009-01-01

    Proteins interacting with membranes can result in substantial membrane deformations and curvatures. This effect is known in its broadest terms as membrane remodeling. This review article will survey current multiscale simulation methodologies that have been employed to examine protein-mediated membrane remodeling. PMID:19922811

  20. Rho kinase as a target for cerebral vascular disorders

    PubMed Central

    Bond, Lisa M; Sellers, James R; McKerracher, Lisa

    2015-01-01

    The development of novel pharmaceutical treatments for disorders of the cerebral vasculature is a serious unmet medical need. These vascular disorders are typified by a disruption in the delicate Rho signaling equilibrium within the blood vessel wall. In particular, Rho kinase overactivation in the smooth muscle and endothelial layers of the vessel wall results in cytoskeletal modifications that lead to reduced vascular integrity and abnormal vascular growth. Rho kinase is thus a promising target for the treatment of cerebral vascular disorders. Indeed, preclinical studies indicate that Rho kinase inhibition may reduce the formation/growth/rupture of both intracranial aneurysms and cerebral cavernous malformations. PMID:26062400

  1. Vascular Integrity in the Pathogenesis of Brain Arteriovenous Malformation

    PubMed Central

    Zhang, Rui; Zhu, Wan

    2015-01-01

    Brain arteriovenous malformation (bAVM) is an important cause of intracranial hemorrhage (ICH), particularly in the young population. ICH is the first clinical symptom in about 50 % of bAVM patients. The vessels in bAVM are fragile and prone to rupture, causing bleeding into the brain. About 30 % of unruptured and non-hemorrhagic bAVMs demonstrate microscopic evidence of hemosiderin in the vascular wall. In bAVM mouse models, vascular mural cell coverage is reduced in the AVM lesion, accompanied by vascular leakage and microhemorrhage. In this review, we discuss possible signaling pathways involved in abnormal vascular development in bAVM. PMID:26463919

  2. Chromosomal Abnormalities and Schizophrenia

    PubMed Central

    BASSETT, ANNE S.; CHOW, EVA W.C.; WEKSBERG, ROSANNA

    2011-01-01

    Schizophrenia is a common and serious psychiatric illness with strong evidence for genetic causation, but no specific loci yet identified. Chromosomal abnormalities associated with schizophrenia may help to understand the genetic complexity of the illness. This paper reviews the evidence for associations between chromosomal abnormalities and schizophrenia and related disorders. The results indicate that 22q11.2 microdeletions detected by fluorescence in-situ hybridization (FISH) are significantly associated with schizophrenia. Sex chromosome abnormalities seem to be increased in schizophrenia but insufficient data are available to indicate whether schizophrenia or related disorders are increased in patients with sex chromosome aneuploidies. Other reports of chromosomal abnormalities associated with schizophrenia have the potential to be important adjuncts to linkage studies in gene localization. Advances in molecular cytogenetic techniques (i.e., FISH) have produced significant increases in rates of identified abnormalities in schizophrenia, particularly in patients with very early age at onset, learning difficulties or mental retardation, or dysmorphic features. The results emphasize the importance of considering behavioral phenotypes, including adult onset psychiatric illnesses, in genetic syndromes and the need for clinicians to actively consider identifying chromosomal abnormalities and genetic syndromes in selected psychiatric patients. PMID:10813803

  3. Nucleosome dynamics during chromatin remodeling in vivo

    PubMed Central

    Ramachandran, Srinivas; Henikoff, Steven

    2016-01-01

    ABSTRACT Precise positioning of nucleosomes around regulatory sites is achieved by the action of chromatin remodelers, which use the energy of ATP to slide, evict or change the composition of nucleosomes. Chromatin remodelers act to bind nucleosomes, disrupt histone-DNA interactions and translocate the DNA around the histone core to reposition nucleosomes. Hence, remodeling is expected to involve nucleosomal intermediates with a structural organization that is distinct from intact nucleosomes. We describe the identification of a partially unwrapped nucleosome structure using methods that map histone-DNA contacts genome-wide. This alternative nucleosome structure is likely formed as an intermediate or by-product during nucleosome remodeling by the RSC complex. Identification of the loss of histone-DNA contacts during chromatin remodeling by RSC in vivo has implications for the regulation of transcriptional initiation. PMID:26933790

  4. Lipid Acyl Chain Remodeling in Yeast

    PubMed Central

    Renne, Mike F.; Bao, Xue; De Smet, Cedric H.; de Kroon, Anton I. P. M.

    2015-01-01

    Membrane lipid homeostasis is maintained by de novo synthesis, intracellular transport, remodeling, and degradation of lipid molecules. Glycerophospholipids, the most abundant structural component of eukaryotic membranes, are subject to acyl chain remodeling, which is defined as the post-synthetic process in which one or both acyl chains are exchanged. Here, we review studies addressing acyl chain remodeling of membrane glycerophospholipids in Saccharomyces cerevisiae, a model organism that has been successfully used to investigate lipid synthesis and its regulation. Experimental evidence for the occurrence of phospholipid acyl chain exchange in cardiolipin, phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine is summarized, including methods and tools that have been used for detecting remodeling. Progress in the identification of the enzymes involved is reported, and putative functions of acyl chain remodeling in yeast are discussed. PMID:26819558

  5. Nucleosome dynamics during chromatin remodeling in vivo.

    PubMed

    Ramachandran, Srinivas; Henikoff, Steven

    2016-01-01

    Precise positioning of nucleosomes around regulatory sites is achieved by the action of chromatin remodelers, which use the energy of ATP to slide, evict or change the composition of nucleosomes. Chromatin remodelers act to bind nucleosomes, disrupt histone-DNA interactions and translocate the DNA around the histone core to reposition nucleosomes. Hence, remodeling is expected to involve nucleosomal intermediates with a structural organization that is distinct from intact nucleosomes. We describe the identification of a partially unwrapped nucleosome structure using methods that map histone-DNA contacts genome-wide. This alternative nucleosome structure is likely formed as an intermediate or by-product during nucleosome remodeling by the RSC complex. Identification of the loss of histone-DNA contacts during chromatin remodeling by RSC in vivo has implications for the regulation of transcriptional initiation. PMID:26933790

  6. 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

  7. Remodeling of tissue-engineered bone structures in vivo.

    PubMed

    Hofmann, Sandra; Hilbe, Monika; Fajardo, Robert J; Hagenmüller, Henri; Nuss, Katja; Arras, Margarete; Müller, Ralph; von Rechenberg, Brigitte; Kaplan, David L; Merkle, Hans P; Meinel, Lorenz

    2013-09-01

    Implant design for bone regeneration is expected to be optimized when implant structures resemble the anatomical situation of the defect site. We tested the validity of this hypothesis by exploring the feasibility of generating different in vitro engineered bone-like structures originating from porous silk fibroin scaffolds decorated with RGD sequences (SF-RGD), seeded with human mesenchymal stem cells (hMSC). Scaffolds with small (106-212 μm), medium (212-300 μm), and large pore diameter ranges (300-425 μm) were seeded with hMSC and subsequently differentiated in vitro into bone-like tissue resembling initial scaffold geometries and featuring bone-like structures. Eight weeks after implantation into calvarial defects in mice, the in vitro engineered bone-like tissues had remodeled into bone featuring different proportions of woven/lamellar bone bridging the defects. Regardless of pore diameter, all implants integrated well, vascularization was advanced, and bone marrow ingrowth had started. Ultimately, in this defect model, the geometry of the in vitro generated tissue-engineered bone structure, trabecular- or plate-like, had no significant impact on the healing of the defect, owing to an efficient remodeling of its structure after implantation. PMID:23958323

  8. FIBROBLAST CYTOSKELETAL REMODELING CONTRIBUTES TO CONNECTIVE TISSUE TENSION

    PubMed Central

    Langevin, Helene M.; Bouffard, Nicole A.; Fox, James R.; Palmer, Bradley M.; Wu, Junru; Iatridis, James C.; Barnes, William D.; Badger, Gary J.; Howe, Alan K.

    2011-01-01

    The viscoelastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the viscoelastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast’s processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the viscoelastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular and immune cell populations residing within connective tissue. PMID:20945345

  9. Remodeling of tissue-engineered bone structures in vivo

    PubMed Central

    Hofmann, Sandra; Hilbe, Monika; Fajardo, Robert J.; Hagenmüller, Henri; Nuss, Katja; Arras, Margarete; Müller, Ralph; von Rechenberg, Brigitte; Kaplan, David L.; Merkle, Hans P.; Meinel, Lorenz

    2013-01-01

    Implant design for bone regeneration is expected to be optimized when implant structures resemble the anatomical situation of the defect site. We tested the validity of this hypothesis by exploring the feasibility of generating different in vitro engineered bone-like structures originating from porous silk fibroin scaffolds decorated with RGD sequences (SF-RGD), seeded with human mesenchymal stem cells (hMSC). Scaffolds with small (106 – 212 μm), medium (212 – 300 μm) and large pore diameter ranges (300 – 425 μm) were seeded with hMSC and subsequently differentiated in vitro into bone-like tissue resembling initial scaffold geometries and featuring bone-like structures. Eight weeks after implantation into calvarial defects in mice, the in vitro engineered bone-like tissues had remodeled into bone featuring different proportions of woven/lamellar bone bridging the defects. Regardless of pore diameter all implants integrated well, vascularization was advanced and, bone marrow ingrowth had started. Ultimately, in this defect model, the geometry of the in vitro generated tissue-engineered bone structure, trabecular- or plate-like, had no significant impact on the healing of the defect, owing to an efficient remodeling of its structure after implantation. PMID:23958323

  10. Multifractal and Lacunarity Analysis of Microvascular Morphology and Remodeling

    PubMed Central

    Gould, Daniel J.; Vadakkan, Tegy J.; Poché, Ross A.; Dickinson, Mary E.

    2011-01-01

    Purpose Classical measures of vessel morphology including diameter and density are employed to study microvasculature in endothelial membrane labeled mice. These measurements prove sufficient for some studies; however they are less well suited for quantifying changes in microcirculatory networks lacking hierarchical structure. We demonstrate automated multifractal analysis and lacunarity may be used with classical methods to quantify microvascular morphology. Methods We present an automated extraction tool with a processing pipeline to characterize 2D representations of 3D microvasculature, using multifractal analysis and lacunarity. We apply our analysis on four tissues and the hyaloid vasculature during remodeling. Results We found that the vessel networks analyzed have multifractal geometries and that kidney microvasculature has the largest fractal dimension and the lowest lacunarity compared to microvasculature networks in the cortex, skin, and thigh muscle. Also, we found that during hyaloid remodeling, there were differences in multifractal spectra reflecting the functional transition from a space filling vasculature which nurtures the lens to a less dense vasculature as it regresses, permitting unobstructed vision. Conclusion Multifractal analysis and lacunarity are valuable additions to classical measures of vascular morphology and will have utility in future studies of normal, developing and pathological tissues. PMID:21166933

  11. Cardiac and vascular changes with kidney transplantation

    PubMed Central

    Ali, A.; Macphee, I.; Kaski, J. C.; Banerjee, D.

    2016-01-01

    Cardiovascular event rates are high in patients with chronic kidney disease (CKD), increasing with deteriorating kidney function, highest in CKD patients on dialysis, and improve with kidney transplantation (KTx). The cardiovascular events in CKD patients such as myocardial infarction and heart failure are related to abnormalities of vascular and cardiac structure and function. Many studies have investigated the structural and functional abnormalities of the heart and blood vessels in CKD, and the changes that occur with KTx, but the evidence is often sparse and occasionally contradictory. We have reviewed the available evidence and identified areas where more research is required to improve the understanding and mechanisms of these changes. There is enough evidence demonstrating improvement of left ventricular hypertrophy, except in children, and sufficient evidence of improvement of left ventricular function, with KTx. There is reasonable evidence of improvement in vascular function and stiffness. However, the evidence for improvement of vascular structure and atherosclerosis is insufficient. Further studies are necessary to establish the changes in vascular structure, and to understand the mechanisms of vascular and cardiac changes, following KTx. PMID:26937071

  12. Calcium signalling remodelling and disease.

    PubMed

    Berridge, Michael J

    2012-04-01

    A wide range of Ca2+ signalling systems deliver the spatial and temporal Ca2+ signals necessary to control the specific functions of different cell types. Release of Ca2+ by InsP3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca2+ signals being set either too high or too low. Such subtle dysregulation of Ca2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease. PMID:22435804

  13. Role of vascular endothelial growth factor signaling in Schistosoma-induced experimental pulmonary hypertension

    PubMed Central

    2014-01-01

    Abstract There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model. PMID:25006448

  14. Micropatterning electrospun scaffolds to create intrinsic vascular networks.

    PubMed

    Jeffries, Eric M; Nakamura, Shintaro; Lee, Kee-Won; Clampffer, Jimmy; Ijima, Hiroyuki; Wang, Yadong

    2014-11-01

    Sufficient vascularization is critical to sustaining viable tissue-engineered (TE) constructs after implantation. Despite significant progress, current approaches lack suturability, porosity, and biodegradability, which hinders rapid perfusion and remodeling in vivo. Consequently, TE vascular networks capable of direct anastomosis to host vasculature and immediate perfusion upon implantation still remain elusive. Here, a hybrid fabrication method is presented for micropatterning fibrous scaffolds that are suturable, porous, and biodegradable. Fused deposition modeling offers an inexpensive and automated approach to creating sacrificial templates with vascular-like branching. By electrospinning around these poly(vinyl alcohol) templates and dissolving them in water, microvascular patterns were transferred to fibrous scaffolds. Results indicated that these scaffolds have sufficient suture retention strength to permit direct anastomosis in future studies. Vascularization of these scaffolds is demonstrated by in vitro endothelialization and perfusion. PMID:25142314

  15. 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

  16. Cell elongation is key to in silico replication of in vitro vasculogenesis and subsequent remodeling

    PubMed Central

    Merks, Roeland M.H.; Brodsky, Sergey V.; Goligorksy, Michael S.; Newman, Stuart A.; Glazier, James A.

    2008-01-01

    Vasculogenesis, the de novo growth of the primary vascular network from initially dispersed endothelial cells, is the first step in the development of the circulatory system in vertebrates. In the first stages of vasculogenesis, endothelial cells elongate and form a network-like structure, called the primary capillary plexus, which subsequently remodels, with the size of the vacancies between ribbons of endothelial cells coarsening over time. To isolate such intrinsic morphogenetic ability of endothelial cells from its regulation by long-range guidance cues and additional cell types, we use an in vitro model of human umbilical vein endothelial cells (HUVEC) in Matrigel. This quasi-two-dimensional endothelial cell culture model would most closely correspond to vasculogenesis in flat areas of the embryo like the yolk sac. Several studies have used continuum mathematical models to explore in vitro vasculogenesis: such models describe cell ensembles but ignore the endothelial cells’ shapes and active surface fluctuations. While these models initially reproduce vascular-like morphologies, they eventually stabilize into a disconnected pattern of vascular “islands.” Also, they fail to reproduce temporally correct network coarsening. Using a cell-centered computational model, we show that the endothelial cells’ elongated shape is key to correct spatiotemporal in silico replication of stable vascular network growth. We validate our simulation results against HUVEC cultures using time-resolved image analysis and find that our simulations quantitatively reproduce in vitro vasculogenesis and subsequent in vitro remodeling. PMID:16325173

  17. A Novel Protective Function of 5-Methoxytryptophan in Vascular Injury

    PubMed Central

    Ho, Yen-Chun; Wu, Meng-Ling; Su, Chen-Hsuan; Chen, Chung-Huang; Ho, Hua-Hui; Lee, Guan-Lin; Lin, Wei-Shiang; Lin, Wen-Yu; Hsu, Yu-Juei; Kuo, Cheng-Chin; Wu, Kenneth K.; Yet, Shaw-Fang

    2016-01-01

    5-Methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of tryptophan metabolism, was recently shown to suppress inflammatory mediator-induced cancer cell proliferation and migration. However, the role of 5-MTP in vascular disease is unknown. In this study, we investigated whether 5-MTP protects against vascular remodeling following arterial injury. Measurements of serum 5-MTP levels in healthy subjects and patients with coronary artery disease (CAD) showed that serum 5-MTP concentrations were inversely correlated with CAD. To test the role of 5-MTP in occlusive vascular disease, we subjected mice to a carotid artery ligation model of neointima formation and treated mice with vehicle or 5-MTP. Compared with vehicle-treated mice, 5-MTP significantly reduced intimal thickening by 40% 4 weeks after ligation. BrdU incorporation assays revealed that 5-MTP significantly reduced VSMC proliferation both in vivo and in vitro. Furthermore, 5-MTP reduced endothelial loss and detachment, ICAM-1 and VCAM-1 expressions, and inflammatory cell infiltration in the ligated arterial wall, suggesting attenuation of endothelial dysfunction. Signaling pathway analysis indicated that 5-MTP mediated its effects predominantly via suppressing p38 MAPK signaling in endothelial and VSMCs. Our data demonstrate a novel vascular protective function of 5-MTP against arterial injury-induced intimal hyperplasia. 5-MTP might be a therapeutic target for preventing and/or treating vascular remodeling. PMID:27146795

  18. A Novel Protective Function of 5-Methoxytryptophan in Vascular Injury.

    PubMed

    Ho, Yen-Chun; Wu, Meng-Ling; Su, Chen-Hsuan; Chen, Chung-Huang; Ho, Hua-Hui; Lee, Guan-Lin; Lin, Wei-Shiang; Lin, Wen-Yu; Hsu, Yu-Juei; Kuo, Cheng-Chin; Wu, Kenneth K; Yet, Shaw-Fang

    2016-01-01

    5-Methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of tryptophan metabolism, was recently shown to suppress inflammatory mediator-induced cancer cell proliferation and migration. However, the role of 5-MTP in vascular disease is unknown. In this study, we investigated whether 5-MTP protects against vascular remodeling following arterial injury. Measurements of serum 5-MTP levels in healthy subjects and patients with coronary artery disease (CAD) showed that serum 5-MTP concentrations were inversely correlated with CAD. To test the role of 5-MTP in occlusive vascular disease, we subjected mice to a carotid artery ligation model of neointima formation and treated mice with vehicle or 5-MTP. Compared with vehicle-treated mice, 5-MTP significantly reduced intimal thickening by 40% 4 weeks after ligation. BrdU incorporation assays revealed that 5-MTP significantly reduced VSMC proliferation both in vivo and in vitro. Furthermore, 5-MTP reduced endothelial loss and detachment, ICAM-1 and VCAM-1 expressions, and inflammatory cell infiltration in the ligated arterial wall, suggesting attenuation of endothelial dysfunction. Signaling pathway analysis indicated that 5-MTP mediated its effects predominantly via suppressing p38 MAPK signaling in endothelial and VSMCs. Our data demonstrate a novel vascular protective function of 5-MTP against arterial injury-induced intimal hyperplasia. 5-MTP might be a therapeutic target for preventing and/or treating vascular remodeling. PMID:27146795

  19. Vascular and Cellular Calcium in Normal and Hypertensive Pregnancy

    PubMed Central

    Adamova, Zuzana; Ozkan, Sifa; Khalil, Raouf A.

    2010-01-01

    Normal pregnancy is associated with significant hemodynamic changes in the cardiovascular system in order to meet the metabolic demands of mother and fetus. These changes include increased cardiac output, decreased vascular resistance, and vascular remodeling in the uterine and systemic circulation. Preeclampsia (PE) is a major complication of pregnancy characterized by proteinuria and hypertension. Several risk factors have been implicated in the pathogenesis of PE including genetic and dietary factors. Ca2+ is an essential dietary element and an important regulator of many cellular processes including vascular function. The importance of adequate dietary Ca2+ intake during pregnancy is supported by many studies. Pregnancy-associated changes in Ca2+ metabolism and plasma Ca2+ have been observed. During pregnancy, changes in intracellular free Ca2+ concentration ([Ca2+]i) have been described in red blood cells, platelets and immune cells. Also, during pregnancy, an increase in [Ca2+]i in endothelial cells (EC) stimulates the production of vasodilator substances such as nitric oxide and prostacyclin. Normal pregnancy is also associated with decreased vascular smooth muscle (VSM) [Ca2+]i and possibly the Ca2+-sensitization pathways of VSM contraction including protein kinase C, Rho-kinase, and mitogen-activated protein kinase. Ca2+-dependent matrix metalloproteinases could also promote extracellular matrix degradation and vascular remodeling during pregnancy. Disruption in the balance between dietary, plasma and vascular cell Ca2+ may be responsible for some of the manifestation of PE including procoagulation, decreased vasodilation, and increased vasoconstriction and vascular resistance. The potential benefits of Ca2+ supplements during pregnancy, and the use of modulators of vascular Ca2+ to reduce the manifestations of PE in susceptible women remain an important area for experimental and clinical research. PMID:19500073

  20. Facilitation of base excision repair by chromatin remodeling.

    PubMed

    Hinz, John M; Czaja, Wioletta

    2015-12-01

    Base Excision Repair (BER) is a conserved, intracellular DNA repair system that recognizes and removes chemically modified bases to insure genomic integrity and prevent mutagenesis. Aberrant BER has been tightly linked with a broad spectrum of human pathologies, such as several types of cancer, neurological degeneration, developmental abnormalities, immune dysfunction and aging. In the cell, BER must recognize and remove DNA lesions from the tightly condensed, protein-coated chromatin. Because chromatin is necessarily refractory to DNA metabolic processes, like transcription and replication, the compaction of the genomic material is also inhibitory to the repair systems necessary for its upkeep. Multiple ATP-dependent chromatin remodelling (ACR) complexes play essential roles in modulating the protein-DNA interactions within chromatin, regulating transcription and promoting activities of some DNA repair systems, including double-strand break repair and nucleotide excision repair. However, it remains unclear how BER operates in the context of chromatin, and if the chromatin remodelling processes that govern transcription and replication also actively regulate the efficiency of BER. In this review we highlight the emerging role of ACR in regulation of BER. PMID:26422134

  1. Numerical Simulation of the Flow in Vascular Grafts for Surgical Applications

    NASA Astrophysics Data System (ADS)

    McGah, Patrick; Aliseda, Alberto

    2009-11-01

    Numerical simulation of the human blood vessels, is becoming an important tool in surgical planning and research. Accurate vascular simulations might grant physicians the predictive capability to perform pre-surgical planning. We focus our attention on the implantation of vascular grafts. The high rate of failure of this common vascular interaction is intimately related to the fluid mechanics in the affected region and the subsequent wall tissue remodeling. Here, we will present our current work in developing a methodology for the numerical simulation of vascular grafts which incorporates physiologically realistic geometries and flow boundary conditions. In particular, we seek to correlate the wall shear stress and its spatial (WSSG) and temporal (OSI) variability to wall remodeling as observed in patient specific longitudinal studies. The pulsatility (Remean= 800 , Repeak= 2000, Wo = 2) of the flow gives rise to additional fluid dynamics phenomena such as instability, flow separation, transition, and unsteadiness. Our goal is to describe and evaluate their effect on the wall physiology.

  2. 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

  3. Allergen-induced airway remodeling is impaired in galectin-3 deficient mice1

    PubMed Central

    Ge, Xiao Na; Bahaie, Nooshin S.; Kang, Bit Na; Hosseinkhani, Reza M.; Ha, Sung Gil; Frenzel, Elizabeth M.; Liu, Fu-Tong; Rao, Savita P.; Sriramarao, P.

    2010-01-01

    The role played by the β-galactoside-binding lectin galectin-3 (Gal-3) in airway remodeling, a characteristic feature of asthma that leads to airway dysfunction and poor clinical outcome in humans, was investigated in a murine model of chronic allergic airway inflammation. Wild-type (WT) and Gal-3 knock-out (KO) mice were subjected to repetitive allergen challenge with ovalbumin (OVA) up to 12 weeks and bronchoalveolar lavage fluid (BALF) and lung tissue collected after the last challenge were evaluated for cellular features associated with airway remodeling. Compared to WT mice, chronic OVA challenge in Gal-3 KO mice resulted in diminished remodeling of the airways with significantly reduced mucus secretion, sub-epithelial fibrosis, smooth muscle thickness, and peribronchial angiogenesis. The higher degree of airway remodeling in WT mice was associated with higher Gal-3 expression in the BALF as well as lung tissue. Cell counts in BALF and lung immunohistology demonstrated that eosinophil infiltration in OVA-challenged Gal-3 KO mice was significantly reduced compared to WT mice. Evaluation of cellular mediators associated with eosinophil recruitment and airway remodeling revealed that levels of eotaxin-1, IL-5, IL-13, FIZZ1 and TGF-β were substantially lower in Gal-3 KO mice. Finally, leukocytes from Gal-3 KO mice demonstrated decreased trafficking (rolling) on vascular endothelial adhesion molecules compared to WT cells. Overall, these studies demonstrate that Gal-3 is an important lectin that promotes airway remodeling via airway recruitment of inflammatory cells, specifically eosinophils, and the development of a Th2 phenotype as well as increased expression of eosinophil-specific chemokines, pro-fibrogenic and angiogenic mediators. PMID:20543100

  4. Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

    PubMed Central

    Eberson, Lance S.; Sanchez, Pablo A.; Majeed, Beenish A.; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

    2015-01-01

    It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young’s modulus. The increase in effective Young’s modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN. PMID:25875748

  5. Collagen vascular disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001223.htm Collagen vascular disease To use the sharing features on ... were previously said to have "connective tissue" or "collagen vascular" disease. We now have names for many ...

  6. Heart and vascular services

    MedlinePlus

    ... branch of medicine that focuses on the cardiovascular system. ... Circulatory system; Vascular system; Cardiovascular system ... to diagnose, monitor or treat diseases of the circulatory and vascular system include: Cardiac CT for calcium scoring Cardiac MRI ...

  7. Society for Vascular Medicine

    MedlinePlus

    ... Annual Meeting Events Calendar Vascular Medicine Events Job Bank Professional Practice Position Statements PAD Awareness Vascular Related ... for a new job? Try the SVM Job Bank . Browse the jobs or sign up for job ...

  8. Heart and vascular services

    MedlinePlus

    ... gov/ency/article/007459.htm Heart and vascular services To use the sharing features on this page, ... blood vessels (arteries and veins). Heart and vascular services refers to the branch of medicine that focuses ...

  9. Lead Poisoning in Remodeling of Old Homes

    ERIC Educational Resources Information Center

    Barnes, Bart

    1973-01-01

    An article based on Dr. Muriel D. Wolf's study of elevated blood lead levels in children and adults present during the remodeling of old homes. Lead poisoning examples, symptoms, and precautions are given. (ST)

  10. Bone Remodeling Under Pathological Conditions.

    PubMed

    Xiao, Wenmei; Li, Shuai; Pacios, Sandra; Wang, Yu; Graves, Dana T

    2016-01-01

    Bone is masterfully programmed to repair itself through the coupling of bone formation following bone resorption, a process referred to as coupling. In inflammatory or other conditions, the balance between bone resorption and bone formation shifts so that a net bone loss results. This review focuses on four pathologic conditions in which remodeling leads to net loss of bone, postmenopausal osteoporosis, arthritis, periodontal disease, and disuse bone loss, which is similar to bone loss associated with microgravity. In most of these there is an acceleration of the resorptive process due to increased formation of bone metabolic units. This initially leads to a net bone loss since the time period of resorption is much faster than the time needed for bone formation that follows. In addition, each of these processes is characterized by an uncoupling that leads to net bone loss. Mechanisms responsible for increased rates of bone resorption, i.e. the formation of more bone metabolic units, involve enhanced expression of inflammatory cytokines and increased expression of RANKL. Moreover, the reasons for uncoupling are discussed which range from a decrease in expression of growth factors and bone morphogenetic proteins to increased expression of factors that inhibit Wnt signaling. PMID:26599114

  11. Remodeling kitchens: A smorgasbord of energy savings

    SciTech Connect

    Sullivan, B.

    1995-09-01

    The kitchen is often the busiest room in the house and is most likely to remodeled repeatedly over the life of a house. The kitchen also represents a concentration of household energy use. Remodeling a kitchen can mean introducing a host of new energy-saving features or making major energy blunders. This article discusses ways to utilized the best features: layout and design; appliances; lighting; windows and skylights; ventilation; insulation and air sealing; water; household recycling; green building materials.

  12. Effect of material damping on bone remodelling.

    PubMed

    Misra, J C; Samanta, S

    1987-01-01

    This paper considers the effect of internal material damping on the stresses, strains, and surface and internal remodelling behaviour in a section of axisymmetrical bone with a force-fitted axially oriented medullary pin. The bone response to several loading situations is modelled using visco-elastic equations. An approximate method is developed to analyse the proposed mathematical model. By considering a numerical example, the effect of material damping on the remodelling stresses is quantified. PMID:3584150

  13. Chromatin remodeling by nucleosome disassembly in vitro.

    PubMed

    Lorch, Yahli; Maier-Davis, Barbara; Kornberg, Roger D

    2006-02-28

    The RSC chromatin-remodeling complex completely disassembles a nucleosome in the presence of the histone chaperone Nap1 and ATP. Disassembly occurs in a stepwise manner, with the removal of H2A/H2B dimers, followed by the rest of the histones and the release of naked DNA. RSC and related chromatin-remodeling complexes may be responsible for the removal of promoter nucleosomes during transcriptional activation in vivo. PMID:16492771

  14. Persistent severe hypereosinophilic asthma is not associated with airway remodeling.

    PubMed

    Alagha, Khuder; Jarjour, Baihas; Bommart, Sebastien; Aviles, Berta; Varrin, Muriel; Gamez, Anne Sophie; Molinari, Nicolas; Vachier, Isabelle; Paganin, Fabrice; Chanez, Pascal; Bourdin, Arnaud

    2015-02-01

    Hypereosinophilic asthma (HEA) is considered as a specific severe asthma phenotype. Whether eosinophils have a link with airway remodeling characterized by pathological (thickening of the basement membrane), functional (persistent airflow impairment and decline in lung function) and imaging features (increase airway wall thickness at CT scan) is still debated. In a one year prospective cohort of 142 severe asthma patients (according to IMI), 14 persistent HEA patients (defined by a persistent blood eosinophilia >500/mm(3) at two consecutive visits) were identified and compared with ten patients without any blood eosinophilia during the follow-up period (NEA, blood eosinophilia always <500/mm(3)). Airflow and lung volumes were recorded. Bronchial biopsies obtained at enrollment were stained for eosinophils (EG2) and basement membrane thickness (BM) was quantified. Imaging by CT scan acquisition was standardized and bronchial abnormalities quantified. ACQ score and exacerbations were prospectively recorded. HEA was not associated with preeminent features of airway remodeling assessed by airflow impairment (Best ever FEV1 values 97% ± 20 in HEA vs. 80 ± 24% in NEA, p = 0.020), decline of FEV1 (FEV1 Decline 40 ± 235 ml/y in HEA vs. 19 ± 40 ml/y in NEA, P = 0.319), submucosal abnormalities (BM thickness 7.80 ± 2.66 μm in HEA vs. 6.84 ± 2.59 in NEA, p = 0.37) and airway wall thickening at CT-scan (0.250 ± 0.036 mm vs. 0.261 ± 0.043, p = 0.92). Eosinophils blood count was inversely correlated with semiquantitative imaging score (rho -0.373, p = 0.039). Smoking history and positive skin prick tests were independent risk factors for increased BM thickening. Outcomes were similar in both populations (Control and exacerbations). Persistent HEA is not associated with evidences of airway remodeling. PMID:25592243

  15. Quantification of Blood Flow and Topology in Developing Vascular Networks

    PubMed Central

    Kloosterman, Astrid; Hierck, Beerend; Westerweel, Jerry; Poelma, Christian

    2014-01-01

    Since fluid dynamics plays a critical role in vascular remodeling, quantification of the hemodynamics is crucial to gain more insight into this complex process. Better understanding of vascular development can improve prediction of the process, and may eventually even be used to influence the vascular structure. In this study, a methodology to quantify hemodynamics and network structure of developing vascular networks is described. The hemodynamic parameters and topology are derived from detailed local blood flow velocities, obtained by in vivo micro-PIV measurements. The use of such detailed flow measurements is shown to be essential, as blood vessels with a similar diameter can have a large variation in flow rate. Measurements are performed in the yolk sacs of seven chicken embryos at two developmental stages between HH 13+ and 17+. A large range of flow velocities (1 µm/s to 1 mm/s) is measured in blood vessels with diameters in the range of 25–500 µm. The quality of the data sets is investigated by verifying the flow balances in the branching points. This shows that the quality of the data sets of the seven embryos is comparable for all stages observed, and the data is suitable for further analysis with known accuracy. When comparing two subsequently characterized networks of the same embryo, vascular remodeling is observed in all seven networks. However, the character of remodeling in the seven embryos differs and can be non-intuitive, which confirms the necessity of quantification. To illustrate the potential of the data, we present a preliminary quantitative study of key network topology parameters and we compare these with theoretical design rules. PMID:24823933

  16. Vascular Dysfunction in Diabetes and Glaucoma: A Complex Relationship Reviewed.

    PubMed

    Gerber, Austin L; Harris, Alon; Siesky, Brent; Lee, Eric; Schaab, Tara J; Huck, Andrew; Amireskandari, Annahita

    2015-08-01

    Open-angle glaucoma (OAG) is a multifactorial disease characterized by progressive retinal ganglion cell death and visual field loss. Intraocular pressure, ocular perfusion pressure, and systemic vascular irregularities have all been identified as contributing factors for glaucoma onset and progression. Focal and systemic vascular abnormalities have also been well documented in diabetic patients. The relationship between diabetes mellitus and OAG remains enigmatic in the literature. As the pathogenesis of both diabetes mellitus and OAG involves compromised vascular regulation, this review was undertaken to further investigate their precise relationship. A literature review of published population-based studies was performed, with a focus on studies regarding blood flow abnormalities. Although current studies support the role of vascular contributions to both diseases, the association between glaucoma and diabetes yields contrasting results. PMID:25264988

  17. Dynamics of the Ethanolamine Glycerophospholipid Remodeling Network

    PubMed Central

    Hermansson, Martin; Somerharju, Pentti; Chuang, Jeffrey

    2012-01-01

    Acyl chain remodeling in lipids is a critical biochemical process that plays a central role in disease. However, remodeling remains poorly understood, despite massive increases in lipidomic data. In this work, we determine the dynamic network of ethanolamine glycerophospholipid (PE) remodeling, using data from pulse-chase experiments and a novel bioinformatic network inference approach. The model uses a set of ordinary differential equations based on the assumptions that (1) sn1 and sn2 acyl positions are independently remodeled; (2) remodeling reaction rates are constant over time; and (3) acyl donor concentrations are constant. We use a novel fast and accurate two-step algorithm to automatically infer model parameters and their values. This is the first such method applicable to dynamic phospholipid lipidomic data. Our inference procedure closely fits experimental measurements and shows strong cross-validation across six independent experiments with distinct deuterium-labeled PE precursors, demonstrating the validity of our assumptions. In constrast, fits of randomized data or fits using random model parameters are worse. A key outcome is that we are able to robustly distinguish deacylation and reacylation kinetics of individual acyl chain types at the sn1 and sn2 positions, explaining the established prevalence of saturated and unsaturated chains in the respective positions. The present study thus demonstrates that dynamic acyl chain remodeling processes can be reliably determined from dynamic lipidomic data. PMID:23251394

  18. Mitochondria, myocardial remodeling, and cardiovascular disease.

    PubMed

    Verdejo, Hugo E; del Campo, Andrea; Troncoso, Rodrigo; Gutierrez, Tomás; Toro, Barbra; Quiroga, Clara; Pedrozo, Zully; Munoz, Juan Pablo; Garcia, Lorena; Castro, Pablo F; Lavandero, Sergio

    2012-12-01

    The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca(2+) buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca(2+) handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease. PMID:22972531

  19. Epigenomic regulation of oncogenesis by chromatin remodeling.

    PubMed

    Kumar, R; Li, D-Q; Müller, S; Knapp, S

    2016-08-25

    Disruption of the intricate gene expression program represents one of major driving factors for the development, progression and maintenance of human cancer, and is often associated with acquired therapeutic resistance. At the molecular level, cancerous phenotypes are the outcome of cellular functions of critical genes, regulatory interactions of histones and chromatin remodeling complexes in response to dynamic and persistent upstream signals. A large body of genetic and biochemical evidence suggests that the chromatin remodelers integrate the extracellular and cytoplasmic signals to control gene activity. Consequently, widespread dysregulation of chromatin remodelers and the resulting inappropriate expression of regulatory genes, together, lead to oncogenesis. We summarize the recent developments and current state of the dysregulation of the chromatin remodeling components as the driving mechanism underlying the growth and progression of human tumors. Because chromatin remodelers, modifying enzymes and protein-protein interactions participate in interpreting the epigenetic code, selective chromatin remodelers and bromodomains have emerged as new frontiers for pharmacological intervention to develop future anti-cancer strategies to be used either as single-agent or in combination therapies with chemotherapeutics or radiotherapy. PMID:26804164

  20. Regulatory Circuits Controlling Vascular Cell Calcification

    PubMed Central

    Sallam, Tamer; Cheng, Henry; Demer, Linda L.; Tintut, Yin

    2013-01-01

    Vascular calcification is a common feature of chronic kidney disease, cardiovascular disease, and aging. Such abnormal calcium deposition occurs in medial and/or intimal layers of blood vessels as well as in cardiac valves. Once considered a passive and inconsequential finding, the presence of calcium deposits in the vasculature is widely accepted as a predictor of increased morbidity and mortality. Recognition of the importance of vascular calcification in health is driving research into mechanisms that govern its development, progression, and regression. Diverse, but highly interconnected factors, have been implicated, including disturbances in lipid metabolism, oxidative stress, inflammatory cytokines, and mineral and hormonal balances, which can lead to formation of osteoblast-like cells in the artery wall. A tight balance of procalcific and anticalcific regulators dictates the extent of disease. In this review, we focus on the main regulatory circuits modulating vascular cell calcification. PMID:23269436

  1. 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.

  2. Role of Corin in Trophoblast Invasion and Uterine Spiral Artery Remodeling in Pregnancy

    PubMed Central

    Cui, Yujie; Wang, Wei; Dong, Ningzheng; Lou, Jinglei; Srinivasan, Dinesh Kumar; Cheng, Weiwei; Huang, Xiaoyi; Liu, Meng; Fang, Chaodong; Peng, Jianhao; Chen, Shenghan; Wu, Shannon; Liu, Zhenzhen; Dong, Liang; Zhou, Yiqing; Wu, Qingyu

    2012-01-01

    Summary In pregnancy, trophoblast invasion and uterine spiral artery remodeling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodeling has long been implicated in preeclampsia, a major complication of pregnancy, but the underlying mechanisms remain unclear1, 2. Corin is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone important in regulating blood pressure3. Unexpectedly, corin expression was detected in the pregnant uterus4. Here we identify a novel function of corin and ANP in promoting trophoblast invasion and spiral artery remodeling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of preeclampsia. In these mice, trophoblast invasion and uterine spiral artery remodeling were markedly impaired. Consistently, we find that ANP potently stimulated human trophoblasts in invading Matrigels. In patients with preeclampsia, uterine corin mRNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified corin gene mutations in preeclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to preeclampsia. PMID:22437503

  3. Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma.

    PubMed

    Johnson, Jill R; Folestad, Erika; Rowley, Jessica E; Noll, Elisa M; Walker, Simone A; Lloyd, Clare M; Rankin, Sara M; Pietras, Kristian; Eriksson, Ulf; Fuxe, Jonas

    2015-04-01

    Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRβ, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRβ inhibitor (CP-673451) to investigate the role of PDGFRβ signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRβ signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRβ signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma. PMID:25637607

  4. Effect of diosmetin on airway remodeling in a murine model of chronic asthma.

    PubMed

    Ge, Ai; Liu, Yanan; Zeng, Xiaoning; Kong, Hui; Ma, Yuan; Zhang, Jiaxiang; Bai, Fangfang; Huang, Mao

    2015-08-01

    Bronchial asthma, one of the most common allergic diseases, is characterized by airway hyperresponsiveness (AHR), inflammation, and remodeling. The anti-oxidant flavone aglycone diosmetin ameliorates the inflammation in pancreatitis, but little is known about its impact on asthma. In this study, the effects of diosmetin on chronic asthma were investigated with an emphasis on the modulation of airway remodeling in BALB/c mice challenged with ovalbumin (OVA). It was found that diosmetin significantly relieved inflammatory cell infiltration, goblet cell hyperplasia, and collagen deposition in the lungs of asthmatic mice and notably reduced AHR in these animals. The OVA-induced increases in total cell and eosinophil counts in bronchoalveolar lavage fluid were reversed, and the level of OVA-specific immunoglobulin E in serum was attenuated by diosmetin administration, implying an anti-Th2 activity of diosmetin. Furthermore, diosmetin remarkably suppressed the expression of smooth muscle actin alpha chain, indicating a potent anti-proliferative effect of diosmetin on airway smooth muscle cells (ASMCs). Matrix metallopeptidase-9, transforming growth factor-β1, and vascular endothelial growth factor levels were also alleviated by diosmetin, suggesting that the remission of airway remodeling might be attributed to the decline of these proteins. Taken together, our findings provided a novel profile of diosmetin with anti-remodeling therapeutic benefits, highlighting a new potential of diosmetin in remitting the ASMC proliferation in chronic asthma. PMID:26033789

  5. Lung morphometry changes in prevention of airway remodeling by protocatechuic aldehyde in asthmatic mice.

    PubMed

    Zhang, Jiankai; Ma, Mulan; Qin, Dongyun; Huang, Jianping; Cui, Xiaojun; Wu, Yongfu; Yang, Huiling; Fu, Hui; Liao, Cui

    2015-01-01

    Airway remodeling can lead to irreversible airflow obstruction and persistent airway hyper-responsiveness, which is the pathological basis of refractory asthma. To investigate the preventive effect of protocatechuic aldehyde on airway remodeling in asthmatic mice by lung morphometry methods. BALB/c mice were used to establish model of airway remodeling by ovalbumin (OVA) inhalation. Bronchoalveolar lavage fluid (BALF) were collected for eosinophils (EOS) count and detection of interleukin 4 (IL-4), interleukin-13 (IL-13) and interferon (IFN-γ) content. The left lung pathological sections were performed HE, AB-PAS and Masson staining. The epithelial lamina thickness of the left main bronchus (Re), the smooth muscle layer thickness (Rm), the number of goblet cells and goblet cell area percentage (%Ac) and gas side of the road and vascular collagen deposition (%Aco, %Avc) situation were measured. Protocatechuic aldehyde gavage made the reduction of BALF EOS count. IL-4 and IL-13 levels also decreased, while the IFN-γ level increased. The left main bronchus Re, Rm, goblet cell count, Ac% and Aco% and Avc% reduced. Protocatechuic aldehyde can significantly control airway inflammation and prevent airway remodeling. PMID:26221226

  6. Factors regulating capillary remodeling in a reversible model of inflammatory corneal angiogenesis.

    PubMed

    Mukwaya, Anthony; Peebo, Beatrice; Xeroudaki, Maria; Ali, Zaheer; Lennikov, Anton; Jensen, Lasse; Lagali, Neil

    2016-01-01

    Newly formed microcapillary networks arising in adult organisms by angiogenic and inflammatory stimuli contribute to pathologies such as corneal and retinal blindness, tumor growth, and metastasis. Therapeutic inhibition of pathologic angiogenesis has focused on targeting the VEGF pathway, while comparatively little attention has been given to remodeling of the new microcapillaries into a stabilized, functional, and persistent vascular network. Here, we used a novel reversible model of inflammatory angiogenesis in the rat cornea to investigate endogenous factors rapidly invoked to remodel, normalize and regress microcapillaries as part of the natural response to regain corneal avascularity. Rapid reversal of an inflammatory angiogenic stimulus suppressed granulocytic activity, enhanced recruitment of remodelling macrophages, induced capillary intussusception, and enriched pathways and processes involving immune cells, chemokines, morphogenesis, axonal guidance, and cell motility, adhesion, and cytoskeletal functions. Whole transcriptome gene expression analysis revealed suppression of numerous inflammatory and angiogenic factors and enhancement of endogenous inhibitors. Many of the identified genes function independently of VEGF and represent potentially new targets for molecular control of the critical process of microvascular remodeling and regression in the cornea. PMID:27561355

  7. Lung morphometry changes in prevention of airway remodeling by protocatechuic aldehyde in asthmatic mice

    PubMed Central

    Zhang, Jiankai; Ma, Mulan; Qin, Dongyun; Huang, Jianping; Cui, Xiaojun; Wu, Yongfu; Yang, Huiling; Fu, Hui; Liao, Cui

    2015-01-01

    Airway remodeling can lead to irreversible airflow obstruction and persistent airway hyper-responsiveness, which is the pathological basis of refractory asthma. To investigate the preventive effect of protocatechuic aldehyde on airway remodeling in asthmatic mice by lung morphometry methods. BALB/c mice were used to establish model of airway remodeling by ovalbumin (OVA) inhalation. Bronchoalveolar lavage fluid (BALF) were collected for eosinophils (EOS) count and detection of interleukin 4 (IL-4), interleukin-13 (IL-13) and interferon (IFN-γ) content. The left lung pathological sections were performed HE, AB-PAS and Masson staining. The epithelial lamina thickness of the left main bronchus (Re), the smooth muscle layer thickness (Rm), the number of goblet cells and goblet cell area percentage (%Ac) and gas side of the road and vascular collagen deposition (%Aco, %Avc) situation were measured. Protocatechuic aldehyde gavage made the reduction of BALF EOS count. IL-4 and IL-13 levels also decreased, while the IFN-γ level increased. The left main bronchus Re, Rm, goblet cell count, Ac% and Aco% and Avc% reduced. Protocatechuic aldehyde can significantly control airway inflammation and prevent airway remodeling. PMID:26221226

  8. Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma

    PubMed Central

    Folestad, Erika; Rowley, Jessica E.; Noll, Elisa M.; Walker, Simone A.; Lloyd, Clare M.; Rankin, Sara M.; Pietras, Kristian; Eriksson, Ulf; Fuxe, Jonas

    2015-01-01

    Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRβ, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRβ inhibitor (CP-673451) to investigate the role of PDGFRβ signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRβ signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRβ signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma. PMID:25637607

  9. Factors regulating capillary remodeling in a reversible model of inflammatory corneal angiogenesis

    PubMed Central

    Mukwaya, Anthony; Peebo, Beatrice; Xeroudaki, Maria; Ali, Zaheer; Lennikov, Anton; Jensen, Lasse; Lagali, Neil

    2016-01-01

    Newly formed microcapillary networks arising in adult organisms by angiogenic and inflammatory stimuli contribute to pathologies such as corneal and retinal blindness, tumor growth, and metastasis. Therapeutic inhibition of pathologic angiogenesis has focused on targeting the VEGF pathway, while comparatively little attention has been given to remodeling of the new microcapillaries into a stabilized, functional, and persistent vascular network. Here, we used a novel reversible model of inflammatory angiogenesis in the rat cornea to investigate endogenous factors rapidly invoked to remodel, normalize and regress microcapillaries as part of the natural response to regain corneal avascularity. Rapid reversal of an inflammatory angiogenic stimulus suppressed granulocytic activity, enhanced recruitment of remodelling macrophages, induced capillary intussusception, and enriched pathways and processes involving immune cells, chemokines, morphogenesis, axonal guidance, and cell motility, adhesion, and cytoskeletal functions. Whole transcriptome gene expression analysis revealed suppression of numerous inflammatory and angiogenic factors and enhancement of endogenous inhibitors. Many of the identified genes function independently of VEGF and represent potentially new targets for molecular control of the critical process of microvascular remodeling and regression in the cornea. PMID:27561355

  10. Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy.

    PubMed

    Mandell, Erica; Powers, Kyle N; Harral, Julie W; Seedorf, Gregory J; Hunter, Kendall S; Abman, Steven H; Dodson, R Blair

    2015-12-15

    High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment. PMID:26475735

  11. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    PubMed

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  12. Retinal vascular changes in hypertensive patients in Ibadan, Sub-Saharan Africa

    PubMed Central

    Oluleye, Sunday Tunji; Olusanya, Bolutife Ayokunu; Adeoye, Abiodun Moshood

    2016-01-01

    Background Earlier studies in Nigeria reported the rarity of retinal vascular changes in hypertensives. The aim of this study was to describe the various retinal vascular changes in the hypertensive patients of Nigeria. Patients and methods Nine hundred and three hypertensive patients were studied. This study was approved by the ethical and research committee of the University of Ibadan and University College Hospital, Ibadan, Nigeria. Blood pressure and anthropometric measurements were measured. Cardiac echocardiography was performed on 156 patients. All patients had dilated fundoscopy and fundus photography using the Kowa portable fundus camera and an Apple iPhone with 20 D lens. Statistical analysis was done with Statistical Packages for the Social Sciences (Version 21). Results The mean age of patients was 57 years with a male:female ratio of 1. No retinopathy was found in 556 (61.5%) patients. In all, 175 (19.4%) patients had features of hypertensive retinopathy. Retinal vascular occlusion was a significant finding in 121 patients (13.4%), of which branch retinal vein occlusion, 43 (4.7%), and central retinal vein occlusion, 30 (3.3%), were the most prominent ones in cases. Hemicentral retinal vein occlusion, 26 (2.9%), and central retinal artery occlusion, 17 (1.9%), were significant presentations. Other findings included nonarteritic anterior ischemic optic neuropathy in five (0.6%) patients, hypertensive choroidopathy in seven (0.8%) patients, and hemorrhagic choroidal detachment in five (0.6%) patients. Left ventricular (LV) geometry was abnormal in 85 (55.5%) patients. Concentric remodeling, eccentric hypertrophy, and concentric hypertrophy were observed in 43 (27.6%), 26 (17.2%), and 15 (9.7%) patients, respectively. LV hypertrophy was found in 42 (27%) patients, while 60 (39%) patients had increased relative wall thickness. In this study, bivariate analysis showed a correlation between LV relative wall thickness and severity of retinopathy in both eyes

  13. Vascular restoration therapy and bioresorbable vascular scaffold

    PubMed Central

    Wang, Yunbing; Zhang, Xingdong

    2014-01-01

    This article describes the evolution of minimally invasive intervention technologies for vascular restoration therapy from early-stage balloon angioplasty in 1970s, metallic bare metal stent and metallic drug-eluting stent technologies in 1990s and 2000s, to bioresorbable vascular scaffold (BVS) technology in large-scale development in recent years. The history, the current stage, the challenges and the future of BVS development are discussed in detail as the best available approach for vascular restoration therapy. The criteria of materials selection, design and processing principles of BVS, and the corresponding clinical trial results are also summarized in this article. PMID:26816624

  14. Vascular Precursor Cells

    PubMed Central

    Chaudhury, Hera; Goldie, Lauren C.

    2011-01-01

    Understanding the mechanisms that regulate the proliferation and differentiation of human stem and progenitor cells is critically important for the development and optimization of regenerative medicine strategies. For vascular regeneration studies, specifically, a true “vascular stem cell” population has not yet been identified. However, a number of cell types that exist endogenously, or can be generated or propagated ex vivo, function as vascular precursor cells and can participate in and/or promote vascular regeneration. Herein, we provide an overview of what is known about the regulation of their differentiation specifically toward a vascular endothelial cell phenotype. PMID:22866199

  15. Morphological abnormalities in elasmobranchs.

    PubMed

    Moore, A B M

    2015-08-01

    A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed. PMID:25903257

  16. Cardiac remodelling and RAS inhibition.

    PubMed

    Ferrario, Carlos M

    2016-06-01

    Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin-angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS. PMID:27105891

  17. The role of mechanotransduction on vascular smooth muscle myocytes cytoskeleton and contractile function

    PubMed Central

    Ye, George J.C.; Nesmith, Alexander P.; Parker, Kevin Kit

    2016-01-01

    Smooth muscle exhibits a highly organized structural hierarchy that extends over multiple spatial scales to perform a wide range of functions at the cellular, tissue, and organ levels. Early efforts primarily focused on understanding vascular smooth muscle function through biochemical signaling. However, accumulating evidence suggests that mechanotransduction, the process through which cells convert mechanical stimuli into biochemical cues, is requisite for regulating contractility. Cytoskeletal proteins that comprise the extracellular, intercellular, and intracellular domains are mechanosensitive and can remodel their structure and function in response to external mechanical cues. Pathological stimuli such as malignant hypertension can act through the same mechanotransductive pathways to induce maladaptive remodeling, leading to changes in cellular shape and loss of contractile function. In both health and disease, the cytoskeletal architecture integrates the mechanical stimuli and mediates structural and functional remodeling in the vascular smooth muscle. PMID:25125187

  18. Chromosome abnormalities in glioma

    SciTech Connect

    Li, Y.S.; Ramsay, D.A.; Fan, Y.S.

    1994-09-01

    Cytogenetic studies were performed in 25 patients with gliomas. An interesting finding was a seemingly identical abnormality, an extra band on the tip of the short arm of chromosome 1, add(1)(p36), in two cases. The abnormality was present in all cells from a patient with a glioblastoma and in 27% of the tumor cells from a patient with a recurrent irradiated anaplastic astrocytoma; in the latter case, 7 unrelated abnormal clones were identified except 4 of those clones shared a common change, -Y. Three similar cases have been described previously. In a patient with pleomorphic astrocytoma, the band 1q42 in both homologues of chromosome 1 was involved in two different rearrangements. A review of the literature revealed that deletion of the long arm of chromosome 1 including 1q42 often occurs in glioma. This may indicate a possible tumor suppressor gene in this region. Cytogenetic follow-up studies were carried out in two patients and emergence of unrelated clones were noted in both. A total of 124 clonal breakpoints were identified in the 25 patients. The breakpoints which occurred three times or more were: 1p36, 1p22, 1q21, 1q25, 3q21, 7q32, 8q22, 9q22, 16q22, and 22q13.

  19. [Congenital foot abnormalities].

    PubMed

    Delpont, M; Lafosse, T; Bachy, M; Mary, P; Alves, A; Vialle, R

    2015-03-01

    The foot may be the site of birth defects. These abnormalities are sometimes suspected prenatally. Final diagnosis depends on clinical examination at birth. These deformations can be simple malpositions: metatarsus adductus, talipes calcaneovalgus and pes supinatus. The prognosis is excellent spontaneously or with a simple orthopedic treatment. Surgery remains outstanding. The use of a pediatric orthopedist will be considered if malposition does not relax after several weeks. Malformations (clubfoot, vertical talus and skew foot) require specialized care early. Clubfoot is characterized by an equine and varus hindfoot, an adducted and supine forefoot, not reducible. Vertical talus combines equine hindfoot and dorsiflexion of the forefoot, which is performed in the midfoot instead of the ankle. Skew foot is suspected when a metatarsus adductus is resistant to conservative treatment. Early treatment is primarily orthopedic at birth. Surgical treatment begins to be considered after walking age. Keep in mind that an abnormality of the foot may be associated with other conditions: malposition with congenital hip, malformations with syndromes, neurological and genetic abnormalities. PMID:25524290

  20. Vascular aging: Chronic oxidative stress and impairment of redox signaling—consequences for vascular homeostasis and disease

    PubMed Central

    Bachschmid, Markus M.; Schildknecht, Stefan; Matsui, Reiko; Zee, Rebecca; Haeussler, Dagmar; Cohen, Richard A.; Pimental, David; van der Loo, Bernd

    2013-01-01

    Characteristic morphological and molecular alterations such as vessel wall thickening and reduction of nitric oxide occur in the aging vasculature leading to the gradual loss of vascular homeostasis. Consequently, the risk of developing acute and chronic cardiovascular diseases increases with age. Current research of the underlying molecular mechanisms of endothelial function demonstrates a duality of reactive oxygen and nitrogen species in contributing to vascular homeostasis or leading to detrimental effects when formed in excess. Furthermore, changes in function and redox status of vascular smooth muscle cells contribute to age-related vascular remodeling. The age-dependent increase in free radical formation causes deterioration of the nitric oxide signaling cascade, alters and activates prostaglandin metabolism, and promotes novel oxidative posttranslational protein modifications that interfere with vascular and cell signaling pathways. As a result, vascular dysfunction manifests. Compensatory mechanisms are initially activated to cope with age-induced oxidative stress, but become futile, which results in irreversible oxidative modifications of biological macromolecules. These findings support the ‘free radical theory of aging’ but also show that reactive oxygen and nitrogen species are essential signaling molecules, regulating vascular homeostasis. PMID:22380696

  1. IFPA Gabor Than Award lecture: Transformation of the spiral arteries in human pregnancy: key events in the remodelling timeline.

    PubMed

    Harris, L K

    2011-03-01

    During human pregnancy, the uterine spiral arteries are progressively remodelled to form dilated conduits lacking maternal vasomotor control. This phenomenon ensures that a constant supply of blood is delivered to the materno-fetal interface at an optimal velocity for nutrient exchange. Conversion of a tonic maternal arteriole composed of multiple layers of vascular smooth muscle, elastin and numerous other extracellular matrix components, into a highly dilated yet durable vessel, requires tight regulatory control and the coordinated actions of multiple cell types. Initial disruption of the vascular wall, characterised by foci of endothelial cell loss, and separation and misalignment of vascular smooth muscle cells (VSMC), is coincident with an influx of uterine natural killer (uNK) cells and macrophages. uNK cells are a source of angiogenic growth factors and matrix degrading proteases, thus they possess the capacity to initiate changes in VSMC phenotype and instigate extracellular matrix catabolism. However, complete vascular cell loss, mediated in part by apoptosis and dedifferentiation, is only achieved following colonisation of the arteries by extravillous trophoblast (EVT). EVT produce a variety of chemokines, cytokines and matrix degrading proteases, enabling them to influence the fate of other cells within the placental bed and complete the remodelling process. The complex interplay of cell-cell and cell-matrix interactions required for effective vascular transformation will be examined, with a particular focus on the role of (i) uNK cells and (ii) the enzyme matrix metalloproteinase-12 (MMP-12). Parallels with remodelling events occurring in other vascular beds will also be drawn. PMID:21167598

  2. 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. PMID:19501583

  3. Inositol 1,4,5-Trisphosphate (IP3) Receptor Up-regulation in Hypertension Is Associated with Sensitization of Ca2+ Release and Vascular Smooth Muscle Contractility*

    PubMed Central

    Abou-Saleh, Haissam; Pathan, Asif R.; Daalis, Arwa; Hubrack, Satanay; Abou-Jassoum, Hamda; Al-Naeimi, Hamda; Rusch, Nancy J.; Machaca, Khaled

    2013-01-01

    Resistance arteries show accentuated responsiveness to vasoconstrictor agonists in hypertension, and this abnormality relies partly on enhanced Ca2+ signaling in vascular smooth muscle (VSM). Although inositol 1,4,5-triphosphate receptors (IP3Rs) are abundant in VSM, their role in the molecular remodeling of the Ca2+ signaling machinery during hypertension has not been addressed. Therefore, we compared IP3R expression and function between mesenteric arteries of normotensive and hypertensive animals. Levels of IP3R transcript and protein were significantly increased in mesenteric arteries of hypertensive animals, and pharmacological inhibition of the IP3R revealed a higher contribution of IP3-dependent Ca2+ release to vascular contraction in these arteries. Subsequently, we established cultured aortic VSM A7r5 cells as a cellular model that replicates IP3R up-regulation during hypertension by depolarizing the VSM cell membrane. IP3R up-regulation requires Ca2+ influx through L-type Ca2+ channels, followed by activation of the calcineurin-NFAT axis, resulting in IP3R transcription. Functionally, IP3R up-regulation in VSM is associated with enhancement and sensitization of IP3-dependent Ca2+ release, resulting in increased VSM contraction in response to agonist stimulation. PMID:24097979

  4. Amaurosis fugax associated with congenital vascular defect

    PubMed Central

    Giltner, John W; Thomas, Edward R; Rundell, William K

    2016-01-01

    A 68-year-old female with no significant past medical history presented with loss of vision in the lower half of her left eye that lasted <5 minutes. No abnormalities were found on ocular or physical exam. Computed tomography angiography and carotid ultrasound were performed, which confirmed the diagnosis as amaurosis fugax with two abnormalities leading to the transient retinal vessel occlusion. First, it was found that the patient has a congenital vascular anomaly, which consisted most notably of a right-sided aortic arch. This vascular anomaly also consisted of abnormal branching of the left subclavian and common carotid arteries, predisposing the patient to turbulent blood flow and increased risk of the formation of an atherosclerotic plaque at the origin of the common carotid artery. This is an abnormal location for a plaque leading to amaurosis fugax compared to the most common location at the carotid bifurcation. Endarterectomy was not performed because of the difficult location of the plaque and tortuosity of the vessel. Rather, medical intervention with antiplatelet and lipid-lowering therapy was initiated to lower the risk of future retinal or cerebral thromboembolic events. PMID:27445507

  5. Age-associated Pro-inflammatory Remodeling and Functional Phenotype in the Heart and Large Arteries

    PubMed Central

    Wang, Mingyi; Shah, Ajay M

    2015-01-01

    The aging population is increasing dramatically. Aging–associated stress simultaneously drives proinflammatory remodeling, involving angiotensin II and other factors, in both the heart and large arteries. The structural remodeling and functional changes that occur with aging include cardiac and vascular wall stiffening, systolic hypertension and suboptimal ventricular-arterial coupling, features that are often clinically silent and thus termed a silent syndrome. These age-related effects are the result of responses initiated by cardiovascular proinflammatory cells. Local proinflammatory signals are coupled between the heart and arteries due to common mechanical and humoral messengers within a closed circulating system. Thus, targeting proinflammatory signaling molecules would be a promising approach to improve age-associated suboptimal ventricular-arterial coupling, a major predisposing factor for the pathogenesis of clinical cardiovascular events such as heart failure. PMID:25665458

  6. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  7. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  8. Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension

    PubMed Central

    Landskroner, Kyle; Bauer, Yasmina; Vercauteren, Magali; Rey, Markus; Renault, Berengère; Studer, Rolf; Vezzali, Enrico; Freti, Diego; Hadana, Hakim; Schläpfer, Manuela; Cattaneo, Christophe; Bortolamiol, Céline; Weber, Edgar; Whitby, Brian R.; Delahaye, Stéphane; Wanner, Daniel; Steiner, Pauline; Nayler, Oliver; Hess, Patrick; Clozel, Martine

    2015-01-01

    Aims: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling. Methods and Results: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg−1·d−1), but not bosentan (300 mg·kg−1·d−1), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue. Conclusions: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan. PMID:26230396

  9. Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins

    PubMed Central

    Barallobre-Barreiro, Javier; Oklu, Rahmi; Lynch, Marc; Fava, Marika; Baig, Ferheen; Yin, Xiaoke; Barwari, Temo; Potier, David N.; Albadawi, Hassan; Jahangiri, Marjan; Porter, Karen E.; Watkins, Michael T.; Misra, Sanjay; Stoughton, Julianne; Mayr, Manuel

    2016-01-01

    Aims Extracellular matrix remodelling has been implicated in a number of vascular conditions, including venous hypertension and varicose veins. However, to date, no systematic analysis of matrix remodelling in human veins has been performed. Methods and results To understand the consequences of venous hypertension, normal and varicose veins were evaluated using proteomics approaches targeting the extracellular matrix. Varicose saphenous veins removed during phlebectomy and normal saphenous veins obtained during coronary artery bypass surgery were collected for proteomics analysis. Extracellular matrix proteins were enriched from venous tissues. The proteomics analysis revealed the presence of >150 extracellular matrix proteins, of which 48 had not been previously detected in venous tissue. Extracellular matrix remodelling in varicose veins was characterized by a loss of aggrecan and several small leucine-rich proteoglycans and a compensatory increase in collagen I and laminins. Gene expression analysis of the same tissues suggested that the remodelling process associated with venous hypertension predominantly occurs at the protein rather than the transcript level. The loss of aggrecan in varicose veins was paralleled by a reduced expression of aggrecanases. Chymase and tryptase β1 were among the up-regulated proteases. The effect of these serine proteases on the venous extracellular matrix was further explored by incubating normal saphenous veins with recombinant enzymes. Proteomics analysis revealed extensive extracellular matrix degradation after digestion with tryptase β1. In comparison, chymase was less potent and degraded predominantly basement membrane-associated proteins. Conclusion The present proteomics study provides unprecedented insights into the expression and degradation of structural and regulatory components of the vascular extracellular matrix in varicosis. PMID:27068509

  10. Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

    SciTech Connect

    Straub, Adam C.; Stolz, Donna B.; Vin, Harina; Ross, Mark A.; Soucy, Nicole V.; Klei, Linda R.; Barchowsky, Aaron

    2007-08-01

    The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei, L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic.

  11. Obesity and carotid artery remodeling

    PubMed Central

    Kozakova, M; Palombo, C; Morizzo, C; Højlund, K; Hatunic, M; Balkau, B; Nilsson, P M; Ferrannini, E

    2015-01-01

    Background/Objective: The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions characterized by body size-dependent increase in stroke volume (SV) and blood pressure (BP). Subjects/Methods: Common carotid artery (CCA) luminal diameter (LD), IMT and CWS were measured in three different populations in order to study: (A) cross-sectional associations between SV, BP, anthropometric parameters and CCA LD (266 healthy subjects with wide range of body weight (24–159 kg)); (B) longitudinal associations between CCA LD and 3-year IMT progression rate (ΔIMT; 571 healthy non-obese subjects without increased cardiovascular (CV) risk); (C) the impact of obesity on CCA geometry and CWS (88 obese subjects without CV complications and 88 non-obese subjects matched for gender and age). Results: CCA LD was independently associated with SV that was determined by body size. In the longitudinal study, baseline LD was an independent determinant of ΔIMT, and ΔIMT of subjects in the highest LD quartile was significantly higher (28±3 μm) as compared with those in the lower quartiles (8±3, 16±4 and 16±3 μm, P=0.001, P<0.05 and P=0.01, respectively). In addition, CCA CWS decreased during the observational period in the highest LD quartile (from 54.2±8.6 to 51.6±7.4 kPa, P<0.0001). As compared with gender- and age-matched lean individuals, obese subjects had highly increased CCA LD and BP (P<0.0001 for both), but only slightly higher CWS (P=0.05) due to a significant increase in IMT (P=0.005 after adjustment for confounders). Conclusions: Our findings suggest that in obese subjects, the CCA wall thickens to compensate the luminal enlargement caused by body size-induced increase in SV, and therefore, to normalize the wall stress. CCA diameter in obesity could

  12. A fly's view of neuronal remodeling.

    PubMed

    Yaniv, Shiri P; Schuldiner, Oren

    2016-09-01

    Developmental neuronal remodeling is a crucial step in sculpting the final and mature brain connectivity in both vertebrates and invertebrates. Remodeling includes degenerative events, such as neurite pruning, that may be followed by regeneration to form novel connections during normal development. Drosophila provides an excellent model to study both steps of remodeling since its nervous system undergoes massive and stereotypic remodeling during metamorphosis. Although pruning has been widely studied, our knowledge of the molecular and cellular mechanisms is far from complete. Our understanding of the processes underlying regrowth is even more fragmentary. In this review, we discuss recent progress by focusing on three groups of neurons that undergo stereotypic pruning and regrowth during metamorphosis, the mushroom body γ neurons, the dendritic arborization neurons and the crustacean cardioactive peptide peptidergic neurons. By comparing and contrasting the mechanisms involved in remodeling of these three neuronal types, we highlight the common themes and differences as well as raise key questions for future investigation in the field. WIREs Dev Biol 2016, 5:618-635. doi: 10.1002/wdev.241 For further resources related to this article, please visit the WIREs website. PMID:27351747

  13. The role of midkine in skeletal remodelling

    PubMed Central

    Liedert, A; Schinke, T; Ignatius, A; Amling, M

    2014-01-01

    Bone tissue is subjected to continuous remodelling, replacing old or damaged bone throughout life. In bone remodelling, the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts ensure the maintenance of bone mass and strength. In early life, the balance of these cellular activities is tightly regulated by various factors, including systemic hormones, the mechanical environment and locally released growth factors. Age-related changes in the activity of these factors in bone remodelling can result in diseases with low bone mass, such as osteoporosis. Osteoporosis is a systemic and age-related skeletal disease characterized by low bone mass and structural degeneration of bone tissue, predisposing the patient to an increased fracture risk. The growth factor midkine (Mdk) plays a key role in bone remodelling and it is expressed during bone formation and fracture repair. Using a mouse deficient in Mdk, our group have identified this protein as a negative regulator of bone formation and mechanically induced bone remodelling. Thus, specific Mdk antagonists might represent a therapeutic option for diseases characterized by low bone mass, such as osteoporosis. Linked Articles This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4 PMID:24102259

  14. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  15. Exercises to Improve Gait Abnormalities

    MedlinePlus

    ... Home About iChip Articles Directories Videos Resources Contact Exercises to Improve Gait Abnormalities Home » Article Categories » Exercise and Fitness Font Size: A A A A Exercises to Improve Gait Abnormalities Next Page The manner ...

  16. Microvascular Repair: Post-Angiogenesis Vascular Dynamics

    PubMed Central

    LeBlanc, Amanda J.; Krishnan, Laxminarayanan; Sullivan, Christopher J.; Williams, Stuart K.; Hoying, James B.

    2013-01-01

    Vascular compromise and the accompanying perfusion deficits cause or complicate a large array of disease conditions and treatment failures. This has prompted the exploration of therapeutic strategies to repair or regenerate vasculatures thereby establishing more competent microcirculatory beds. Growing evidence indicates that an increase in vessel numbers within a tissue does not necessarily promote an increase in tissue perfusion. Effective regeneration of a microcirculation entails the integration of new stable microvessel segments into the network via neovascularization. Beginning with angiogenesis, neovascularization entails an integrated series of vascular activities leading to the formation of a new mature microcirculation and includes vascular guidance and inosculation, vessel maturation, pruning, arterio-venous specification, network patterning, structural adaptation, intussusception, and microvascular stabilization. While the generation of new vessel segments is necessary to expand a network, without the concomitant neovessel remodeling and adaptation processes intrinsic to microvascular network formation, these additional vessel segments give rise to a dysfunctional microcirculation. While many of the mechanisms regulating angiogenesis have been detailed, a thorough understanding of the mechanisms driving post-angiogenesis activities specific to neovascularization has yet to be fully realized, but is necessary in order to develop effective therapeutic strategies for repairing compromised microcirculations as a means to treat disease. PMID:22734666

  17. A protocol for phenotypic detection and characterization of vascular cells of different origins in a lung neovascularization model in rodents

    PubMed Central

    Jones, Rosemary C; Capen, Diane E; Cohen, Kenneth S; Munn, Lance L; Jain, Rakesh K; Duda, Dan G

    2009-01-01

    The goal of many current studies of neovascularization is to define the phenotype of vascular cell populations of different origins and to determine how such cells promote assembly of vascular channel. Here, we describe a protocol to immunophenotype vascular cells by high-resolution imaging and by fluorescence-activated flow cytometry in an in vivo rodent model of pulmonary microvascular remodeling. Analysis of cells by this combined approach will characterize their phenotype, quantify their number and identify their role in the assembly of vascular channels. PMID:18323810

  18. Renovascular remodeling and renal injury after extended angiotensin II infusion.

    PubMed

    Casare, Fernando Augusto Malavazzi; Thieme, Karina; Costa-Pessoa, Juliana Martins; Rossoni, Luciana Venturini; Couto, Gisele Kruger; Fernandes, Fernanda Barrinha; Casarini, Dulce Elena; Oliveira-Souza, Maria

    2016-06-01

    Chronic angiotensin II (ANG II) infusion for 1 or 2 wk leads to progressive hypertension and induces inward hypertrophic remodeling in preglomerular vessels, which is associated with increased renal vascular resistance (RVR) and decreased glomerular perfusion. Considering the ability of preglomerular vessels to exhibit adaptive responses, the present study was performed to evaluate glomerular perfusion and renal function after 6 wk of ANG II infusion. To address this study, male Wistar rats were submitted to sham surgery (control) or osmotic minipump insertion (ANG II 200 ng·kg(-1)·min(-1), 42 days). A group of animals was treated or cotreated with losartan (10 mg·kg(-1)·day(-1)), an AT1 receptor antagonist, between days 28 and 42 Chronic ANG II infusion increased systolic blood pressure to 185 ± 4 compared with 108 ± 2 mmHg in control rats. Concomitantly, ANG II-induced hypertension increased intrarenal ANG II level and consequently, preglomerular and glomerular injury. Under this condition, ANG II enhanced the total renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow and induced pressure natriuresis. These changes were accompanied by lower RVR and enlargement of the lumen of interlobular arteries and afferent arterioles, consistent with impairment of renal autoregulatory capability and outward preglomerular remodeling. The glomerular injury culminated with podocyte effacement, albuminuria, tubulointerstitial macrophage infiltration and intrarenal extracellular matrix accumulation. Losartan attenuated most of the effects of ANG II. Our findings provide new information regarding the contribution of ANG II infusion over 2 wk to renal hemodynamics and function via the AT1 receptor. PMID:26962104

  19. A Multiscale Computational Framework to Understand Vascular Adaptation

    PubMed Central

    Garbey, Marc; Rahman, Mahbubur; Berceli, Scott A.

    2015-01-01

    The failure rate for vascular interventions (vein bypass grafting, arterial angioplasty/stenting) remains unacceptably high. Over the past two decades, researchers have applied a wide variety of approaches to investigate the primary failure mechanisms, neointimal hyperplasia and aberrant remodeling of the wall, in an effort to identify novel therapeutic strategies. Despite incremental progress, specific cause/effect linkages among the primary drivers of the pathology, (hemodynamic factors, inflammatory biochemical mediators, cellular effectors) and vascular occlusive phenotype remain lacking. We propose a multiscale computational framework of vascular adaptation to develop a bridge between theory and experimental observation and to provide a method for the systematic testing of relevant clinical hypotheses. Cornerstone to our model is a feedback mechanism between environmental conditions and dynamic tissue plasticity described at the cellular level with an agent based model. Our implementation (i) is modular, (ii) starts from basic mechano-biology principle at the cell level and (iii) facilitates the agile development of the model. PMID:25977733

  20. Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis

    PubMed Central

    Ponticos, Markella; Smith, Barbara D.

    2014-01-01

    Extracellular matrix (ECM) within the vascular network provides both a structural and regulatory role. The ECM is a dynamic composite of multiple proteins that form structures connecting cells within the network. Blood vessels are distended by blood pressure and, therefore, require ECM components with elasticity yet with enough tensile strength to resist rupture. The ECM is involved in conducting mechanical signals to cells. Most importantly, ECM regulates cellular function through chemical signaling by controlling activation and bioavailability of the growth factors. Cells respond to ECM by remodeling their microenvironment which becomes dysregulated in vascular diseases such hypertension, restenosis and atherosclerosis. This review examines the cellular and ECM components of vessels, with specific emphasis on the regulation of collagen type I and implications in vascular disease. PMID:24474961

  1. Critical Endothelial Regulation by LRP5 during Retinal Vascular Development

    PubMed Central

    Huang, Wei; Li, Qing; Amiry-Moghaddam, Mahmood; Hokama, Madoka; Sardi, Sylvia H.; Nagao, Masashi; Warman, Matthew L.; Olsen, Bjorn R.

    2016-01-01

    Vascular abnormalities in the eye are the leading cause of many forms of inherited and acquired human blindness. Loss-of-function mutations in the Wnt-binding co-receptor LRP5 leads to aberrant ocular vascularization and loss of vision in genetic disorders such as osteoporosis-pseudoglioma syndrome. The canonical Wnt-β-catenin pathway is known to regulate retinal vascular development. However, it is unclear what precise role LPR5 plays in this process. Here, we show that loss of LRP5 function in mice causes retinal hypovascularization during development as well as retinal neovascularization in adulthood with disorganized and leaky vessels. Using a highly specific Flk1-CreBreier line for vascular endothelial cells, together with several genetic models, we demonstrate that loss of endothelium-derived LRP5 recapitulates the retinal vascular defects in Lrp5-/- mice. In addition, restoring LRP5 function only in endothelial cells in Lrp5-/- mice rescues their retinal vascular abnormalities. Furthermore, we show that retinal vascularization is regulated by LRP5 in a dosage dependent manner and does not depend on LRP6. Our study provides the first direct evidence that endothelium-derived LRP5 is both necessary and sufficient to mediate its critical role in the development and maintenance of retinal vasculature. PMID:27031698

  2. Critical Endothelial Regulation by LRP5 during Retinal Vascular Development.

    PubMed

    Huang, Wei; Li, Qing; Amiry-Moghaddam, Mahmood; Hokama, Madoka; Sardi, Sylvia H; Nagao, Masashi; Warman, Matthew L; Olsen, Bjorn R

    2016-01-01

    Vascular abnormalities in the eye are the leading cause of many forms of inherited and acquired human blindness. Loss-of-function mutations in the Wnt-binding co-receptor LRP5 leads to aberrant ocular vascularization and loss of vision in genetic disorders such as osteoporosis-pseudoglioma syndrome. The canonical Wnt-β-catenin pathway is known to regulate retinal vascular development. However, it is unclear what precise role LPR5 plays in this process. Here, we show that loss of LRP5 function in mice causes retinal hypovascularization during development as well as retinal neovascularization in adulthood with disorganized and leaky vessels. Using a highly specific Flk1-CreBreier line for vascular endothelial cells, together with several genetic models, we demonstrate that loss of endothelium-derived LRP5 recapitulates the retinal vascular defects in Lrp5-/- mice. In addition, restoring LRP5 function only in endothelial cells in Lrp5-/- mice rescues their retinal vascular abnormalities. Furthermore, we show that retinal vascularization is regulated by LRP5 in a dosage dependent manner and does not depend on LRP6. Our study provides the first direct evidence that endothelium-derived LRP5 is both necessary and sufficient to mediate its critical role in the development and maintenance of retinal vasculature. PMID:27031698

  3. Imaging Pediatric Vascular Lesions.

    PubMed

    Nguyen, Tuyet A; Krakowski, Andrew C; Naheedy, John H; Kruk, Peter G; Friedlander, Sheila Fallon

    2015-12-01

    Vascular anomalies are commonly encountered in pediatric and dermatology practices. Most of these lesions are benign and easy to diagnose based on history and clinical exam alone. However, in some cases the diagnosis may not be clear. This may be of particular concern given that vascular anomalies may occasionally be associated with an underlying syndrome, congenital disease, or serious, life-threatening condition. Defining the type of vascular lesion early and correctly is particularly important to determine the optimal approach to management and treatment of each patient. The care of pediatric patients often requires collaboration from a multitude of specialties including pediatrics, dermatology, plastic surgery, radiology, ophthalmology, and neurology. Although early characterization of vascular lesions is important, consensus guidelines regarding the evaluation and imaging of vascular anomalies does not exist to date. Here, the authors provide an overview of pediatric vascular lesions, current classification systems for characterizing these lesions, the various imaging modalities available, and recommendations for appropriate imaging evaluation. PMID:26705446

  4. Imaging Pediatric Vascular Lesions

    PubMed Central

    Nguyen, Tuyet A.; Krakowski, Andrew C.; Naheedy, John H.; Kruk, Peter G.

    2015-01-01

    Vascular anomalies are commonly encountered in pediatric and dermatology practices. Most of these lesions are benign and easy to diagnose based on history and clinical exam alone. However, in some cases the diagnosis may not be clear. This may be of particular concern given that vascular anomalies may occasionally be associated with an underlying syndrome, congenital disease, or serious, life-threatening condition. Defining the type of vascular lesion early and correctly is particularly important to determine the optimal approach to management and treatment of each patient. The care of pediatric patients often requires collaboration from a multitude of specialties including pediatrics, dermatology, plastic surgery, radiology, ophthalmology, and neurology. Although early characterization of vascular lesions is important, consensus guidelines regarding the evaluation and imaging of vascular anomalies does not exist to date. Here, the authors provide an overview of pediatric vascular lesions, current classification systems for characterizing these lesions, the various imaging modalities available, and recommendations for appropriate imaging evaluation. PMID:26705446

  5. Félix Voisin and the genesis of abnormals.

    PubMed

    Doron, Claude-Olivier

    2015-12-01

    This article traces the genealogy of the category of 'abnormals' in psychiatry. It focuses on the French alienist Felix Voisin (1794-1872) who played a decisive role in the creation of alienist knowledge and institutions for problem children, criminals, idiots and lunatics. After a presentation of the category of 'abnormals' as understood at the end of the nineteenth century, I identify in the works of Voisin a key moment in the concept's evolution. I show how, based on concepts borrowed from phrenology and applied first to idiocy, Voisin allows alienism to establish links between the medico-legal (including penitentiary) and medical-educational fields (including difficult childhood). I stress the extent to which this enterprise is related to Voisin's humanism, which claimed to remodel pedagogy and the right to punish on the anthropological particularities of individuals, in order to improve them. PMID:26574056

  6. [Microscopic anatomy of abnormal structure in root tuber of Pueraria lobata].

    PubMed

    Duan, Hai-yan; Cheng, Ming-en; Peng, Hua-sheng; Zhang, He-ting; Zhao, Yu-jiao

    2015-11-01

    Puerariae Lobatae Radix, also known as Gegen, is a root derived from Pueraria lobata. Based on field investigation and the developmental anatomy of root tuber, we have elucidated the relationship between the growth of root tuber and the anomalous structure. The results of analysis showed that the root system of P. lobata was developed from seed and adventitious root and there existed root tuber, adventitious root and conductive root according to morphology and function. The root tuber was developed from adventitious root, its secondary structure conformed to the secondary structure of dicotyledon's root. With the development of root, the secondary phloem of root tuber appeared abnormal vascular tissue, which was distributed like ring in the outside of secondary vascular tissue. The root tuber might have 4-6 concentric circular permutation abnormal vascular tissuelobate, and was formed by the internal development of abnormal vascular tissue. The xylem and phloem of abnormal vascular tissue were the main body of the root tuber. The results reveal the abnormal anatomical structure development of P. lobata, also provides the theoretical basis for reasonable harvest medicinal parts and promoting sustainable utilization of resources of P. lobata. PMID:27097408

  7. Orthopedic issues in vascular anomalies.

    PubMed

    Spencer, Samantha A; Sorger, Joel

    2014-08-01

    Vascular malformations impact the musculoskeletal system depending on the tissue involved (skin, subcutis, muscle, cartilage, or bone), the extent of involvement, and the type of anomalous vessels (arteries, capillaries, veins, or lymphatics). These malformations can cause a multitude of musculoskeletal problems for the patient and their Orthopedic Surgeon to manage. Leg-length discrepancy, intra-articular involvement, muscular lesions, and primary or secondary scoliosis are just to name a few. All of these problems can cause pain, deformity, and a range of functional limitations. Surgical and nonsurgical treatment plans both have a role in the care of these patients. Patients with vascular malformations may also suffer from life-threatening cardiovascular and hematologic abnormalities. For those patients who undergo surgery, thromboembolic risk is elevated, wound breakdown and infection are much more common, and bleeding risk continues well into the postoperative course. Because of the complex nature of these disorders, the clinician must have a full understanding of the types of lesions, their natural history, appropriate diagnostic studies, associated medical problems, indications for treatment, and all the treatment options. For severe malformations, especially syndromes such as CLOVES and Klippel-Trenaunay syndrome, interdisciplinary team management is essential for the best outcomes. PMID:25241103

  8. Molecular analysis of arterial remodeling: a novel application of infrared imaging

    NASA Astrophysics Data System (ADS)

    Herman, Brad C.; Kundi, Rishi; Yamanouchi, Dai; Kent, K. Craig; Liu, Bo; Pleshko, Nancy

    2009-02-01

    Arterial remodeling, i.e. changes in size and/or structure of arteries, plays an important role in vascular disease. Conflicting findings have been reported as to whether an abundance of collagen causes inward or outward remodeling, phenomena that result in either a smaller or larger lumen, respectively. We hypothesize that the amount, type and quality of collagen influence the remodeling response. Here, we create mechanical injury to the rat carotid artery using a balloon catheter, and this leads to inward remodeling. Treatment of the artery with Connective Tissue Growth Factor (CTGF) causes outward remodeling. We investigated the arterial composition in injured CTGF-treated and non-CTGF-treated and sham CTGF-treated and non-CTGF treated arteries 14 days post-injury (n = 7-8 per group) using infrared imaging. A Perkin Elmer Spotlight Spectrum 300 FT-IR microscope was used for data collection. Cross-sections of paraffinembedded arteries were scanned at 2 cm-1 spectral resolution with spatial resolution of 6.25 μm/pixel, and data analyzed using Malvern Instruments ISys 5.0. Post-injury, we found a nearly 50% reduction in the average 1338/AM2 area ratio (correlated to collagen helical integrity). The most dramatic change was a 600% increase in the 1660/1690 peak height ratio, which has previously been related to collagen crosslink maturity. In all cases, CTGF treatment resulted in the observed changes in peak parameters normalized back to control values. Overall, these preliminary studies demonstrate that infrared imaging can provide insight into the underlying molecular changes that contribute to arterial disease.

  9. Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model.

    PubMed

    Aguero, Jaume; Ishikawa, Kiyotake; Hadri, Lahouaria; Santos-Gallego, Carlos; Fish, Kenneth; Hammoudi, Nadjib; Chaanine, Antoine; Torquato, Samantha; Naim, Charbel; Ibanez, Borja; Pereda, Daniel; García-Alvarez, Ana; Fuster, Valentin; Sengupta, Partho P; Leopold, Jane A; Hajjar, Roger J

    2014-10-15

    In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca(2+)-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism. PMID:25158063

  10. Echocardiographic abnormalities in the assessment of cardiac organ damage in never-treated hypertensive patients.

    PubMed

    Milan, Alberto; Avenatti, Eleonora; Puglisi, Elisabetta; Abram, Sara; Magnino, Corrado; Naso, Diego; Tosello, Francesco; Fabbri, Ambra; Vairo, Alessandro; Mulatero, Paolo; Rabbia, Franco; Veglio, Franco

    2012-01-01

    Hypertension-related cardiac organ damage, other than left ventricular (LV) hypertrophy (LVH), has been described: in particular, concentric remodeling, LV diastolic dysfunction (DD), and left atrial (LA) enlargement are significantly associated with cardiovascular morbility and mortality in different populations. This study evaluated the prevalence of these latter morphofunctional abnormalities, in never-treated essential hypertensive patients and the role of such a serial assessment of hypertensive cardiac damage in improving cardiovascular risk stratification in these patients. A total of 100 never-treated essential hypertensive subjects underwent a complete clinical and echocardiographic evaluation. Left ventricular morphology, systolic and diastolic function, and LA dimension (linear and volume) were evaluated by echocardiography. Left ventricular hypertrophy was present in 14% of the patients, whereas concentric remodeling was present in 25% of the subjects. Among patients free from LV morphology abnormalities, the most frequent abnormality was LA enlargement (global prevalence 57%); the percentage of patients with at least one parameter consistent with DD was 22% in the entire population, but DD was present as the only cardiac abnormality in 1% of our patient. Left atrial volume indexed for body surface area was the most sensitive parameter in identifying hypertension-related cardiac modification. The global prevalence of cardiac alteration reached 73% in never-treated hypertensive patients. Left ventricular remodeling and LA enlargement evaluation may grant a better assessment of cardiac organ damage and cardiovascular risk stratification of hypertensive patients without evidence of LVH after routine examination. PMID:22738434

  11. Spirometric abnormalities among welders

    SciTech Connect

    Rastogi, S.K.; Gupta, B.N.; Husain, T.; Mathur, N.; Srivastava, S. )

    1991-10-01

    A group of manual welders age group 13-60 years having a mean exposure period of 12.4 {plus minus} 1.12 years were subjected to spirometry to evaluate the prevalence of spirometric abnormalities. The welders showed a significantly higher prevalence of respiratory impairment than that observed among the unexposed controls as a result of exposure to welding gases which comprised fine particles of lead, zinc, chromium, and manganese. This occurred despite the lower concentration of the pollutants at the work place. In the expose group, the smoking welders showed a prevalence of respiratory impairment significantly higher than that observed in the nonsmoking welders. The results of the pulmonary function tests showed a predominantly restrictive type of pulmonary impairment followed by a mixed ventilatory defect among the welders. The effect of age on pulmonary impairment was not discernible. Welders exposed for over 10 years showed a prevalence of respiratory abnormalities significantly higher than those exposed for less than 10 years. Smoking also had a contributory role.

  12. Aortic Remodelling Is Improved by 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside Involving the Smad3 Pathway in Spontaneously Hypertensive Rats

    PubMed Central

    Duan, Ju; Han, Xin; Ling, Shuang; Gan, Woting; Sun, Li; Ni, Rong-Zhen; Xu, Jin-Wen

    2015-01-01

    Hypertension is a common health problem that substantially increases the risk of cardiovascular disease. The condition increases blood pressure, which causes alterations in vascular structure and leads to the development of vascular pathologies. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG), a resveratrol analogue extracted from a Chinese medicinal plant, has been proven to have numerous vascular protection functions. This study investigated whether THSG can improve vascular remodeling, which has thus far remained unclear. Orally administering THSG to spontaneously hypertensive rats (SHRs) aged 12 weeks for 14 weeks significantly inhibited intima-media thickness in the lower parts of the aortic arch, increased the vascular diastolic rate in response to acetylcholine, and reduced remodelling-related mRNA expression, such as that of ACTA2, CCL3, COL1A2, COL3A1, TIMP1 WISP2, IGFBP1, ECE1, KLF5, MYL1 BMP4, FN1, and PAI-1. Immunofluorescence staining also showed an inhibitory effect similar to that of THSG on PAI-1 protein expression in rat aortas. Results from immunoprecipitation and a Western blot assay showed that THSG inhibited the acetylation of Smad3. A chromatin immunoprecipitation assay showed that THSG prevented Smad3 binding to the PAI-1 proximal promoter in SHR aortas. In conclusion, our results demonstrated that the inhibitory effect of THSG on aortic remodelling involved the deacetylating role of Smad3 with increasing blood flow and with constant blood pressure. PMID:26693246

  13. Aortic Remodelling Is Improved by 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside Involving the Smad3 Pathway in Spontaneously Hypertensive Rats.

    PubMed

    Duan, Ju; Han, Xin; Ling, Shuang; Gan, Woting; Sun, Li; Ni, Rong-Zhen; Xu, Jin-Wen

    2015-01-01

    Hypertension is a common health problem that substantially increases the risk of cardiovascular disease. The condition increases blood pressure, which causes alterations in vascular structure and leads to the development of vascular pathologies. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG), a resveratrol analogue extracted from a Chinese medicinal plant, has been proven to have numerous vascular protection functions. This study investigated whether THSG can improve vascular remodeling, which has thus far remained unclear. Orally administering THSG to spontaneously hypertensive rats (SHRs) aged 12 weeks for 14 weeks significantly inhibited intima-media thickness in the lower parts of the aortic arch, increased the vascular diastolic rate in response to acetylcholine, and reduced remodelling-related mRNA expression, such as that of ACTA2, CCL3, COL1A2, COL3A1, TIMP1 WISP2, IGFBP1, ECE1, KLF5, MYL1 BMP4, FN1, and PAI-1. Immunofluorescence staining also showed an inhibitory effect similar to that of THSG on PAI-1 protein expression in rat aortas. Results from immunoprecipitation and a Western blot assay showed that THSG inhibited the acetylation of Smad3. A chromatin immunoprecipitation assay showed that THSG prevented Smad3 binding to the PAI-1 proximal promoter in SHR aortas. In conclusion, our results demonstrated that the inhibitory effect of THSG on aortic remodelling involved the deacetylating role of Smad3 with increasing blood flow and with constant blood pressure. PMID:26693246

  14. Clinical pharmacology and vascular risk.

    PubMed

    Silvestrelli, G; Corea, F; Micheli, S; Lanari, A

    2010-01-01

    Pharmacological treatment and several drugs of abuse have been associated with ischemic heart disease (IHD) and cerebrovascular diseases (CVD). However, there is a paucity of data on the independent risk of vascular disease (VD) associated with pharmacological treatment and no controlled trials demonstrating a reduction in risk with abstinence. Information about IHD and CVD-related drug abuse is mainly limited to epidemiological studies focused on urban populations. The potential link between some pharmacological treatments (estrogen, some oncologic drugs and some atypical antipsychotics) and cerebrovascular adverse events was analyzed, but disagreement about an association persists. Drugs of abuse, including cocaine, amphetamines and heroin, have been associated with an increased vascular risk. These drugs can cause abrupt changes in blood pressure, vasculitic-type changes, lead to embolization caused by infective endocarditis, and hemostatic and hematologic abnormalities that can result in increased blood viscosity and platelet aggregation. Long-term treatment strategies based on medication, psychological support, and outreach programs play an important role in treatment of drug dependency. In these last years public interest in risk factors for VD has been constantly increasing and the successful identification and management of pharmacological treatment and drug abuse can be challenging. One of the major public health issues for the future will be to focus more on new vascular risk factor recognition and management. The objective of this chapter is to review the relevance of IHD and CVD associated with various pharmacological treatments and drug abuse with focusing on ischemic disease. This chapter reports the clinical evidence of this association and analyzes the experimental role of new drugs as a growing risk factor of VD with the hypothetical new association. In conclusion, in this chapter great attention is paid to evaluating the scientific and real

  15. Chronic miR-29 antagonism promotes favorable plaque remodeling in atherosclerotic mice.

    PubMed

    Ulrich, Victoria; Rotllan, Noemi; Araldi, Elisa; Luciano, Amelia; Skroblin, Philipp; Abonnenc, Mélanie; Perrotta, Paola; Yin, Xiaoke; Bauer, Ashley; Leslie, Kristen L; Zhang, Pei; Aryal, Binod; Montgomery, Rusty L; Thum, Thomas; Martin, Kathleen; Suarez, Yajaira; Mayr, Manuel; Fernandez-Hernando, Carlos; Sessa, William C

    2016-01-01

    Abnormal remodeling of atherosclerotic plaques can lead to rupture, acute myocardial infarction, and death. Enhancement of plaque extracellular matrix (ECM) may improve plaque morphology and stabilize lesions. Here, we demonstrate that chronic administration of LNA-miR-29 into an atherosclerotic mouse model improves indices of plaque morphology. This occurs due to upregulation of miR-29 target genes of the ECM (col1A and col3A) resulting in reduced lesion size, enhanced fibrous cap thickness, and reduced necrotic zones. Sustained LNA-miR-29 treatment did not affect circulating lipids, blood chemistry, or ECM of solid organs including liver, lung, kidney, spleen, or heart. Collectively, these data support the idea that antagonizing miR-29 may promote beneficial plaque remodeling as an independent approach to stabilize vulnerable atherosclerotic lesions. PMID:27137489

  16. Adolescent Alcohol Exposure: Burden of Epigenetic Reprogramming, Synaptic Remodeling, and Adult Psychopathology.

    PubMed

    Kyzar, Evan J; Floreani, Christina; Teppen, Tara L; Pandey, Subhash C

    2016-01-01

    Adolescence represents a crucial phase of synaptic maturation characterized by molecular changes in the developing brain that shape normal behavioral patterns. Epigenetic mechanisms play an important role in these neuromaturation processes. Perturbations of normal epigenetic programming during adolescence by ethanol can disrupt these molecular events, leading to synaptic remodeling and abnormal adult behaviors. Repeated exposure to binge levels of alcohol increases the risk for alcohol use disorder (AUD) and comorbid psychopathology including anxiety in adulthood. Recent studies in the field clearly suggest that adolescent alcohol exposure causes widespread and persistent changes in epigenetic, neurotrophic, and neuroimmune pathways in the brain. These changes are manifested by altered synaptic remodeling and neurogenesis in key brain regions leading to adult psychopathology such as anxiety and alcoholism. This review details the molecular mechanisms underlying adolescent alcohol exposure-induced changes in synaptic plasticity and the development of alcohol addiction-related phenotypes in adulthood. PMID:27303256

  17. Adolescent Alcohol Exposure: Burden of Epigenetic Reprogramming, Synaptic Remodeling, and Adult Psychopathology

    PubMed Central

    Kyzar, Evan J.; Floreani, Christina; Teppen, Tara L.; Pandey, Subhash C.

    2016-01-01

    Adolescence represents a crucial phase of synaptic maturation characterized by molecular changes in the developing brain that shape normal behavioral patterns. Epigenetic mechanisms play an important role in these neuromaturation processes. Perturbations of normal epigenetic programming during adolescence by ethanol can disrupt these molecular events, leading to synaptic remodeling and abnormal adult behaviors. Repeated exposure to binge levels of alcohol increases the risk for alcohol use disorder (AUD) and comorbid psychopathology including anxiety in adulthood. Recent studies in the field clearly suggest that adolescent alcohol exposure causes widespread and persistent changes in epigenetic, neurotrophic, and neuroimmune pathways in the brain. These changes are manifested by altered synaptic remodeling and neurogenesis in key brain regions leading to adult psychopathology such as anxiety and alcoholism. This review details the molecular mechanisms underlying adolescent alcohol exposure-induced changes in synaptic plasticity and the development of alcohol addiction-related phenotypes in adulthood. PMID:27303256

  18. Growth and Remodeling in Blood Vessels Studied In Vivo With Fractal Analysis

    NASA Technical Reports Server (NTRS)

    Parsons-Wingerter, Patricia A.

    2003-01-01

    Every cell in the human body must reside in close proximity to a blood vessel (within approximately 200 mm) because blood vessels provide the oxygen, metabolite, and fluid exchanges required for cellular existence. The growth and remodeling of blood vessels are required to support the normal physiology of embryonic development, reproductive biology, wound healing and adaptive remodeling to exercise, as well as abnormal tissue change in diseases such as cancer, diabetes, and coronary heart disease. Cardiovascular and hemodynamic (blood flow dynamics) alterations experienced by astronauts during long-term spaceflight, including orthostatic intolerance, fluid shifts in the body, and reduced numbers of red (erythrocyte) and white (immune) blood cells, are identified as risk factors of very high priority in the NASA task force report on risk reduction for human spaceflight, the "Critical Path Roadmap."

  19. Transcriptomic analysis reveals abnormal muscle repair and remodeling in survivors of critical illness with sustained weakness.

    PubMed

    Walsh, Christopher J; Batt, Jane; Herridge, Margaret S; Mathur, Sunita; Bader, Gary D; Hu, Pingzhao; Dos Santos, Claudia C

    2016-01-01

    ICU acquired weakness (ICUAW) is a common complication of critical illness characterized by structural and functional impairment of skeletal muscle. The resulting physical impairment may persist for years after ICU discharge, with few patients regaining functional independence. Elucidating molecular mechanisms underscoring sustained ICUAW is crucial to understanding outcomes linked to different morbidity trajectories as well as for the development of novel therapies. Quadriceps muscle biopsies and functional measures of muscle strength and mass were obtained at 7 days and 6 months post-ICU discharge from a cohort of ICUAW patients. Unsupervised co-expression network analysis of transcriptomic profiles identified discrete modules of co-expressed genes associated with the degree of muscle weakness and atrophy in early and sustained ICUAW. Modules were enriched for genes involved in skeletal muscle regeneration and extracellular matrix deposition. Collagen deposition in persistent ICUAW was confirmed by histochemical stain. Modules were further validated in an independent cohort of critically ill patients with sepsis-induced multi-organ failure and a porcine model of ICUAW, demonstrating disease-associated conservation across species and peripheral muscle type. Our findings provide a pathomolecular basis for sustained ICUAW, implicating aberrant expression of distinct skeletal muscle structural and regenerative genes in early and persistent ICUAW. PMID:27411715

  20. Transcriptomic analysis reveals abnormal muscle repair and remodeling in survivors of critical illness with sustained weakness

    PubMed Central

    Walsh, Christopher J.; Batt, Jane; Herridge, Margaret S.; Mathur, Sunita; Bader, Gary D.; Hu, Pingzhao; dos Santos, Claudia C.

    2016-01-01

    ICU acquired weakness (ICUAW) is a common complication of critical illness characterized by structural and functional impairment of skeletal muscle. The resulting physical impairment may persist for years after ICU discharge, with few patients regaining functional independence. Elucidating molecular mechanisms underscoring sustained ICUAW is crucial to understanding outcomes linked to different morbidity trajectories as well as for the development of novel therapies. Quadriceps muscle biopsies and functional measures of muscle strength and mass were obtained at 7 days and 6 months post-ICU discharge from a cohort of ICUAW patients. Unsupervised co-expression network analysis of transcriptomic profiles identified discrete modules of co-expressed genes associated with the degree of muscle weakness and atrophy in early and sustained ICUAW. Modules were enriched for genes involved in skeletal muscle regeneration and extracellular matrix deposition. Collagen deposition in persistent ICUAW was confirmed by histochemical stain. Modules were further validated in an independent cohort of critically ill patients with sepsis-induced multi-organ failure and a porcine model of ICUAW, demonstrating disease-associated conservation across species and peripheral muscle type. Our findings provide a pathomolecular basis for sustained ICUAW, implicating aberrant expression of distinct skeletal muscle structural and regenerative genes in early and persistent ICUAW. PMID:27411715

  1. Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation.

    PubMed

    Kapustin, A N; Shanahan, C M

    2016-06-01

    Vascular smooth muscle cell (VSMC) phenotypic conversion from a contractile to 'synthetic' state contributes to vascular pathologies including restenosis, atherosclerosis and vascular calcification. We have recently found that the secretion of exosomes is a feature of 'synthetic' VSMCs and that exosomes are novel players in vascular repair processes as well as pathological vascular thrombosis and calcification. Pro-inflammatory cytokines and growth factors as well as mineral imbalance stimulate exosome secretion by VSMCs, most likely by the activation of sphingomyelin phosphodiesterase 3 (SMPD3) and cytoskeletal remodelling. Calcium stress induces dramatic changes in VSMC exosome composition and accumulation of phosphatidylserine (PS), annexin A6 and matrix metalloproteinase-2, which converts exosomes into a nidus for calcification. In addition, by presenting PS, VSMC exosomes can also provide the catalytic surface for the activation of coagulation factors. Recent data showing that VSMC exosomes are loaded with proteins and miRNA regulating cell adhesion and migration highlight VSMC exosomes as potentially important communication messengers in vascular repair. Thus, the identification of signalling pathways regulating VSMC exosome secretion, including activation of SMPD3 and cytoskeletal rearrangements, opens up novel avenues for a deeper understanding of vascular remodelling processes. PMID:26864864

  2. Vascular Dysfunction in Pneumocystis-Associated Pulmonary Hypertension Is Related to Endothelin Response and Adrenomedullin Concentration.

    PubMed

    Siemsen, Dan W; Dobrinen, Erin; Han, Soo; Chiocchi, Kari; Meissner, Nicole; Swain, Steve D

    2016-02-01

    Pulmonary hypertension subsequent to an infectious disease can be due to vascular structural remodeling or to functional alterations within various vascular cell types. In our previous mouse model of Pneumocystis-associated pulmonary hypertension, we found that vascular remodeling was not responsible for observed increases in right ventricular pressures. Here, we report that the vascular dysfunction we observed could be explained by an enhanced response to endothelin-1 (20% greater reduction in lumen diameter, P ≤ 0.05), corresponding to an up-regulation of similar magnitude (P ≤ 0.05) of the endothelin A receptor in the lung tissue. This effect was potentially augmented by a decrease in production of the pulmonary vasodilator adrenomedullin of almost 70% (P ≤ 0.05). These changes did not occur in interferon-γ knockout mice similarly treated, which do not develop pulmonary hypertension under these circumstances. Surprisingly, we did not observe any relevant changes in the vascular endothelial nitric oxide synthase vasodilatory response, which is a common potential site of inflammatory alterations to pulmonary vascular function. Our results indicate the diverse mechanisms by which inflammatory responses to prior infections can cause functionally relevant changes in vascular responses in the lung, promoting the development of pulmonary hypertension. PMID:26687815

  3. Optimization of Cranio-Orbital Remodeling: Application of a Mathematical Model.

    PubMed

    Isaac, Kathryn V; Koenemann, Jochen; Fukasawa, Ricardo; Qian, David; Linhares, Andre; Saber, Nikoo R; Drake, James; Forrest, Christopher R; Phillips, John H; Nguyen, Phuong D

    2015-07-01

    Cranio-orbital remodeling aims to correct the dysmorphic skull associated with craniosynostosis. Traditionally, the skull is reconstructed into a shape that is subjectively normal according to the surgeon's perception. We present a novel technique using a mathematical algorithm to define the optimal location for bony osteotomies and to objectively reshape the fronto-orbital bar into an ideal normal skull contour. Using pre-operative computed tomography images, the abnormal skull contour at the frontal-orbital region was obtained for infants planned to undergo cranio-orbital remodeling. The ideal skull shape was derived from an age- and sex-matched normative skull library. For each patient, the mathematical technique of dynamic programming (DP) was applied to compare the abnormal and ideal skull shapes. The DP algorithm identifies the optimal location of osteotomy sites and calculates the objective difference in surface area remaining between the normative and dysmorphic skull shape for each solution applied. By selecting the optimal solution with minimal objective difference, the surgeon is guided to reproducibly recreate the normal skull contour with defined osteotomies. The DP algorithm was applied in 13 cases of cranio-orbital remodeling. Five female and 8 male infants with a mean age of 11 months were treated for craniosynostosis classified as metopic (n = 7), unicoronal (n = 4), or bicoronal (n = 2). The mean OR time was 190.2  min (SD 33.6), mean estimated blood loss 244  cc (SD 147.6), and 10 infants required blood transfusions. Compared with a historical crania-orbital remodeling group treated without application of the algorithm, there was no significant difference in OR time, estimated blood loss, or transfusion rate. This novel technique enables the craniofacial surgeon to objectively reshape the fronto-orbital bar and reproducibly reconstruct a skull shape resembling that of normal infants. PMID:26163851