Vascular risk factors and the effect of white matter lesions on extrapyramidal signs in Alzheimer's disease.

PubMed

Park, Moon Ho; Min, Joo Young; Kwon, Do-Young; Lee, Seung Hwan; Na, Hae Ri; Cho, Sung Tae; Na, Duk L

2011-06-01

Extrapyramidal signs (EPSs), which are important characteristics of Parkinson's disease (PD), occur frequently in Alzheimer's disease (AD). Although AD and PD share common clinical features such as EPSs, these diseases vary with respect to vascular risk factors. The presence of vascular risk factors increases the risk of AD; however, these factors have been known to be inversely associated with PD. We aimed to assess the effect of vascular risk factors and white matter lesions (WMLs) on EPSs in AD. We recruited 1,187 AD patients and 333 controls with neither cognitive impairment nor EPSs. All participants underwent detailed clinical evaluations which included assessments of vascular risk factors, cognitive function, and EPSs, as well as WMLs on brain MRIs. EPS subtypes were classified into tremor-dominant, postural instability gait difficulty, or indeterminate; WMLs subtypes were classified into periventricular WML (pvWML) or deep WML (dWML). EPSs were present in 17.9% of subjects with AD and were significantly associated with vascular risk factors such as age, male gender, diabetes mellitus, and WMLs. Additionally, a multivariate logistic regression analysis showed that EPSs in AD were associated with pvWML (odds ratio (OR), 1.61-2.52), not with dWML. With respect to EPS subtypes, the majority (78.4%) of EPSs in AD were postural instability gait difficulty, which was also associated with WMLs (OR 1.84-2.41), pvWML (OR 2.09-3.14), and dWML (OR 1.83-3.42). EPSs in AD are associated with selected vascular risk factors as well as WMLs.

Outcomes and factors influencing prognosis in patients with vascular pythiosis.

PubMed

Sermsathanasawadi, Nuttawut; Praditsuktavorn, Banjerd; Hongku, Kiattisak; Wongwanit, Chumpol; Chinsakchai, Khamin; Ruangsetakit, Chanean; Hahtapornsawan, Suteekhanit; Mutirangura, Pramook

2016-08-01

Vascular pythiosis, caused by Pythium insidiosum, is associated with a high mortality rate. We reviewed the outcomes and established the factors predicting prognosis of patients treated in our institution with surgery, antifungal therapy, or immunotherapy. We undertook a retrospective record review of patients with vascular pythiosis treated in Siriraj Hospital, Bangkok, Thailand, between January 2005 and January 2015. Patient characteristics, type of surgery, adjunctive antifungal treatment, adjunctive immunotherapy, and disease status of surgical arterial and surrounding soft tissue margins were recorded. We calculated the mortality rate and established factors predicting prognosis. The records of 11 patients were reviewed. All patients had thalassemia. Nine patients (81.8%) had a history of contact with contaminated water. The clinical presentations were chronic ulcers (45.5%), toe gangrene (27.3%), pulsatile mass (27.3%), and acute limb ischemia (27.3%). Above-knee amputation was required in 10 patients (90.9%). The mortality rate was 36.4%. Independent variables between survivors and nonsurvivors were lack of an arterial disease-free surgical margin (P = .003), lack of a surrounding soft tissue disease-free surgical margin (P < .05), a suprainguinal lesion (P < .05) and duration of symptoms (P < .05). Adjuvant itraconazole, terbinafine, and Pythium vaccine have a role to play in patients with a disease-free arterial surgical margin but in whom infected surrounding soft tissue could not be completely excised. Achieving adequate disease-free surgical margins-especially the arterial margin-at amputation or débridement is the most important prognostic factor in patients with vascular pythiosis. Early detection combined with a multidisciplinary approach to treatment, including surgery, antifungal agents, and immunotherapy, allows the best possible outcome to be obtained. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights

Vascular endothelial growth factors: A comparison between invertebrates and vertebrates.

PubMed

Kipryushina, Yulia O; Yakovlev, Konstantin V; Odintsova, Nelly A

2015-12-01

This review aims to summarize recent data concerning the structure and role of the members of the vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) families in the context of early development, organogenesis and regeneration, with a particular emphasis on the role of these factors in the development of invertebrates. Homologs of VEGF and/or VEGFR have been found in all Eumetazoa, in both Radiata and Bilateria, where they are expressed in the descendants of different germ layers and play a pivotal role in the development of animals with and without a vascular system. VEGF is a well-known angiogenesis regulator, but this factor also control cell migration during neurogenesis and the development of branching organs (the trachea) in invertebrate and vertebrate species. A possible explanation for the origin of Vegf/Vegfr in the animal kingdom and a pathway of Vegf/Vegfr evolution are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Improving Global Vascular Risk Prediction with Behavioral and Anthropometric Factors: The Multi-ethnic Northern Manhattan Cohort Study

PubMed Central

Sacco, Ralph L.; Khatri, Minesh; Rundek, Tatjana; Xu, Qiang; Gardener, Hannah; Boden-Albala, Bernadette; Di Tullio, Marco R.; Homma, Shunichi; Elkind, Mitchell SV; Paik, Myunghee C

2010-01-01

Objective To improve global vascular risk prediction with behavioral and anthropometric factors. Background Few cardiovascular risk models are designed to predict the global vascular risk of MI, stroke, or vascular death in multi-ethnic individuals, and existing schemes do not fully include behavioral risk factors. Methods A randomly-derived, population-based, prospective cohort of 2737 community participants free of stroke and coronary artery disease were followed annually for a median of 9.0 years in the Northern Manhattan Study (mean age 69 years; 63.2% women; 52.7% Hispanic, 24.9% African-American, 19.9% white). A global vascular risk score (GVRS) predictive of stroke, myocardial infarction, or vascular death was developed by adding variables to the traditional Framingham cardiovascular variables based on the likelihood ratio criterion. Model utility was assessed through receiver operating characteristics, calibration, and effect on reclassification of subjects. Results Variables which significantly added to the traditional Framingham profile included waist circumference, alcohol consumption, and physical activity. Continuous measures for blood pressure and fasting blood sugar were used instead of hypertension and diabetes. Ten -year event-free probabilities were 0.95 for the first quartile of GVRS, 0.89 for the second quartile, 0.79 for the third quartile, and 0.56 for the fourth quartile. The addition of behavioral factors in our model improved prediction of 10 -year event rates compared to a model restricted to the traditional variables. Conclusion A global vascular risk score that combines both traditional, behavioral, and anthropometric risk factors, uses continuous variables for physiological parameters, and is applicable to non-white subjects could improve primary prevention strategies. PMID:19958966

Vascular endothelial growth factor c/vascular endothelial growth factor receptor 3 signaling regulates chemokine gradients and lymphocyte migration from tissues to lymphatics.

PubMed

Iwami, Daiki; Brinkman, C Colin; Bromberg, Jonathan S

2015-04-01

Circulation of leukocytes via blood, tissue and lymph is integral to adaptive immunity. Afferent lymphatics form CCL21 gradients to guide dendritic cells and T cells to lymphatics and then to draining lymph nodes (dLN). Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 (VEGFR-3) are the major lymphatic growth factor and receptor. We hypothesized these molecules also regulate chemokine gradients and lymphatic migration. CD4 T cells were injected into the foot pad or ear pinnae, and migration to afferent lymphatics and dLN quantified by flow cytometry or whole mount immunohistochemistry. Vascular endothelial growth factor receptor 3 or its signaling or downstream actions were modified with blocking monoclonal antibodies (mAbs) or other reagents. Anti-VEGFR-3 prevented migration of CD4 T cells into lymphatic lumen and significantly decreased the number that migrated to dLN. Anti-VEGFR-3 abolished CCL21 gradients around lymphatics, although CCL21 production was not inhibited. Heparan sulfate (HS), critical to establish CCL21 gradients, was down-regulated around lymphatics by anti-VEGFR-3 and this was dependent on heparanase-mediated degradation. Moreover, a Phosphoinositide 3-kinase (PI3K)α inhibitor disrupted HS and CCL21 gradients, whereas a PI3K activator prevented the effects of anti-VEGFR-3. During contact hypersensitivity, VEGFR-3, CCL21, and HS expression were all attenuated, and anti-heparanase or PI3K activator reversed these effects. Vascular endothelial growth factor C/VEGFR-3 signaling through PI3Kα regulates the activity of heparanase, which modifies HS and CCL21 gradients around lymphatics. The functional and physical linkages of these molecules regulate lymphatic migration from tissues to dLN. These represent new therapeutic targets to influence immunity and inflammation.

Cognitive Function and Vascular Risk Factors Among Older African American Adults

PubMed Central

Park, Moon Ho; Tsang, Siny; Sperling, Scott A.; Manning, Carol

2017-01-01

To evaluate the association between vascular risk factors and cognitive impairment among older African American (AA) adults in a primary care clinic. Participants included 96 AA adults aged 60 years or older who were evaluated for global and domain-specific cognition. Participants were interviewed using the Computerized Assessment of Memory and Cognitive Impairment (CAMCI). The relationship between CAMCI cognitive domain scores and vascular risk factors were examined using hierarchical regression models. Patients who smoked, those with higher SBP/DBP values had lower accuracy rates on CAMCI cognitive domains (attention, executive, memory).Those with higher BMI had better attention scores. Patients with higher HbA1C values had worse verbal memory. Patients with higher blood pressure were significantly faster in responding to tasks in the executive domain. Primary care providers working with older AA adults with these VRFs could implement cognitive screening earlier into their practice to reduce barriers of seeking treatment. PMID:28417319

Novel vascular endothelial growth factor blocker improves cellular viability and reduces hypobaric hypoxia-induced vascular leakage and oedema in rat brain.

PubMed

Saraswat, Deepika; Nehra, Sarita; Chaudhary, Kamal; CVS, Siva Prasad

2015-05-01

Vascular endothelial growth factor (VEGF) is an important cerebral angiogenic and permeability factor under hypoxia. There is a need to find effective molecules that may ameliorate hypoxia-induced cerebral oedema. In silico identification of novel candidate molecules that block VEGF-A site were identified and validated with a Ramachandran plot. The active site residues of VEGF-A were detected by Pocketfinder, CASTp, and DogSiteScorer. Based on in silico data, three VEGF-A blocker (VAB) candidate molecules (VAB1, VAB2, and VAB3) were checked for improvement in cellular viability and regulation of VEGF levels in N2a cells under hypoxia (0.5% O2 ). Additionally, the best candidate molecule's efficacy was assessed in male Sprague-Dawley rats for its ameliorative effect on cerebral oedema and vascular leakage under hypobaric hypoxia 7260 m. All experimental results were compared with the commercially available VEGF blocker sunitinib. Vascular endothelial growth factor-A blocker 1 was found most effective in increasing cellular viability and maintaining normal VEGF levels under hypoxia (0.5% oxygen) in N2a cells. Vascular endothelial growth factor-A blocker 1 effectively restored VEGF levels, decreased cerebral oedema, and reduced vascular leakage under hypobaric hypoxia when compared to sunitinib-treated rats. Vascular endothelial growth factor-A blocker 1 may be a promising candidate molecule for ameliorating hypobaric hypoxia-induced vasogenic oedema by regulating VEGF levels. © 2015 Wiley Publishing Asia Pty Ltd.

Vascular factors in suspected normal pressure hydrocephalus

PubMed Central

Agerskov, Simon; Rabiei, Katrin; Marlow, Thomas; Jensen, Christer; Guo, Xinxin; Kern, Silke; Wikkelsø, Carsten; Skoog, Ingmar

2016-01-01

Objective: We examined clinical and imaging findings of suspected idiopathic normal pressure hydrocephalus (iNPH) in relation to vascular risk factors and white matter lesions (WMLs), using a nested case-control design in a representative, population-based sample. Methods: From a population-based sample, 1,235 persons aged 70 years or older were examined with CT of the brain between 1986 and 2000. We identified 55 persons with hydrocephalic ventricular enlargement, i.e., radiologic findings consistent with iNPH. Among these, 26 had clinical signs that fulfilled international guideline criteria for probable iNPH. These cases were labeled suspected iNPH. Each case was matched to 5 controls from the same sample, based on age, sex, and study cohort. Data on risk factors were obtained from clinical examinations and the Swedish Hospital Discharge Register. History of hypertension, diabetes mellitus (DM), smoking, overweight, history of coronary artery disease, stroke/TIA, and WMLs on CT were examined. Risk factors associated with iNPH with a p value <0.1 in χ2 tests were included in conditional logistic regression models. Results: In the regression analyses, suspected iNPH was related to moderate to severe WMLs (odds ratio [OR] 5.2; 95% confidence interval [CI]: 1.5–17.6), while hydrocephalic ventricular enlargement was related to hypertension (OR 2.7; 95% CI: 1.1–6.8), moderate to severe WMLs (OR 6.5; 95% CI: 2.1–20.3), and DM (OR 4.3; 95% CI: 1.1–16.3). Conclusions: Hypertension, WMLs, and DM were related to clinical and imaging features of iNPH, suggesting that vascular mechanisms are involved in the pathophysiology. These findings might have implications for understanding disease mechanisms in iNPH and possibly prevention. PMID:26773072

Vascular risk factors and neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study.

PubMed

Steinberg, Martin; Hess, Kyle; Corcoran, Chris; Mielke, Michelle M; Norton, Maria; Breitner, John; Green, Robert; Leoutsakos, Jeannie; Welsh-Bohmer, Kathleen; Lyketsos, Constantine; Tschanz, Joann

2014-02-01

Knowledge of potentially modifiable risk factors for neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is important. This study longitudinally explores modifiable vascular risk factors for NPS in AD. Participants enrolled in the Cache County Study on Memory in Aging with no dementia at baseline were subsequently assessed over three additional waves, and those with incident (new onset) dementia were invited to join the Dementia Progression Study for longitudinal follow-up. A total of 327 participants with incident AD were identified and assessed for the following vascular factors: atrial fibrillation, hypertension, diabetes mellitus, angina, coronary artery bypass surgery, myocardial infarction, cerebrovascular accident, and use of antihypertensive or diabetes medicines. A vascular index (VI) was also calculated. NPS were assessed over time using the Neuropsychiatric Inventory (NPI). Affective and Psychotic symptom clusters were assessed separately. The association between vascular factors and change in NPI total score was analyzed using linear mixed model and in symptom clusters using a random effects model. No individual vascular risk factors or the VI significantly predicted change in any individual NPS. The use of antihypertensive medications more than four times per week was associated with higher total NPI and Affective cluster scores. Use of antihypertensive medication was associated with higher total NPI and Affective cluster scores. The results of this study do not otherwise support vascular risk factors as modifiers of longitudinal change in NPS in AD. Copyright © 2013 John Wiley & Sons, Ltd.

Melasma treatment: A novel approach using a topical agent that contains an anti-estrogen and a vascular endothelial growth factor inhibitor.

PubMed

Cohen, Philip R

2017-04-01

Melasma is an acquired disorder of pigmentation that presents with asymptomatic symmetric darkening of the face. The pathogenesis of this condition is multifactorial and influenced by several factors including female sex hormones, genetic predisposition and ultraviolet light exposure. The management of melasma is usually directed at more than one of the causative etiologic factors and often incorporates a combination of topical agents, with or without the addition of physical modalities. Estrogen and angiogenesis are significant factors in the etiology of melasma. A useful addition to the therapeutic armentarium for treating melasma would include a topical agent that could effect both of these causative factors. Specifically, a topical preparation consisting of an anti-estrogen and a vascular endothelial growth factor inhibitor would accomplish this goal. Suitable candidates that target estrogen receptors and vascular endothelial growth factor are currently used in medical oncology as systemic antineoplastic agents. The anti-estrogen could be either a selective estrogen receptor modulator (such as tamoxifen or raloxifene) or an aromatase inhibitor (such as anastrozole or letrozole or exemestane). The vascular endothelial growth factor inhibitor would be bevacizumab. In conclusion, a novel-topically administered-therapy for melasma would combine an anti-estrogen and a vascular endothelial growth factor inhibitor. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions

PubMed Central

Yamakawa, Hiroyuki; Muraoka, Naoto; Miyamoto, Kazutaka; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Umei, Tomohiko; Akiyama, Mizuha; Kuishi, Yuki; Kurokawa, Junko; Furukawa, Tetsushi; Fukuda, Keiichi; Ieda, Masaki

2015-01-01

Summary Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming. PMID:26626177

Cognitive patterns in relation to biomarkers of cerebrovascular disease and vascular risk factors.

PubMed

Miralbell, Júlia; López-Cancio, Elena; López-Oloriz, Jorge; Arenillas, Juan Francisco; Barrios, Maite; Soriano-Raya, Juan José; Galán, Amparo; Cáceres, Cynthia; Alzamora, Maite; Pera, Guillem; Toran, Pere; Dávalos, Antoni; Mataró, Maria

2013-01-01

Risk factors for vascular cognitive impairment (VCI) are the same as traditional risk factors for cerebrovascular disease (CVD). Early identification of subjects at higher risk of VCI is important for the development of effective preventive strategies. In addition to traditional vascular risk factors (VRF), circulating biomarkers have emerged as potential tools for early diagnoses, as they could provide in vivo measures of the underlying pathophysiology. While VRF have been consistently linked to a VCI profile (i.e., deficits in executive functions and processing speed), the cognitive correlates of CVD biomarkers remain unclear. In this population-based study, the aim was to study and compare cognitive patterns in relation to VRF and circulating biomarkers of CVD. The Barcelona-AsIA Neuropsychology Study included 747 subjects older than 50, without a prior history of stroke or coronary disease and with a moderate to high vascular risk (mean age, 66 years; 34.1% women). Three cognitive domains were derived from factoral analysis: visuospatial skills/speed, verbal memory and verbal fluency. Multiple linear regression was used to assess relationships between cognitive performance (multiple domains) and a panel of circulating biomarkers, including indicators of inflammation, C-reactive protein (CRP) and resistin, endothelial dysfunction, asymmetric dimethylarginine (ADMA), thrombosis, plasminogen activator inhibitor 1 (PAI-1), as well as traditional VRF, metabolic syndrome and insulin resistance (homeostatic model assessment for insulin resistance index). Analyses were adjusted for age, gender, years of education and depressive symptoms. Traditional VRF were related to lower performance in verbal fluency, insulin resistance accounted for lower performance in visuospatial skills/speed and the metabolic syndrome predicted lower performance in both cognitive domains. From the biomarkers of CVD, CRP was negatively related to verbal fluency performance and increasing ADMA

Fibroblast growth factor regulates insulin-like growth factor-binding protein production by vascular smooth muscle cells.

PubMed

Ververis, J; Ku, L; Delafontaine, P

1994-02-01

Insulin-like growth factor I is an important mitogen for vascular smooth muscle cells, and its effects are regulated by several binding proteins. Western ligand blotting of conditioned medium from rat aortic smooth muscle cells detected a 24 kDa binding protein and a 28 kDa glycosylated variant of this protein, consistent with insulin-like growth factor binding protein-4 by size. Low amounts of a glycosylated 38 to 42 kDa doublet (consistent with binding protein-3) and a 31 kDa non-glycosylated protein also were present. Basic fibroblast growth factor markedly increased secretion of the 24 kDa binding protein and its 28 kDa glycosylated variant. This effect was dose- and time-dependent and was inhibited by co-incubation with cycloheximide. Crosslinking of [125I]-insulin-like growth factor I to cell monolayers revealed no surface-associated binding proteins, either basally or after agonist treatment. Induction of binding protein production by fibroblast growth factor at sites of vascular injury may be important in vascular proliferative responses in vivo.

Detrimental effect of systemic vascular risk factors on brain hemodynamic function assessed with MRI.

PubMed

King, Kevin S; Sheng, Min; Liu, Peiying; Maroules, Christopher D; Rubin, Craig D; Peshock, Ron M; McColl, Roderick W; Lu, Hanzhang

2018-06-01

Background and purpose Vascular risk factors have been associated with decreased cerebral blood flow (CBF) but this is etiologically nonspecific and may result from vascular insufficiency or a response to decreased brain metabolic activity. We apply new MRI techniques to measure oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO 2 ), hypothesizing that decreased CBF related to these vascular risk factors will be associated with increased OEF, confirming a primary vascular insufficiency. Methods 3T MRI was obtained on 70 community-based participants in this IRB-approved study with informed consent, with previous assessment of systolic blood pressure, hypertension medication, elevated serum triglycerides, low serum HDL, and diabetes mellitus. CBF was measured using phase contrast adjusted for brain volume (ml/100 g/min), OEF (%) was obtained from T2-Relaxation-Under-Spin-Tagging (TRUST), and CMRO 2 (μmol/100 g/min) was derived using the Fick principle. Stepwise linear regression identified optimal predictors of CBF with age, sex, and hematocrit included for adjustment. This predictive model was then evaluated against OEF and CMRO 2 . Results Hypertriglyceridemia was associated with low CBF and high OEF. High systolic blood pressure was associated with high CBF and low OEF, which was primarily attributable to those with pressures above 160 mmHg. Neither risk factor was associated with significant differences in cerebral metabolic rate. Conclusion Low CBF related to hypertriglyceridemia was accompanied by high OEF with no significant difference in CMRO 2 , confirming subclinical vascular insufficiency. High CBF related to high systolic blood pressure likely reflected limitations of autoregulation at higher blood pressures.

ISCHEMIC CENTRAL RETINAL VEIN OCCLUSION IN THE ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR ERA.

PubMed

Tam, Emily K; Golchet, Pamela; Yung, Madeline; DeCroos, Francis C; Spirn, Marc; Lehmann-Clarke, Lydia; Ambresin, Aude; Tsui, Irena

2018-02-01

Anti-vascular endothelial growth factor therapy has improved the prognosis for patients with central retinal vein occlusion (CRVO). However, most studies published to date exclude ischemic CRVO. The purpose of this study was to describe the outcome in eyes with ischemic CRVO treated with anti-vascular endothelial growth factor therapy. Thirty-seven patients with ischemic CRVO from 3 centers were followed for at least 6 months. Data on patient demographic, vision status, and anti-vascular endothelial growth factor treatments were collected. Average number of injections during the study period was 5. Younger age was associated with improved vision (P = 0.006). Patients with improved visual outcomes tended to have macular edema as the primary indication for treatment, whereas patients with worse outcomes tended to have neovascularization as the primary indication for treatment. This study highlights significant variability in the use of anti-vascular endothelial growth factor therapy for ischemic CRVO and underscores that eyes with neovascularization tend to have worse visual outcomes.

Vascular Endothelial Growth Factor (VEGF) and Platelet (PF-4) Factor 4 Inputs Modulate Human Microvascular Endothelial Signaling in a Three-Dimensional Matrix Migration Context*

PubMed Central

Hang, Ta-Chun; Tedford, Nathan C.; Reddy, Raven J.; Rimchala, Tharathorn; Wells, Alan; White, Forest M.; Kamm, Roger D.; Lauffenburger, Douglas A.

2013-01-01

The process of angiogenesis is under complex regulation in adult organisms, particularly as it often occurs in an inflammatory post-wound environment. As such, there are many impacting factors that will regulate the generation of new blood vessels which include not only pro-angiogenic growth factors such as vascular endothelial growth factor, but also angiostatic factors. During initial postwound hemostasis, a large initial bolus of platelet factor 4 is released into localized areas of damage before progression of wound healing toward tissue homeostasis. Because of its early presence and high concentration, the angiostatic chemokine platelet factor 4, which can induce endothelial anoikis, can strongly affect angiogenesis. In our work, we explored signaling crosstalk interactions between vascular endothelial growth factor and platelet factor 4 using phosphotyrosine-enriched mass spectrometry methods on human dermal microvascular endothelial cells cultured under conditions facilitating migratory sprouting into collagen gel matrices. We developed new methods to enable mass spectrometry-based phosphorylation analysis of primary cells cultured on collagen gels, and quantified signaling pathways over the first 48 h of treatment with vascular endothelial growth factor in the presence or absence of platelet factor 4. By observing early and late signaling dynamics in tandem with correlation network modeling, we found that platelet factor 4 has significant crosstalk with vascular endothelial growth factor by modulating cell migration and polarization pathways, centered around P38α MAPK, Src family kinases Fyn and Lyn, along with FAK. Interestingly, we found EphA2 correlational topology to strongly involve key migration-related signaling nodes after introduction of platelet factor 4, indicating an influence of the angiostatic factor on this ambiguous but generally angiogenic signal in this complex environment. PMID:24023389

Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions.

PubMed

Yamakawa, Hiroyuki; Muraoka, Naoto; Miyamoto, Kazutaka; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Umei, Tomohiko; Akiyama, Mizuha; Kuishi, Yuki; Kurokawa, Junko; Furukawa, Tetsushi; Fukuda, Keiichi; Ieda, Masaki

2015-12-08

Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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

PubMed Central

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

2002-01-01

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

Vascular endothelial growth factor (VEGF) inhibition--a critical review.

PubMed

Moreira, Irina Sousa; Fernandes, Pedro Alexandrino; Ramos, Maria João

2007-03-01

Angiogenesis, or formation of new blood capillaries from preexisting vessels, plays both beneficial and damaging roles in the organism. It is a result of a complex balance of positive and negative regulators, and vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors involved in tumor angiogenesis. VEGF increases vascular permeability, which might facilitate tumor dissemination via the circulation causing a greater delivery of oxygen and nutrients; it recruits circulating endothelial precursor cells, and acts as a survival factor for immature tumor blood vessels. The endotheliotropic activities of VEGF are mediated through the VEGF-specific tyrosine-kinase receptors: VEGFR-1, VEGFR-2 and VEGFR-3. VEGF and its receptors play a central role in tumor angiogenesis, and therefore the blockade of this pathway is a promising therapeutic strategy for inhibiting angiogenesis and tumor growth. A number of different strategies to inhibit VEGF signal transduction are in development and they include the development of humanized neutralizing anti-VEGF monoclonal antibodies, receptor antagonists, soluble receptors, antagonistic VEGF mutants, and inhibitors of VEGF receptor function. These agents can be divided in two broad classes, namely agents designed to target the VEGF activity and agents designed to target the surface receptor function. The main purpose of this review is to summarize all the available information regarding the importance of the pro-angiogenic factor VEGF in cancer therapy. After an overview of the VEGF family and their respective receptors, we shall focus our attention on the different VEGF-inhibitors existent nowadays. Agents based upon anti-VEGF therapy have provided solid proofs about their success, and therefore we believe that a critical review is of the utmost importance to help researchers in their future work.

Roles of vascular and metabolic components in cognitive dysfunction of Alzheimer disease: short- and long-term modification by non-genetic risk factors.

PubMed

Sato, Naoyuki; Morishita, Ryuichi

2013-11-05

It is well known that a specific set of genetic and non-genetic risk factors contributes to the onset of Alzheimer disease (AD). Non-genetic risk factors include diabetes, hypertension in mid-life, and probably dyslipidemia in mid-life. This review focuses on the vascular and metabolic components of non-genetic risk factors. The mechanisms whereby non-genetic risk factors modify cognitive dysfunction are divided into four components, short- and long-term effects of vascular and metabolic factors. These consist of (1) compromised vascular reactivity, (2) vascular lesions, (3) hypo/hyperglycemia, and (4) exacerbated AD histopathological features, respectively. Vascular factors compromise cerebrovascular reactivity in response to neuronal activity and also cause irreversible vascular lesions. On the other hand, representative short-term effects of metabolic factors on cognitive dysfunction occur due to hypoglycemia or hyperglycemia. Non-genetic risk factors also modify the pathological manifestations of AD in the long-term. Therefore, vascular and metabolic factors contribute to aggravation of cognitive dysfunction in AD through short-term and long-term effects. β-amyloid could be involved in both vascular and metabolic components. It might be beneficial to support treatment in AD patients by appropriate therapeutic management of non-genetic risk factors, considering the contributions of these four elements to the manifestation of cognitive dysfunction in individual patients, though all components are not always present. It should be clarified how these four components interact with each other. To answer this question, a clinical prospective study that follows up clinical features with respect to these four components: (1) functional MRI or SPECT for cerebrovascular reactivity, (2) MRI for ischemic lesions and atrophy, (3) clinical episodes of hypoglycemia and hyperglycemia, (4) amyloid-PET and tau-PET for pathological features of AD, would be required.

Constructing a blood vessel on the porous scaffold modified with vascular endothelial growth factor and basic fibroblast growth factor

NASA Astrophysics Data System (ADS)

Sevostyanova, V. V.; Matveeva, V. G.; Antonova, L. V.; Velikanova, E. A.; Shabaev, A. R.; Senokosova, E. A.; Krivkina, E. O.; Vasyukov, G. Yu.; Glushkova, T. V.; Kudryavtseva, Yu. A.; Barbarash, O. L.; Barbarash, L. S.

2016-11-01

Incorporation of the growth factors into biodegradable polymers is a promising approach for the fabrication of tissue-engineered vascular grafts. Here we blended poly(ɛ-caprolactone) (PCL) with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) following incorporation of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) and then fabricated electrospun 2 mm diameter vascular grafts. Grafts without the growth factors were used as a control group. Structure of the grafts was assessed utilizing scanning electron microscopy. We further implanted our grafts into rat abdominal aorta for 1 and 3 months with the aim to test endothelialization, cell infiltration, and patency in vivo. Histological and immunofluorescence examination demonstrated enhanced endothelialization and cell infiltration of the grafts with either VEGF or bFGF compared to those without the growth factors. Grafts with VEGF showed higher patency compared to those with bFGF; however, bFGF promoted migration of smooth muscle cells and fibroblasts into the graft. Therefore, we conclude that incorporation of VEGF and bFGF into the inner and medial/outer layer, respectively, can be a promising option for the fabrication of tissue-engineered vascular grafts.

Vascular Endothelial Growth Factor and Angiopoietin are Required for Prostate Regeneration.

PubMed Central

Wang, Gui-min; Kovalenko, Bruce; Huang, Yili; Moscatelli, David

2007-01-01

BACKGROUND The regulation of the prostate size by androgens may be partly the result of androgen effects on the prostatic vasculature. We examined the effect of changes in androgen levels on the expression of a variety of angiogenic factors in the mouse prostate and determined if vascular endothelial growth factor (VEGF)-A and the angiopoietins are involved in the vascular response to androgens. METHODS Expression of angiogenic factors in prostate was quantitated using real-time PCR at different times after castration and after administration of testosterone to castrated mice. Angiopoietins were localized in prostate by immunohistochemistry and in situ hybridization. The roles of VEGF and the angiopoietins in regeneration of the prostate were examined in mice inoculated with cells expressing soluble VEGF receptor-2 or soluble Tie-2. RESULTS Castration resulted in a decrease in VEGF-A, VEGF-B, VEGF-C, placenta growth factor, FGF-2, and FGF-8 expression after one day. In contrast, VEGF-D mRNA levels increased. No changes in angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), hepatocyte growth factor, VEGF receptor-1, VEGF receptor-2 or tie-2 mRNA levels were observed. Administration of testosterone to castrated mice had the opposite effect on expression of these angiogenic factors. Ang-2 was expressed predominately in prostate epithelial cells whereas Ang-1 was expressed in epithelium and smooth muscle. Inoculation of mice with cells expressing soluble VEGF receptor-2 or Tie-2 blocked the increase in vascular density normally observed after administration of testosterone to castrated mice. The soluble receptors also blocked the increase in prostate weight and proliferation of prostatic epithelial cells. CONCLUSION VEGF-A and angiopoietins are required for the vascular response to androgens and for the ability of the prostate to regenerate in response to androgens. PMID:17221843

ACTINOMYCES NEUII ENDOPHTHALMITIS AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTION.

PubMed

Sahni, Sakshi; Watson, Randee Miller; Sheth, Veeral S

2017-01-01

To describe a case of acute endophthalmitis caused by Actinomyces neuii after intravitreal anti-vascular endothelial growth factor injection. Observational case report, review of published literature. A 67-year-old white man with wet age-related macular degeneration developed endophthalmitis secondary to A. neuii on the 10th day after intravitreal anti-vascular endothelial growth factor injection. Both anterior chamber and vitreous cultures were positive for A. neuii. He was treated successfully with intravitreal injection of vancomycin and ceftazidime. This is the first published report of culture-positive endophthalmitis caused by A. neuii after intravitreal injection.

Macrophages control vascular stem/progenitor cell plasticity through tumor necrosis factor-α-mediated nuclear factor-κB activation.

PubMed

Wong, Mei Mei; Chen, Yikuan; Margariti, Andriani; Winkler, Bernhard; Campagnolo, Paola; Potter, Claire; Hu, Yanhua; Xu, Qingbo

2014-03-01

Vascular lineage differentiation of stem/progenitor cells can contribute to both tissue repair and exacerbation of vascular diseases such as in vein grafts. The role of macrophages in controlling vascular progenitor differentiation is largely unknown and may play an important role in graft development. This study aims to identify the role of macrophages in vascular stem/progenitor cell differentiation and thereafter elucidate the mechanisms that are involved in the macrophage- mediated process. We provide in vitro evidence that macrophages can induce endothelial cell (EC) differentiation of the stem/progenitor cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived tumor necrosis factor-α (TNF-α) via TNF-α receptor 1 and canonical nuclear factor-κB activation. Although the overexpression of p65 enhanced EC (or attenuated smooth muscle cell) differentiation, p65 or TNF-α receptor 1 knockdown using lentiviral short hairpin RNA inhibited EC (or rescued smooth muscle cell) differentiation in response to TNF-α. Furthermore, TNF-α-mediated EC differentiation was driven by direct binding of nuclear factor-κB (p65) to specific VE-cadherin promoter sequences. Subsequent experiments using an ex vivo decellularized vessel scaffold confirmed an increase in the number of ECs and reduction in smooth muscle cell marker expression in the presence of TNF-α. The lack of TNF-α in a knockout mouse model of vein graft decreased endothelialization and significantly increased thrombosis formation. Our study highlights the role of macrophages in directing vascular stem/progenitor cell lineage commitment through TNF-α-mediated TNF-α receptor 1 and nuclear factor-κB activation that is likely required for endothelial repair in vascular diseases such as vein graft.

P14.21 Can vascular risk factors influence number of brain metastases?

PubMed Central

Berk, B.; Nagel, S.; Kortmann, R.; Hoffmann, K.; Gaudino, C.; Seidel, C.

2017-01-01

Abstract BACKGROUND: Up to 30-40% of patients with solid tumors develop cerebral metastases. Number of cerebral metastases is relevant for treatment and prognosis. However, factors that determine number of metastases are not well defined. Distribution of metastases is influenced by blood vessels and cerebral small vessel disease can reduce number of metastases. Aim of this pilot study was to analyze the influence of vascular risk factors (arterial hypertension, diabetes mellitus, smoking, hypercholesterolemia) and of peripheral arterial occlusive disease (PAOD) on number of brain metastases. METHODS: 200 patients with pre-therapeutic 3D-brain MRI and available clinical data were analyzed retrospectively. Number of metastases (NoM) was compared between patients with/without vascular risk factors (vasRF). Results: Patients with PAOD had significant less brain metastases than patients without PAOD (NoM=4.43 vs. 6.02, p=0.043), no other single vasRF conferred a significant effect on NoM. NoM differed significantly between different tumor entities. CONCLUSION: Presence of PAOD showed some effect on number of brain metastases implying that tumor-independent vascular factors can influence brain metastasation.

Brain Arterial Diameters as a Risk Factor for Vascular Events.

PubMed

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

2015-08-06

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. 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. 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. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Activating transcription factor 4 regulates stearate-induced vascular calcification.

PubMed

Masuda, Masashi; Ting, Tabitha C; Levi, Moshe; Saunders, Sommer J; Miyazaki-Anzai, Shinobu; Miyazaki, Makoto

2012-08-01

Previously, we reported that stearate, a saturated fatty acid, promotes osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMC). In this study, we examined the molecular mechanisms by which stearate promotes vascular calcification. ATF4 is a pivotal transcription factor in osteoblastogenesis and endoplasmic reticulum (ER) stress. Increased stearate by either supplementation of exogenous stearic acid or inhibition of stearoyl-CoA desaturase (SCD) by CAY10566 induced ATF4 mRNA, phosphorylated ATF4 protein, and total ATF4 protein. Induction occurred through activation of the PERK-eIF2α pathway, along with increased osteoblastic differentiation and mineralization of VSMCs. Either stearate or the SCD inhibitor but not oleate or other fatty acid treatments also increased ER stress as determined by the expression of p-eIF2α, CHOP, and the spliced form of XBP-1, which were directly correlated with ER stearate levels. ATF4 knockdown by lentiviral ATF4 shRNA blocked osteoblastic differentiation and mineralization induced by stearate and SCD inhibition. Conversely, treatment of VSMCs with an adenovirus containing ATF4 induced vascular calcification. Our results demonstrated that activation of ATF4 mediates vascular calcification induced by stearate.

Activating transcription factor 4 regulates stearate-induced vascular calcification

PubMed Central

Masuda, Masashi; Ting, Tabitha C.; Levi, Moshe; Saunders, Sommer J.; Miyazaki-Anzai, Shinobu; Miyazaki, Makoto

2012-01-01

Previously, we reported that stearate, a saturated fatty acid, promotes osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMC). In this study, we examined the molecular mechanisms by which stearate promotes vascular calcification. ATF4 is a pivotal transcription factor in osteoblastogenesis and endoplasmic reticulum (ER) stress. Increased stearate by either supplementation of exogenous stearic acid or inhibition of stearoyl-CoA desaturase (SCD) by CAY10566 induced ATF4 mRNA, phosphorylated ATF4 protein, and total ATF4 protein. Induction occurred through activation of the PERK-eIF2α pathway, along with increased osteoblastic differentiation and mineralization of VSMCs. Either stearate or the SCD inhibitor but not oleate or other fatty acid treatments also increased ER stress as determined by the expression of p-eIF2α, CHOP, and the spliced form of XBP-1, which were directly correlated with ER stearate levels. ATF4 knockdown by lentiviral ATF4 shRNA blocked osteoblastic differentiation and mineralization induced by stearate and SCD inhibition. Conversely, treatment of VSMCs with an adenovirus containing ATF4 induced vascular calcification. Our results demonstrated that activation of ATF4 mediates vascular calcification induced by stearate. PMID:22628618

Breast Angiosarcoma: Case Series and Expression of Vascular Endothelial Growth Factor

PubMed Central

Brar, Rondeep; West, Robert; Witten, Daniela; Raman, Bhargav; Jacobs, Charlotte; Ganjoo, Kristen

2009-01-01

Purpose Angiosarcoma of the breast is a rare, malignant tumor for which little is known regarding prognostic indicators and optimal therapeutic regimens. To address this issue, we performed a retrospective analysis of breast angiosarcoma cases seen at Stanford University along with immunohistochemical analysis for markers of angiogenesis. Methods Breast angiosarcoma cases seen between 1980 and 2008 were examined. Viable tissue blocks were analyzed for expression of vascular endothelial growth factor and its receptors. Results A total of 16 cases were identified. Data was collected regarding epidemiology, treatment, response rates, disease-free survival, and the use of various imaging modalities. Five tissue blocks remained viable for immunohistochemical analysis. Vascular endothelial growth factor-A was positively expressed in 3 of these samples. Conclusion Angiosarcoma of the breast is an aggressive malignancy with a propensity for both local recurrence and distant metastases. Angiogenesis inhibition may represent a novel therapeutic modality in this rare, vascular malignancy. PMID:20737044

Vascular risk factor burden and new-onset depression in the community.

PubMed

Adams, Shayna; Conner, Sarah; Himali, Jayandra J; Beiser, Alexa; Vasan, Ramachandran S; Seshadri, Sudha; Pase, Matthew P

2018-06-01

Depression is associated with an increased likelihood of cardiac events and stroke. We hypothesized that the vascular risk factor burden might itself predispose to both cardiovascular events and depression. Therefore, we examined whether aggregate scores of vascular risk factor burden were associated with the new-onset of depression in the community. We studied 2023 depression- and dementia-free Framingham Heart Study (Framingham, USA) Offspring participants who attended both examination cycles 7 (1998-2001) and 8 (2005-2008). The American Heart Association Ideal Cardiovascular Health metric and the Framingham stroke risk profile were calculated at exam seven. New-onset depression was adjudicated at examination cycle eight as antidepressant medication use or Centre for Epidemiologic Studies Depression Scale scores ≥16, after a mean follow-up of 6.6years (standard deviation=0.7). Of the 2023 participants, 269 (13%) developed new-onset depression. Following adjustments for age, sex, education, and the time interval between baseline and follow-up, the odds of new-onset depression decreased by 10% for each one-point increase in ideal cardiovascular health scores (Odds Ratio [OR], 0.90; 95% confidence interval [CI] 0.81-0.99) and increased by 4% for each percentage point increase in the Framingham stroke risk profile (OR, 1.04; CI, 1.00-1.07). Results were not explained by interim clinical stroke or cerebral white matter injury. In conclusion, vascular risk factor burden was associated with the new onset of depression. Shared vascular risk factors may contribute to the increased risk of cardiovascular events observed in persons with depression. Copyright © 2017 Elsevier Inc. All rights reserved.

Vascular Repair After Menstruation Involves Regulation of Vascular Endothelial Growth Factor-Receptor Phosphorylation by sFLT-1

PubMed Central

Graubert, Michael D.; Asuncion Ortega, Maria; Kessel, Bruce; Mortola, Joseph F.; Iruela-Arispe, M. Luisa

2001-01-01

Regeneration of the endometrium after menstruation requires a rapid and highly organized vascular response. Potential regulators of this process include members of the vascular endothelial growth factor (VEGF) family of proteins and their receptors. Although VEGF expression has been detected in the endometrium, the relationship between VEGF production, receptor activation, and endothelial cell proliferation during the endometrial cycle is poorly understood. To better ascertain the relevance of VEGF family members during postmenstrual repair, we have evaluated ligands, receptors, and activity by receptor phosphorylation in human endometrium throughout the menstrual cycle. We found that VEGF is significantly increased at the onset of menstruation, a result of the additive effects of hypoxia, transforming growth factor-α, and interleukin-1β. Both VEGF receptors, FLT-1 and KDR, followed a similar pattern. However, functional activity of KDR, as determined by phosphorylation studies, revealed activation in the late menstrual and early proliferative phases. The degree of KDR phosphorylation was inversely correlated with the presence of sFLT-1. Endothelial cell proliferation analysis in endometrium showed a peak during the late menstrual and early proliferative phases in concert with the presence of VEGF, VEGF receptor phosphorylation, and decrease of sFLT-1. Together, these results suggest that VEGF receptor activation and the subsequent modulation of sFLT-1 in the late menstrual phase likely contributes to the onset of angiogenesis and endothelial repair in the human endometrium. PMID:11290558

Risk Factor Analysis for Mastectomy Skin Flap Necrosis: Implications for Intraoperative Vascular Analysis.

PubMed

Reintgen, Christian; Leavitt, Adam; Pace, Elizabeth; Molas-Pierson, Justine; Mast, Bruce A

2016-06-01

Skin flap necrosis after mastectomy can be a devastating complication significantly affecting patient outcomes. Routine vascular analysis (fluorescein or laser angiography) of mastectomy skin flaps in all patients has been advocated but is of questionable cost-effectiveness. The purpose of this study was to identify the incidence and causative risk factors for mastectomy skin flap necrosis and thereby calculate the fiscal reality of intraoperative vascular screening. This is an institutional review board-approved retrospective study of all patients from 2007 to 2013 who underwent mastectomy related to breast cancer. Skin flap necrosis was defined as major if it necessitated return to the operating room. Data analysis was done for determination of causative factors of necrosis, including age, body mass index, smoking, previous irradiation, coronary artery disease, chronic obstructive pulmonary disorder, hypertension, gastroesophageal reflux disease, hyperlipidemia, obstructive sleep apnea, asthma, diabetes, thyroid disease, history of lumpectomy, and breast reduction or augmentation. During this time, intraoperative vascular screening was not done. Five hundred eighty-one patients underwent 616 mastectomies with a total of 34 necrotic events (5.5%)-16 major and 18 minor. Analyses via Student t tests, univariate analyses, χ testing, and logistic regression showed that history of smoking was the only patient factor associated with postoperative necrosis (P = 0.008). More frequently represented in the necrosis group, but without statistical significance, are previous lumpectomy (P = 0.069) and immediate reconstruction (P = 0.078).For the entire study period, the actual cost to the hospital for major necrotic events was $7,123.10 or $445.19 for each of the 16 major necrotic events and $209.50 for all 34 necrotic events. Per-patient cost-effective screening would need to be less than $11.54 for all patients, $100.33 for highest risk patients (smokers), and $21.65 for

Risk Factors for Vascular Occlusive Events and Death Due to Bleeding in Trauma Patients; an Analysis of the CRASH-2 Cohort

PubMed Central

Pealing, Louise; Perel, Pablo; Prieto-Merino, David; Roberts, Ian

2012-01-01

Background Vascular occlusive events can complicate recovery following trauma. We examined risk factors for venous and arterial vascular occlusive events in trauma patients and the extent to which the risk of vascular occlusive events varies with the severity of bleeding. Methods and Findings We conducted a cohort analysis using data from a large international, double-blind, randomised, placebo-controlled trial (The CRASH-2 trial) [1]. We studied the association between patient demographic and physiological parameters at hospital admission and the risk of vascular occlusive events. To assess the extent to which risk of vascular occlusive events varies with severity of bleeding, we constructed a prognostic model for the risk of death due to bleeding and assessed the relationship between risk of death due to bleeding and risk of vascular occlusive events. There were 20,127 trauma patients with outcome data including 204 (1.01%) patients with a venous event (pulmonary embolism or deep vein thrombosis) and 200 (0.99%) with an arterial event (myocardial infarction or stroke). There were 81 deaths due to vascular occlusive events. Increasing age, decreasing systolic blood pressure, increased respiratory rates, longer central capillary refill times, higher heart rates and lower Glasgow Coma Scores (all p<0.02) were strong risk factors for venous and arterial vascular occlusive events. Patients with more severe bleeding as assessed by predicted risk of haemorrhage death had a greatly increased risk for all types of vascular occlusive event (all p<0.001). Conclusions Patients with severe traumatic bleeding are at greatly increased risk of venous and arterial vascular occlusive events. Older age and blunt trauma are also risk factors for vascular occlusive events. Effective treatment of bleeding may reduce venous and arterial vascular occlusive complications in trauma patients. PMID:23251374

Is Pseudoexfoliation Syndrome a Risk Factor for Cerebro Vascular Disease?

PubMed

Kan, Emrah; Yılmaz, Ahmet; Demirağ, Mehmet Derya; Çalık, Murat

2017-01-01

To determine the relationship between cerebro vascular disease and pseudoexfoliation syndrome. This cross-sectional case control study consisted of 50 patients with ischemic-type cerebro vascular disease and 50 control subjects. All subjects were investigated for diabetes mellitus and hypertension status and underwent a detailed ophthalmic examination. A diagnosis of pseudoexfoliation syndrome was made if characteristic greyish particulate matter was found on the anterior lens capsule after pupillary dilatation by slit-lamp examination. All subjects were compared in terms of pseudoexfoliation syndrome, diabetes mellitus, and hypertension. Pearson Chi Square and Student's t test were used for statistical analysis. Logistic regression analyses of the risk factors between groups were also made. The presence of pseudoexfoliation syndrome was significantly higher in patients with cerebro vascular disease when compared to the control subjects (p = 0.02). The frequency of diabetes mellitus was similar between the two groups. Arterial hypertension was significantly more frequent in the patient group when compared to the control subjects (p < 0.01). The logistic regression analysis showed that both pseudoexfoliation syndrome and hypertension were significantly associated with cerebro vascular disease. In the present study, we found that pseudoexfoliation syndrome frequency was found to be higher in patients with cerebro vascular disease than in control subjects. A slit-lamp examination of the eye could be an important marker that indicates the risk of cerebro vascular disease. We recommend an evaluation of all subjects with pseudoexfoliation syndrome for the presence of cerebro vascular disease. Longitudinal studies with larger populations are needed to confirm this relationship.

Genetic framework for GATA factor function in vascular biology.

PubMed

Linnemann, Amelia K; O'Geen, Henriette; Keles, Sunduz; Farnham, Peggy J; Bresnick, Emery H

2011-08-16

Vascular endothelial dysfunction underlies the genesis and progression of numerous diseases. Although the GATA transcription factor GATA-2 is expressed in endothelial cells and is implicated in coronary heart disease, it has been studied predominantly as a master regulator of hematopoiesis. Because many questions regarding GATA-2 function in the vascular biology realm remain unanswered, we used ChIP sequencing and loss-of-function strategies to define the GATA-2-instigated genetic network in human endothelial cells. In contrast to erythroid cells, GATA-2 occupied a unique target gene ensemble consisting of genes encoding key determinants of endothelial cell identity and inflammation. GATA-2-occupied sites characteristically contained motifs that bind activator protein-1 (AP-1), a pivotal regulator of inflammatory genes. GATA-2 frequently occupied the same chromatin sites as c-JUN and c-FOS, heterodimeric components of AP-1. Although all three components were required for maximal AP-1 target gene expression, GATA-2 was not required for AP-1 chromatin occupancy. GATA-2 conferred maximal phosphorylation of chromatin-bound c-JUN at Ser-73, which stimulates AP-1-dependent transactivation, in a chromosomal context-dependent manner. This work establishes a link between a GATA factor and inflammatory genes, mechanistic insights underlying GATA-2-AP-1 cooperativity and a rigorous genetic framework for understanding GATA-2 function in normal and pathophysiological vascular states.

Vascularized bone transplant chimerism mediated by vascular endothelial growth factor.

PubMed

Willems, Wouter F; Larsen, Mikko; Friedrich, Patricia F; Bishop, Allen T

2015-01-01

Vascular endothelial growth factor (VEGF) induces angiogenesis and osteogenesis in bone allotransplants. We aim to determine whether bone remodeling in VEGF-treated bone allotransplants results from repopulation with circulation-derived autogenous cells or survival of allogenic transplant-derived cells. Vascularized femoral bone transplants were transplanted from female Dark Agouti rats (DA;RT1(a) ) to male Piebald Viral Glaxo (PVG;RT1(c) ). Arteriovenous bundle implantation and short-term immunosuppression were used to maintain cellular viability. VEGF was encapsulated in biodegradable microspheres and delivered intramedullary in the experimental group (n = 22). In the control group (n = 22), no VEGF was delivered. Rats were sacrificed at 4 or 18 weeks. Laser capture microdissection of bone remodeling areas was performed at the inner and outer cortex. Sex-mismatched genes were quantified with reverse transcription-polymerase chain reaction to determine the amount of male cells to total cells, defined as the relative expression ratio (rER). At 4 weeks, rER was significantly higher at the inner cortex in VEGF-treated transplants as compared to untreated transplants (0.622 ± 0.225 vs. 0.362 ± 0.081, P = 0.043). At 4 weeks, the outer cortex in the control group had a significantly higher rER (P = 0.038), whereas in the VEGF group, the inner cortex had a higher rER (P = 0.015). Over time, in the outer cortex the rER significantly increased to 0.634 ± 0.106 at 18 weeks in VEGF-treated rats (P = 0.049). At 18 weeks, the rER was >0.5 at all cortical areas in both groups. These in vivo findings suggest a chemotactic effect of intramedullary applied VEGF on recipient-derived bone and could imply that more rapid angiogenesis of vascularized allotransplants can be established with microencapsulated VEGF. © 2014 Wiley Periodicals, Inc.

Oxidative stress increases eukaryotic initiation factor 4E phosphorylation in vascular cells.

PubMed Central

Duncan, Roger F; Peterson, Hazel; Hagedorn, Curt H; Sevanian, Alex

2003-01-01

Dysregulated cell growth can be caused by increased activity of protein synthesis eukaryotic initiation factor (eIF) 4E. Dysregulated cell growth is also characteristic of atherosclerosis. It is postulated that exposure of vascular cells, such as endothelial cells, smooth muscle cells and monocytes/macrophages, to oxidants, such as oxidized low-density lipoprotein (oxLDL), leads to the elaboration of growth factors and cytokines, which in turn results in smooth muscle cell hyperproliferation. To investigate whether activation of eIF4E might play a role in this hyperproliferative response, vascular cells were treated with oxLDL, oxidized lipid components of oxLDL and several model oxidants, including H(2)O(2) and dimethyl naphthoquinone. Exposure to each of these compounds led to a dose- and time-dependent increase in eIF4E phosphorylation in all three types of vascular cells, correlated with a modest increase in overall translation rate. No changes in eIF4EBP, eIF2 or eIF4B modification state were observed. Increased eIF4E phosphorylation was paralleled by increased presence of eIF4E in high-molecular-mass protein complexes characteristic of its most active form. Anti-oxidants at concentrations typically employed to block oxidant-induced cell signalling likewise promoted eIF4E phosphorylation. The results of this study indicate that increased eIF4E activity may contribute to the pathophysiological events in early atherogenesis by increasing the expression of translationally inefficient mRNAs encoding growth-promoting proteins. PMID:12215171

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

PubMed

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

2017-11-01

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

ETS transcription factor ETV2/ER71/Etsrp in hematopoietic and vascular development, injury, and regeneration.

PubMed

Zhao, Haiyong; Xu, Canxin; Lee, Tae-Jin; Liu, Fang; Choi, Kyunghee

2017-04-01

The major goal in regenerative medicine is to repair and restore injured, diseased or aged tissue function, thereby promoting general health. As such, the field of regenerative medicine has great translational potential in undertaking many of the health concerns and needs that we currently face. In particular, hematopoietic and vascular systems supply oxygen and nutrients and thus play critical roles in tissue development and tissue regeneration. Additionally, tissue vasculature serves as a tissue stem cell niche and thus contributes to tissue homeostasis. Notably, hematopoietic and vascular systems are sensitive to injury and subject to regeneration. As such, successful hematopoietic and vascular regeneration is prerequisite for efficient tissue repair and organismal survival and health. Recent studies have established that the interplay among the ETS transcription factor ETV2, vascular endothelial growth factor, and its receptor VEGFR2/FLK1 is essential for hematopoietic and vascular development. Emerging studies also support the role of these three factors and possible interplay in hematopoietic and vascular regeneration. Comprehensive understanding of the molecular mechanisms involved in the regulation and function of these three factors may lead to more effective approaches in promoting tissue repair and regeneration. Developmental Dynamics 246:318-327, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Expression of vascular endothelial growth factor mRNA in non-small-cell lung carcinomas

PubMed Central

Fontanini, G; Boldrini, L; Chinè, S; Pisaturo, F; Basolo, F; Calcinai, A; Lucchi, M; Mussi, A; Angeletti, C A; Bevilacqua, G

1999-01-01

The vascular endothelial growth factor (VEGF) has been shown to be strictly related to vascular permeability and endothelial cell growth under physiological and pathological conditions. In tumour development and progression, VEGF plays a pivotal role in the development of the tumoral vascular network, and useful information in the progression of human cancer can be obtained by analysing the vascular endothelial growth factor expression of the tumours. In this study, we investigated the vascular endothelial growth factor transcript expression in non-small-cell lung carcinomas to evaluate the significance of this factor in a group of cancers in which the vascular pattern has been shown to significantly affect progression. Surgical samples of 42 patients with NSCLC were studied using reverse transcription polymerase chain reaction (PCR) analysis and in situ hybridization. Thirty-three out of 42 cases (78.6%) showed VEGF transcript expression predominantly as transcripts for the secretory forms of VEGF (isoforms 121 and 165). In situ hybridization, performed on 24 out of 42 samples, showed that the VEGF transcript expression was in several cases present in the cytoplasm both of neoplastic and normal cells, even if the VEGF mRNA was less expressed in the corresponding non-tumoral part. The VEGF 121 expression was associated with hilar and/or mediastinal nodal involvement (P = 0.02), and, taken together, the VEGF isoforms were shown to significantly influence overall (P = 0.02) and disease-free survival (P = 0.03). As a regulator of tumour angiogenesis, VEGF may represent a useful indicator of progression and poor prognosis in non-small-cell lung carcinomas. © 1999 Cancer Research Campaign PMID:9888482

Molecular mechanisms of maternal vascular dysfunction in preeclampsia.

PubMed

Goulopoulou, Styliani; Davidge, Sandra T

2015-02-01

In preeclampsia, as a heterogeneous syndrome, multiple pathways have been proposed for both the causal as well as the perpetuating factors leading to maternal vascular dysfunction. Postulated mechanisms include imbalance in the bioavailability and activity of endothelium-derived contracting and relaxing factors and oxidative stress. Studies have shown that placenta-derived factors [antiangiogenic factors, microparticles (MPs), cell-free nucleic acids] are released into the maternal circulation and act on the vascular wall to modify the secretory capacity of endothelial cells and alter the responsiveness of vascular smooth muscle cells to constricting and relaxing stimuli. These molecules signal their deleterious effects on the maternal vascular wall via pathways that provide the molecular basis for novel and effective therapeutic interventions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cost and Selection of Ophthalmic Anti-Vascular Endothelial Growth Factor Agents.

PubMed

Li, Emily; Greenberg, Paul B; Voruganti, Indu; Krzystolik, Magdalena G

2016-05-02

Anti-vascular endothelial growth factor (anti-VEGF) drugs - ranibizumab, aflibercept, and off-label bevacizumab - are vital to the treatment of common retinal diseases, including exudative age-related macular degeneration (AMD), diabetic macular edema (DME), and macular edema (ME) associated with retinal vein occlusion (RVO). Given the high prevalence of AMD and retinal vascular diseases, anti-VEGF agents represent a large cost burden to the United States (US) healthcare system. Although ranibizumab and aflibercept are 30-fold more expensive per injection than bevacizumab, the two more costly medications are commonly used in the US, even though all three have been shown to be effective and safe for treatment of these retinal diseases. We investigated the availability and content of professional ophthalmic guidelines on cost consideration in the selection of anti-VEGF agents. We found that current professional guidelines were limited in availability and lacked specific guidance on cost-based anti-VEGF drug selection. This represents a missed opportunity to encourage the practice of value-based medicine. [Full article available at http://rimed.org/rimedicaljournal-2016-05.asp, free with no login].

Isolation of a cDNA for a Growth Factor of Vascular Endothelial Cells from Human Lung Cancer Cells: Its Identity with Insulin‐like Growth Factor II

PubMed Central

Hagiwara, Koichi; Kobayashi, Tatsuo; Tobita, Masato; Kikyo, Nobuaki; Yazaki, Yoshio

1995-01-01

We have found growth‐promoting activity for vascular endothelial cells in the conditioned medium of a human lung cancer cell line, T3M‐11. Purification and characterization of the growth‐promoting activity have been carried out using ammonium sulfate precipitation and gel‐exclusion chromatography. The activity migrated as a single peak just after ribonuclease. It did not bind to a heparin affinity column. These results suggest that the activity is not a heparin‐binding growth factor (including fibroblast growth factors) or a vascular endothelial growth factor. To identify the molecule exhibiting the growth‐promoting activity, a cDNA encoding the growth factor was isolated through functional expression cloning in COS‐1 cells from a cDNA library prepared from T3M‐11 cells. The nucleotide sequence encoded by the cDNA proved to be identical with that of insulin‐like growth factor II. PMID:7730145

Regulation of insulin-like growth factor I receptors on vascular smooth muscle cells by growth factors and phorbol esters.

PubMed

Ververis, J J; Ku, L; Delafontaine, P

1993-06-01

Insulin-like growth factor I (IGF I) is an important mitogen for vascular smooth muscle cells. To characterize regulation of vascular IGF I receptors, we performed radioligand displacement experiments using rat aortic smooth muscle cells (RASMs). Serum deprivation for 48 hours caused a 40% decrease in IGF I receptor number. Exposure of quiescent RASMs to platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), or angiotensin II (Ang II) caused a 1.5-2.0-fold increase in IGF I receptors per cell. After FGF exposure, there was a marked increase in the mitogenic response to IGF I. IGF I downregulated its receptors in the presence of platelet-poor plasma. Stimulation of protein kinase C (PKC) by exposure of quiescent RASMs to phorbol 12-myristate 13-acetate caused a biphasic response in IGF I binding; there was a 42% decrease in receptor number at 45 minutes and a 238% increase at 24 hours. To determine the role of PKC in growth factor-induced regulation of IGF I receptors, we downregulated PKC by exposing RASMs to phorbol 12,13-dibutyrate (PDBu) for 48 hours. PDGF- and FGF- but not Ang II-mediated upregulation of IGF I receptors was completely inhibited in PDBu-treated cells. Thus, acute PKC activation by phorbol esters inhibits IGF I binding, whereas chronic PKC activation increases IGF I binding. PDGF and FGF but not Ang II regulate vascular IGF I receptors through a PKC-dependent pathway. These data provide new insights into the regulation of vascular smooth muscle cell IGF I receptors in vitro and are of potential importance in characterizing vascular proliferative responses in vivo.

Bioprinting for vascular and vascularized tissue biofabrication.

PubMed

Datta, Pallab; Ayan, Bugra; Ozbolat, Ibrahim T

2017-03-15

Bioprinting is a promising technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision. Bioprinting enables the deposition of various biologics including growth factors, cells, genes, neo-tissues and extra-cellular matrix-like hydrogels. Benefits of bioprinting have started to make a mark in the fields of tissue engineering, regenerative medicine and pharmaceutics. Specifically, in the field of tissue engineering, the creation of vascularized tissue constructs has remained a principal challenge till date. However, given the myriad advantages over other biofabrication methods, it becomes organic to expect that bioprinting can provide a viable solution for the vascularization problem, and facilitate the clinical translation of tissue engineered constructs. This article provides a comprehensive account of bioprinting of vascular and vascularized tissue constructs. The review is structured as introducing the scope of bioprinting in tissue engineering applications, key vascular anatomical features and then a thorough coverage of 3D bioprinting using extrusion-, droplet- and laser-based bioprinting for fabrication of vascular tissue constructs. The review then provides the reader with the use of bioprinting for obtaining thick vascularized tissues using sacrificial bioink materials. Current challenges are discussed, a comparative evaluation of different bioprinting modalities is presented and future prospects are provided to the reader. Biofabrication of living tissues and organs at the clinically-relevant volumes vitally depends on the integration of vascular network. Despite the great progress in traditional biofabrication approaches, building perfusable hierarchical vascular network is a major challenge. Bioprinting is an emerging technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision

The power of VEGF (vascular endothelial growth factor) family molecules.

PubMed

Thomas, Jean-Leon; Eichmann, Anne

2013-05-01

Vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors (VEGFRs) are key regulators of both angiogenesis and neurogenesis. The current issue of CMLS discusses recent literature and work implementing these signals in nervous system development, maintenance and disease pathology.

Transforming growth factor β family members in regulation of vascular function: in the light of vascular conditional knockouts.

PubMed

Jakobsson, Lars; van Meeteren, Laurens A

2013-05-15

Blood vessels are composed of endothelial cells, mural cells (smooth muscle cells and pericytes) and their shared basement membrane. During embryonic development a multitude of signaling components orchestrate the formation of new vessels. The process is highly dependent on correct dosage, spacing and timing of these signaling molecules. As vessels mature some cascades remain active, albeit at very low levels, and may be reactivated upon demand. Members of the Transforming growth factor β (TGF-β) protein family are strongly engaged in developmental angiogenesis but are also regulators of vascular integrity in the adult. In humans various genetic alterations within this protein family cause vascular disorders, involving disintegration of vascular integrity. Here we summarize and discuss recent data gathered from conditional and endothelial cell specific genetic loss-of-function of members of the TGF-β family in the mouse. Copyright © 2013 Elsevier Inc. All rights reserved.

Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion

PubMed Central

Gorin, Caroline; Rochefort, Gael Y.; Bascetin, Rumeyza; Ying, Hanru; Lesieur, Julie; Sadoine, Jérémy; Beckouche, Nathan; Berndt, Sarah; Novais, Anita; Lesage, Matthieu; Hosten, Benoit; Vercellino, Laetitia; Merlet, Pascal; Le-Denmat, Dominique; Marchiol, Carmen; Letourneur, Didier; Nicoletti, Antonino; Vital, Sibylle Opsahl; Poliard, Anne; Salmon, Benjamin; Germain, Stéphane

2016-01-01

Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF. Significance The results from the present study show that fibroblast growth factor-2 (FGF-2) priming is more

Genetic and Non-Genetic Factors Affecting the Quality of Anticoagulation Control and Vascular Events in Atrial Fibrillation.

PubMed

Park, Yun Kyung; Lee, Mi Ji; Kim, Jae Ha; Lee, Jin Soo; Park, Rae Woong; Kim, Gyeong-Moon; Chung, Chin-Sang; Lee, Kwang Ho; Kim, June Soo; Lee, Soo-Youn; Bang, Oh Young

2017-06-01

Warfarin has a narrow therapeutic window. We hypothesized that genetic factors related to warfarin metabolism (CYP2C9) and activity (VKORC1) would show stronger associations than modifiable factors with the quality of anticoagulation control and risks for thromboembolism and hemorrhage. In this retrospective cohort analysis, clinical and genetic data were collected from 380 patients with atrial fibrillation (AF) who were followed for an average observation period of 4 years. We evaluated the factors associated with time in therapeutic range (TTR, international normalized ratio [INR]: 2-3) and vascular events (either thromboembolic or hemorrhagic), including both genetic (CYP2C9 and VKORC1 genotype) and modifiable factors (anticoagulation service and warfarin dose assessment interval). The genotypic frequency of CYP2C9*3 (rs1057910) was 9.5% and that of VKORC1 1173C>T (rs9934438) was 16.3%. TTR showed dependence on VKORC1 polymorphism: TTR was higher in carriers of the VKORC1 1173C>T than of the VKORC1 TT genotype (61.7 ± 16.0% versus 56.7 ± 17.4%, P = .031). Multivariate testing showed that the VKORC1 genotype and anticoagulation service were independently related to labile INRs (TTR <65%). Vascular events were observed in 66 patients (18.4%) during the study period. A Cox proportional hazard model showed that the use of anticoagulation service and patients' characteristics, such as AF-thromboembolic risk (CHA 2 DS 2 -VASc score: Congestive heart failure, Hypertension, Age 75 years or older, Diabetes mellitus, previous Stroke or transient ischemic attack, Vascular disease, Age 65 to 74 years, female) and consequence (neurologic disability), but not genetic factors, were independently associated with vascular events. Both genetic factor (VKORC1 genotype) and clinical efforts (anticoagulation service) influenced the quality of anticoagulation control. However, clinical events were more strongly associated with patient characteristics and clinical

Serum placental growth factor, vascular endothelial growth factor, soluble vascular endothelial growth factor receptor-1 and -2 levels in periodontal disease, and adverse pregnancy outcomes.

PubMed

Sert, Tuba; Kırzıoğlu, F Yeşim; Fentoğlu, Ozlem; Aylak, Firdevs; Mungan, Tamer

2011-12-01

The aim of this study is the evaluation of levels of serum interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and soluble VEGF receptor (sVEGFR)-1 and -2 in the association between periodontal disease and adverse pregnancy outcomes. One hundred and nine mothers, who recently gave birth, and 51 women who were not recently pregnant, aged 18 to 35 years, were included in this study. The mothers were classified as term birth, preterm birth (PTB), and preterm low birth weight (PLBW) in respect to their gestational age and baby's birth weight. The birth mothers were grouped as having gingivitis or periodontitis. The non-pregnant group also included periodontally healthy patients. Venous blood samples were collected to evaluate serum IL-1β, IL-6, IL-10, TNF-α, VEGF, PIGF, and sVEGFR-1 and -2 levels. Mother's weight, education, and income level were significantly associated with pregnancy outcomes. Serum levels of IL-1β, TNF-α, IL-6, VEGF, and sVEGFR-1 and -2 showed an increase in significance when related to pregnancy. Whereas in the PLBW group IL-1β, VEGF, and sVEGFR-2 levels were increased, in the PTB group sVEGFR-1 levels were increased. Additionally, the patients in the PLBW group with periodontitis had higher serum levels of IL-1β, VEGF, sVEGFR-2, and IL-1β/IL-10. The serum levels of IL-1β, VEGF, and sVEGFR-1 and -2 may have a potential effect on the mechanism of the association between periodontal disease and adverse pregnancy outcomes.

Psoriasis and Cardiovascular Comorbidities: Focusing on Severe Vascular Events, Cardiovascular Risk Factors and Implications for Treatment

PubMed Central

Hu, Stephen Chu-Sung; Lan, Cheng-Che E.

2017-01-01

Psoriasis is a common and chronic inflammatory disease of the skin. It may impair the physical and psychosocial function of patients and lead to decreased quality of life. Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints. More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities. In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke. In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population. Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders. In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment. PMID:29065479

Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer.

PubMed

Anan, K; Morisaki, T; Katano, M; Ikubo, A; Kitsuki, H; Uchiyama, A; Kuroki, S; Tanaka, M; Torisu, M

1996-03-01

Angiogenesis is a prerequisite for tumor growth and metastasis. Tumor angiogenesis may be mediated by several angiogenic factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-alpha, and basic fibroblast growth factor. Differential mRNA expressions of VEGF, PDGF (A chain), transforming growth factor-alpha and basic fibroblast growth factor in 32 primary invasive breast tumors were examined by reverse transcriptase-polymerase chain reaction. We analyzed relationships between mRNA expressions of these angiogenic factors and the degree of angiogenesis, tumor size, and metastasis. Quantification of angiogenesis was achieved by the immunohistochemical staining of endothelial cells with antibody to CD31. VEGF and PDGF-A mRNAs were expressed more frequently in breast tumors than in nontumor breast tissues, whereas no difference was found in expression frequency of either transforming growth factor-alpha or basic fibroblast growth factor mRNA. Vascular counts in tumors correlated with each expression frequency of VEGF and PDGF-A mRNA. PDGF-A mRNA was expressed more frequently in tumors with lymph node metastasis than in those without metastasis. Expression of VEGF and PDGF mRNAs detected by reverse transcriptase-polymerase chain reaction in breast tumors correlates with tumor-related characteristics of angiogenesis and metastatic potential. Analysis of these mRNAs by reverse transcriptase-polymerase chain reaction may be useful for assessing the biologic behavior of a breast tumor before surgical treatment.

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.

PubMed

Neto-Neves, Evandro M; Brown, Mary B; Zaretskaia, Maria V; Rezania, Samin; Goodwill, Adam G; McCarthy, Brian P; Persohn, Scott A; Territo, Paul R; Kline, Jeffrey A

2017-04-01

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Age and Vascular Burden Determinants of Cortical Hemodynamics Underlying Verbal Fluency.

PubMed

Heinzel, Sebastian; Metzger, Florian G; Ehlis, Ann-Christine; Korell, Robert; Alboji, Ahmed; Haeussinger, Florian B; Wurster, Isabel; Brockmann, Kathrin; Suenkel, Ulrike; Eschweiler, Gerhard W; Maetzler, Walter; Berg, Daniela; Fallgatter, Andreas J

2015-01-01

Aging processes and several vascular burden factors have been shown to increase the risk of dementia including Alzheimer's disease. While pathological alterations in dementia precede diagnosis by many years, reorganization of brain processing might temporarily delay cognitive decline. We hypothesized that in healthy elderly individuals both age-related neural and vascular factors known to be related to the development of dementia impact functional cortical hemodynamics during increased cognitive demands. Vascular burden factors and cortical functional hemodynamics during verbal fluency were assessed in 1052 non-demented elderly individuals (51 to 83 years; cross-sectional data of the longitudinal TREND study) using functional near-infrared spectroscopy (fNIRS). The prediction of functional hemodynamic responses by age in multiple regressions and the impact of single and cumulative vascular burden factors including hypertension, diabetes, obesity, smoking and atherosclerosis were investigated. Replicating and extending previous findings we could show that increasing age predicted functional hemodynamics to be increased in right prefrontal and bilateral parietal cortex, and decreased in bilateral inferior frontal junction during phonological fluency. Cumulative vascular burden factors, with hypertension in particular, decreased left inferior frontal junction hemodynamic responses during phonological fluency. However, age and vascular burden factors showed no statistical interaction on functional hemodynamics. Based on these findings, one might hypothesize that increased fronto-parietal processing may represent age-related compensatory reorganization during increased cognitive demands. Vascular burden factors, such as hypertension, may contribute to regional cerebral hypoperfusion. These neural and vascular hemodynamic determinants should be investigated longitudinally and combined with other markers to advance the prediction of future cognitive decline and dementia.

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

PubMed

Scholz, Gerhard H; Hanefeld, Markolf

2016-10-01

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

Endothelial Snail Regulates Capillary Branching Morphogenesis via Vascular Endothelial Growth Factor Receptor 3 Expression

PubMed Central

Park, Jeong Ae; Kim, Dong Young; Kim, Young-Myeong; Kwon, Young-Guen

2015-01-01

Vascular branching morphogenesis is activated and maintained by several signaling pathways. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) signaling is largely presented in arteries, and VEGFR3 signaling is in veins and capillaries. Recent reports have documented that Snail, a well-known epithelial-to-mesenchymal transition protein, is expressed in endothelial cells, where it regulates sprouting angiogenesis and embryonic vascular development. Here, we identified Snail as a regulator of VEGFR3 expression during capillary branching morphogenesis. Snail was dramatically upregulated in sprouting vessels in the developing retinal vasculature, including the leading-edged vessels and vertical sprouting vessels for capillary extension toward the deep retina. Results from in vitro functional studies demonstrate that Snail expression colocalized with VEGFR3 and upregulated VEGFR3 mRNA by directly binding to the VEGFR3 promoter via cooperating with early growth response protein-1. Snail knockdown in postnatal mice attenuated the formation of the deep capillary plexus, not only by impairing vertical sprouting vessels but also by downregulating VEGFR3 expression. Collectively, these data suggest that the Snail-VEGFR3 axis controls capillary extension, especially in vessels expressing VEGFR2 at low levels. PMID:26147525

VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease.

PubMed

Barratt, Shaney L; Flower, Victoria A; Pauling, John D; Millar, Ann B

2018-04-24

Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.

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

PubMed Central

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

2006-01-01

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

Undertreatment of Vascular Risk Factors in Patients with Monocular Ischaemic Visual Loss.

PubMed

Zarkali, Angeliki; Cheng, Suk Fun; Dados, Agnes; Simister, Robert; Chandratheva, Arvind

2018-05-17

Ischaemic visual loss is often considered a lower risk factor than other transient ischaemic attacks (TIA). We aimed to determine the recurrence risk, prevalence and management of vascular risk factors in these patients. The study took place in the University College Hospital London daily TIA clinic, main referral centre for North-Central London and Moorfields Eye Hospital. Consecutive records for patients with transient (< 24 h) or permanent (> 24 h) ischaemic visual loss were reviewed during the period January 2014-October 2016. Patients diagnosed with temporal arteritis were excluded. Of 400 patients, 224 (56%) were male with mean age 64.5 years (SD 15.1); 263 patients (65.8%) presented with transient and 137 patients (34.2%) with permanent ischaemic visual loss; 51.3% had hypertension (HTN), 35.3% hypercholesterolaemia, 14.5% diabetes, 11.8% ischaemic ocular events, 10.0% ischaemic heart disease, 7.3% atrial fibrillation (AF), 6.3% TIA, 5.3% stroke, and 12.3% were smokers. Median vascular risk factors were 2 (range 1-6), but 122 (30.5%) had ≥3. Those with diabetes (p < 0.001), HTN (p = 0.008), previous myocardial infarction (p = 0.005), or ≥3 vascular risk factors (p = 0.012) were more likely to present with permanent visual loss, while patients with history of transient events, TIA (p = 0.002), or ocular (p = 0.002) presented with transient visual loss. Ninety-day recurrence was 10.5%; this was higher in patients with ≥3 risk factors (hazard ratio 1.42, 95% CI 0.95-2.11, p = 0.111). Patients with past TIA were more likely to be on secondary prevention than those with ocular ischaemia; 60.0 vs. 34.1% received antiplatelets and 76.0 vs. 43.9% statins. At presentation, only 55.2% (16 patients) with known AF were anticoagulated, despite all of them having CHADSVASC ≥1. Approximately one-third of patients with ocular ischaemia had ≥3 vascular risk factors with recurrences higher in these patients. Yet only half of those with previous ischaemic

BIOLOGICAL AND BIOPHYSICAL PROPERTIES OF VASCULAR CONNEXIN CHANNELS

PubMed Central

Johnstone, Scott; Isakson, Brant; Locke, Darren

2010-01-01

Intercellular channels formed by connexin proteins play a pivotal role in the direct movement of ions and larger cytoplasmic solutes between vascular endothelial cells, between vascular smooth muscle cells, and between endothelial and smooth muscle cells. Multiple genetic and epigenetic factors modulate connexin expression levels and/or channel function, including cell type-independent and cell type-specific transcription factors, posttranslational modification and localized membrane targeting. Additionally, differences in protein-protein interactions, including those between connexins, significantly contribute to both vascular homeostasis and disease progression. The biophysical properties of the connexin channels identified in the vasculature, those formed by Cx37, Cx40, Cx43 and/or Cx45 proteins, are discussed in this review in the physiological and pathophysiological context of vessel function. PMID:19815177

Distribution patterns in the native vascular flora of Iceland.

PubMed

Wasowicz, Pawel; Pasierbiński, Andrzej; Przedpelska-Wasowicz, Ewa Maria; Kristinsson, Hörður

2014-01-01

The aim of our study was to reveal biogeographical patterns in the native vascular flora of Iceland and to define ecological factors responsible for these patterns. We analysed dataset of more than 500,000 records containing information on the occurrence of vascular plants. Analysis of ecological factors included climatic (derived from WORLDCLIM data), topographic (calculated from digital elevation model) and geological (bedrock characteristics) variables. Spherical k-means clustering and principal component analysis were used to detect biogeographical patterns and to study the factors responsible for them. We defined 10 biotic elements exhibiting different biogeographical patterns. We showed that climatic (temperature-related) and topographic variables were the most important factors contributing to the spatial patterns within the Icelandic vascular flora and that these patterns are almost completely independent of edaphic factors (bedrock type). Our study is the first one to analyse the biogeographical differentiation of the native vascular flora of Iceland.

Hypoglycemia in Diabetes Mellitus as a Coronary Artery Disease Risk Factor in Patients at Elevated Vascular Risk

PubMed Central

Leong, Aaron; Berkowitz, Seth A.; Triant, Virginia A.; Porneala, Bianca; He, Wei; Atlas, Steven J.; Wexler, Deborah J.

2016-01-01

Context: Although clinical trials have shown that hypoglycemia is associated with coronary artery disease (CAD), little is known whether hypoglycemia is a CAD risk factor in primary care. Objective: We sought to determine whether previous hypoglycemia was associated with incident CAD, and whether this association differed in patients of different underlying vascular risk. Design, setting and participants: This is a longitudinal cohort study of diabetes patients without CAD before January 1, 2006 (n = 9173) followed at an academic network of 13 primary care practices from January 1, 2006 to June 30, 2012. Hypoglycemic events before January 1, 2006 were identified via International Classification of Diseases Ninth Revision codes from emergency department, inpatient and outpatient visits. Main Outcome Measure: Patients were followed until incident CAD or June 30, 2012. Cox regression with time interaction was used to determine the association between hypoglycemia and CAD (significance set at P ≤ .05). We then tested the association among high vascular risk patients (age ≥ 55 y, hemoglobin A1c ≥ 7.5%, ≥2 risk factors [dyslipidemia, hypertension or obesity]), a subset of high vascular risk patients aged 65 years or older, and the remaining patients with lower vascular risk. Results: Three percent of patients (n = 285) had previous hypoglycemia. Hypoglycemia was associated with a 2-fold CAD risk (hazard ratio [HR] 2.15; 95% confidence interval [95%CI] 1.24–3.74), adjusting for time interaction and vascular risk factors. Among high vascular risk patients, the risk was 3-fold (HR 3.01 [95%CI 1.15–7.91], n = 1823 [20% of cohort]), and over 4-fold (HR 4.62 [95%CI 1.65–12.9], n = 996) in the subset aged more than or equal to 65 years. No association was found in the remaining 80% of the cohort with lower vascular risk. Conclusions: Previous hypoglycemia was associated with CAD among high vascular risk patients. Hypoglycemia may not be a CAD risk factor for the

Vascular endothelial growth factor is upregulated by l-dopa in the parkinsonian brain: implications for the development of dyskinesia

PubMed Central

Francardo, Veronica; Lindgren, Hanna S.; Sillivan, Stephanie E.; O’Sullivan, Sean S.; Luksik, Andrew S.; Vassoler, Fair M.; Lees, Andrew J.; Konradi, Christine

2011-01-01

Angiogenesis and increased permeability of the blood–brain barrier have been reported to occur in animal models of Parkinson’s disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood–brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson’s disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson’s disease. PMID:21771855

Towards retrievable vascularized bioartificial pancreas: induction and long-lasting stability of polymeric mesh implant vascularized with the help of acidic and basic fibroblast growth factors and hydrogel coating.

PubMed

Prokop, A; Kozlov, E; Nun Non, S; Dikov, M M; Sephel, G C; Whitsitt, J S; Davidson, J M

2001-01-01

We seek to improve existing methodologies for allogenic grafting of pancreatic islets. The lack of success of encapsulated transplanted islets inside the peritoneal cavity is presently attributed to poor vascularization of the implant. A thick, fibrotic capsule often surrounds the graft, limiting survival. We have tested the hypothesis that neovascularization of the graft material can be induced by the addition of proper angiogenic factors embedded within a polymeric coat. Biocompatible and nonresorbable meshes coated with hydrophilic polymers were implanted in rats and harvested after 1-, 6-, and 12-week intervals. The implant response was assessed by histological observations on the degree of vascularity, fibrosis, and inflammation. Macrostructural geometry of meshes was conducive to tissue ingrowth into the interstitial space between the mesh filaments. Hydrogel coating with incorporated acidic or basic FGF in an electrostatic complex with polyelectrolytes and/or with heparin provided a sustained slow release of the angiogenic growth factor. Anti-factor VIII and anti-collagen type IV antibodies and a GSL I-B4 lectin were used to measure the extent of vascularization. Vigorous and persistent vascularization radiated several hundred microns from the implant. The level of vascularization should provide a sufficient diffusion of nutrients and oxygen to implanted islets. Based on our observations, stable vascularization may require a sustained angiogenic signal to allow for the development of a permanent implant structure.

Aging and vascular endothelial function in humans

PubMed Central

SEALS, Douglas R.; JABLONSKI, Kristen L.; DONATO, Anthony J.

2012-01-01

Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end-products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor α (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging. PMID

Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo

NASA Astrophysics Data System (ADS)

Kim, K. Jin; Li, Bing; Winer, Jane; Armanini, Mark; Gillett, Nancy; Phillips, Heidi S.; Ferrara, Napoleone

1993-04-01

THE development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation1,2. Blood vessel neoformation is also important in the pathogenesis of many disorders1-5, particularly rapid growth and metastasis of solid tumours3-5. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-α and transforming factors-α and -β 1,2. But it is unclear whether any of these agents actually mediates angiogenesis and tumour growth in vivo. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenesis inducer released by a variety of tumour cells and expressed in human tumours in situ. To test whether VEGF may be a tumour angiogenesis factor in vivo, we injected human rhabdomyosar-coma, glioblastoma multiforme or leiomyosarcoma cell lines into nude mice. We report here that treatment with a monoclonal antibody specific for VEGF inhibited the growth of the tumours, but had no effect on the growth rate of the tumour cells In vitro. The density of vessels was decreased in the antibody-treated tumours. These findings demonstrate that inhibition of the action of an angiogenic factor spontaneously produced by tumour cells may suppress tumour growth in vivo.

The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition.

PubMed

Wharton, Whitney; Gleason, Carey E; Dowling, N Maritza; Carlsson, Cynthia M; Brinton, Eliot A; Santoro, M Nanette; Neal-Perry, Genevieve; Taylor, Hugh; Naftolin, Frederick; Lobo, Rogerio A; Merriam, George; Manson, Joann E; Cedars, Marcelle I; Miller, Virginia M; Black, Dennis M; Budoff, Matthew; Hodis, Howard N; Harman, S Mitchell; Asthana, Sanjay

2014-01-01

Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition. All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42-59 years), healthy, and free of cognitive dysfunction. Higher systolic BP was weakly related to poorer performance in auditory working memory and attention (p = 0.004; adjusted for multiple comparisons p = 0.10). This relationship was not associated with endogenous hormone levels, and systolic BP was not related to any other cognitive domain. BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy, recently menopausal women. Lower BP early in menopause may affect cognitive domains known to be associated with AD.

Male sex and vascular risk factors affect cystatin C-derived renal function in older people without diabetes or overt vascular disease.

PubMed

Werner, Karin Birgitta; Elmståhl, Sölve; Christensson, Anders; Pihlsgård, Mats

2014-05-01

to explore the effect of ageing on renal function with cystatin C as the marker of glomerular filtration rate (GFR) in the general population without vascular disease or diabetes. a cross-sectional analysis of a healthy subset from the Good Aging in Skåne-cohort study representative of the Swedish general population. 1252 participants without vascular disease and diabetes (43.9% men) of whom 203 were over 80 years old were included from the original cohort of 2931. plasma cystatin C and plasma creatinine were used as markers for GFR. Estimated GFR (eGFR) was calculated with three chronic kidney disease epidemiology collaboration (CKD-EPI) formulas involving cystatin C, creatinine or both. the median for plasma cystatin C was 0.93 mg/l (60-69 years old), 1.04 (70-79 years old) and 1.24 (80+ years old). The difference in mg/l between the 5th and 95th percentile was 0.46, 0.62 and 0.90 for these age groups. Male sex increased the age effect on plasma cystatin C levels with 0.004 mg/l/year (P = 0.03), adjusted for vascular risk factors. Smoking, lower HDL and higher diastolic blood pressure were associated with higher cystatin C levels. 54.7% (CKD-EPI creatinine) to 73.9% (CKD-EPI cystatin C) of the 80+ had an eGFR < 60 ml/min/1.73 m2. non-diabetics without overt vascular disease exhibit an age related but heterogeneous decline in renal function. The ageing effect is more pronounced in men. At least half of healthy 80+ years old could be expected to have at least CKD Stage 3 with eGFR < 60 ml/min/1.73 m2.

Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology.

PubMed

Ishii, Makoto; Iadecola, Costantino

2016-05-01

Age-related dementia is increasingly recognized as having a mixed pathology, with contributions from both cerebrovascular factors and pathogenic factors associated with Alzheimer's disease (AD). Furthermore, there is accumulating evidence that vascular risk factors in midlife, e.g., obesity, diabetes, and hypertension, increase the risk of developing late-life dementia. Since obesity and changes in body weight/adiposity often drive diabetes and hypertension, understanding the relationship between adiposity and age-related dementia may reveal common underlying mechanisms. Here we offer a brief appraisal of how changes in body weight and adiposity are related to both AD and dementia on vascular basis, and examine the involvement of two key adipocyte-derived hormones: leptin and adiponectin. The evidence suggests that in midlife increased body weight/adiposity and subsequent changes in adipocyte-derived hormones may increase the long-term susceptibility to dementia. On the other hand, later in life, decreases in body weight/adiposity and related hormonal changes are early manifestations of disease that precede the onset of dementia and may promote AD and vascular pathology. Understanding the contribution of adiposity to age-related dementia may help identify the underlying pathological mechanisms common to both vascular dementia and AD, and provide new putative targets for early diagnosis and therapy. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. Copyright © 2015 Elsevier B.V. All rights reserved.

Racial differences in vascular risk factors and outcomes of patients with intracranial atherosclerotic arterial stenosis.

PubMed

Waddy, Salina P; Cotsonis, George; Lynn, Michael J; Frankel, Michael R; Chaturvedi, Seemant; Williams, Janice E; Chimowitz, Marc

2009-03-01

Atherosclerotic intracranial stenosis is an important cause of stroke in blacks, yet there are limited data on vascular risk factors and outcome. We analyzed the vascular risk factors and outcomes of blacks and whites in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial. Baseline characteristics and outcomes (ischemic stroke, brain hemorrhage, or vascular death combined and ischemic stroke alone) were compared between blacks (n=174) and whites (n=331) using univariate and multivariate analyses. Blacks were significantly (P<0.05) more likely than whites to be/have: female, hypertension history, diabetes history, higher LDL, higher total cholesterol, lower triglycerides, unmarried, unemployed, nonprivate insurance, no insurance, stroke as qualifying event, <70% stenosis, symptomatic anterior circulation vessel, no antithrombotic medication before qualifying event, and no family history of myocardial infarction. Blacks more frequently reached an end point of ischemic stroke, brain hemorrhage or vascular death (28% versus 20%; hazard ratio of 1.49, 95% CI 1.03 to 2.17, P=0.03), had a higher 2-year event rate (0.28 versus 0.19), and reached the end point of ischemic stroke alone (25% versus 16% at 2 years; hazard ratio of 1.62, P=0.017). In multivariate analysis, race was associated with ischemic stroke (P=0.0488) but not with the end point ischemic stroke, brain hemorrhage or vascular death (P=0.188). Blacks with intracranial stenosis are at higher risk of stroke recurrence than whites. This risk warrants additional study of factors contributing to stroke in blacks and highlights the need for aggressive risk factor management in blacks to prevent recurrence.

Subjective memory complaints, vascular risk factors and psychological distress in the middle-aged: a cross-sectional study

PubMed Central

2011-01-01

Background Subjective memory complaints (SMC) are common but their significance is still unclear. It has been suggested they are a precursor of mild cognitive impairment (MCI) or dementia and an early indicator of cognitive decline. Vascular risk factors have an important role in the development of dementia and possibly MCI. We therefore aimed to test the hypothesis that vascular risk factors were associated with SMC, independent of psychological distress, in a middle-aged community-dwelling population. Methods A cross-sectional analysis of baseline data from the 45 and Up Study was performed. This is a cohort study of people living in New South Wales (Australia), and we explored the sample of 45, 532 participants aged between 45 and 64 years. SMC were defined as 'fair' or 'poor' on a self-reported five-point Likert scale of memory function. Vascular risk factors of obesity, diabetes, hypertension, hypercholesterolemia and smoking were identified by self-report. Psychological distress was measured by the Kessler Psychological Distress Scale. We tested the model generated from a randomly selected exploratory sample (n = 22, 766) with a confirmatory sample of equal size. Results 5, 479/45, 532 (12%) of respondents reported SMC. Using multivariate logistic regression, only two vascular risk factors: smoking (OR 1.18; 95% CI = 1.03 - 1.35) and hypercholesterolaemia (OR 1.19; 95% CI = 1.04 - 1.36) showed a small independent association with SMC. In contrast psychological distress was strongly associated with SMC. Those with the highest levels of psychological distress were 7.00 (95% CI = 5.41 - 9.07) times more likely to have SMC than the non-distressed. The confirmatory sample also demonstrated the strong association of SMC with psychological distress rather than vascular risk factors. Conclusions In a large sample of middle-aged people without any history of major affective illness or stroke, psychological distress was strongly, and vascular risk factors only weakly

Open and endovascular aneurysm repair in the Society for Vascular Surgery Vascular Quality Initiative.

PubMed

Spangler, Emily L; Beck, Adam W

2017-12-01

The Society for Vascular Surgery Vascular Quality Initiative is a patient safety organization and a collection of procedure-based registries that can be utilized for quality improvement initiatives and clinical outcomes research. The Vascular Quality Initiative consists of voluntary participation by centers to collect data prospectively on all consecutive cases within specific registries which physicians and centers elect to participate. The data capture extends from preoperative demographics and risk factors (including indications for operation), through the perioperative period, to outcomes data at up to 1-year of follow-up. Additionally, longer-term follow-up can be achieved by matching with Medicare claims data, providing long-term longitudinal follow-up for a majority of patients within the Vascular Quality Initiative registries. We present the unique characteristics of the Vascular Quality Initiative registries and highlight important insights gained specific to open and endovascular abdominal aortic aneurysm repair. Copyright © 2017 Elsevier Inc. All rights reserved.

Vascular dysfunction in preeclampsia.

PubMed

Brennan, Lesley J; Morton, Jude S; Davidge, Sandra T

2014-01-01

Preeclampsia is a complex disorder which affects an estimated 5% of all pregnancies worldwide. It is diagnosed by hypertension in the presence of proteinuria after the 20th week of pregnancy and is a prominent cause of maternal morbidity and mortality. As delivery is currently the only known treatment, preeclampsia is also a leading cause of preterm delivery. Preeclampsia is associated with maternal vascular dysfunction, leading to serious cardiovascular risk both during and following pregnancy. Endothelial dysfunction, resulting in increased peripheral resistance, is an integral part of the maternal syndrome. While the cause of preeclampsia remains unknown, placental ischemia resulting from aberrant placentation is a fundamental characteristic of the disorder. Poor placentation is believed to stimulate the release of a number of factors including pro- and antiangiogenic factors and inflammatory activators into the maternal systemic circulation. These factors are critical mediators of vascular function and impact the endothelium in distinctive ways, including enhanced endothelial oxidative stress. The mechanisms of action and the consequences on the maternal vasculature will be discussed in this review. © 2013 John Wiley & Sons Ltd.

Antiangiogenic activity of vitexicarpine in experimentally induced hepatocellular carcinoma: Impact on vascular endothelial growth factor pathway.

PubMed

Hassoun, Shimaa M; Abdel-Rahman, Noha; Eladl, Entsar I; El-Shishtawy, Mamdouh M

2017-06-01

Angiogenesis plays important roles in progression of hepatocellular carcinoma. The antiangiogenic mechanisms of vitexicarpine are not fully defined. Therefore, we conducted the following study to evaluate the antiangiogenic mechanism and antitumor activity of vitexicarpine in vivo model of hepatocellular carcinoma through modulation of vascular endothelial growth factor signaling pathway. Hepatocellular carcinoma was induced in Sprague Dawley rats by thioacetamide. Hepatocellular carcinoma was assessed by measuring serum alpha-fetoprotein and investigating liver sections stained with hematoxylin/eosin. Hepatocellular carcinoma rats were injected with vitexicarpine (150 mg/kg) for 2 weeks. Hepatic vascular endothelial growth factor was measured by enzyme-linked immunosorbent assay. Protein and expression of hepatic phospho-Ser473-AKT (p-AKT) and phospho-Tyr419-Src (p-Src) were determined. The apoptotic pathway was evaluated by assessment of protein expression of caspase-3. Vitexicarpine increased rats' survival time and decreased serum alpha-fetoprotein as well as it ameliorated fibrosis and massive hepatic tissue breakdown. It attenuated hepatocellular carcinoma-induced protein and gene expression of vascular endothelial growth factor, p-AKT, p-Src, and caspase-3. In conclusion, this study suggests that vitexicarpine possesses both antiangiogenic and antitumor activities through inhibition of vascular endothelial growth factor, p-AKT/AKT, and p-Src with subsequent inhibition of apoptotic pathway.

Platelet Activating Factor Contributes to Vascular Leak in Acute Dengue Infection

PubMed Central

Jeewandara, Chandima; Gomes, Laksiri; Wickramasinghe, N.; Gutowska-Owsiak, Danuta; Waithe, Dominic; Paranavitane, S. A.; Shyamali, N. L. A.; Ogg, Graham S.; Malavige, Gathsaurie Neelika

2015-01-01

Background Although plasma leakage is the hallmark of severe dengue infections, the factors that cause increased vascular permeability have not been identified. As platelet activating factor (PAF) is associated with an increase in vascular permeability in other diseases, we set out to investigate its role in acute dengue infection. Materials and Methods PAF levels were initially assessed in 25 patients with acute dengue infection to determine if they were increased in acute dengue. For investigation of the kinetics of PAF, serial PAF values were assessed in 36 patients. The effect of dengue serum on tight junction protein ZO-1 was determined by using human endothelial cell lines (HUVECs). The effect of dengue serum on and trans-endothelial resistance (TEER) was also measured on HUVECs. Results PAF levels were significantly higher in patients with acute dengue (n = 25; p = 0.001) when compared to healthy individuals (n = 12). In further investigation of the kinetics of PAF in serial blood samples of patients (n = 36), PAF levels rose just before the onset of the critical phase. PAF levels were significantly higher in patients with evidence of vascular leak throughout the course of the illness when compared to those with milder disease. Serum from patients with dengue significantly down-regulated expression of tight junction protein, ZO-1 (p = 0.004), HUVECs. This was significantly inhibited (p = 0.004) by use of a PAF receptor (PAFR) blocker. Serum from dengue patients also significantly reduced TEER and this reduction was also significantly (p = 0.02) inhibited by prior incubation with the PAFR blocker. Conclusion Our results suggest the PAF is likely to be playing a significant role in inducing vascular leak in acute dengue infection which offers a potential target for therapeutic intervention. PMID:25646838

Vascular and Inflammatory Factors in the Pathophysiology of Blast-Induced Brain Injury

PubMed Central

Elder, Gregory A.; Gama Sosa, Miguel A.; De Gasperi, Rita; Stone, James Radford; Dickstein, Dara L.; Haghighi, Fatemeh; Hof, Patrick R.; Ahlers, Stephen T.

2015-01-01

Blast-related traumatic brain injury (TBI) has received much recent attention because of its frequency in the conflicts in Iraq and Afghanistan. This renewed interest has led to a rapid expansion of clinical and animal studies related to blast. In humans, high-level blast exposure is associated with a prominent hemorrhagic component. In animal models, blast exerts a variety of effects on the nervous system including vascular and inflammatory effects that can be seen with even low-level blast exposures which produce minimal or no neuronal pathology. Acutely, blast exposure in animals causes prominent vasospasm and decreased cerebral blood flow along with blood-brain barrier breakdown and increased vascular permeability. Besides direct effects on the central nervous system, evidence supports a role for a thoracically mediated effect of blast; whereby, pressure waves transmitted through the systemic circulation damage the brain. Chronically, a vascular pathology has been observed that is associated with alterations of the vascular extracellular matrix. Sustained microglial and astroglial reactions occur after blast exposure. Markers of a central and peripheral inflammatory response are found for sustained periods after blast injury and include elevation of inflammatory cytokines and other inflammatory mediators. At low levels of blast exposure, a microvascular pathology has been observed in the presence of an otherwise normal brain parenchyma, suggesting that the vasculature may be selectively vulnerable to blast injury. Chronic immune activation in brain following vascular injury may lead to neurobehavioral changes in the absence of direct neuronal pathology. Strategies aimed at preventing or reversing vascular damage or modulating the immune response may improve the chronic neuropsychiatric symptoms associated with blast-related TBI. PMID:25852632

Retinal microvascular changes and subsequent vascular events after ischemic stroke.

PubMed

De Silva, D A; Manzano, J J F; Liu, E Y; Woon, F-P; Wong, W-X; Chang, H-M; Chen, C; Lindley, R I; Wang, J J; Mitchell, P; Wong, T-Y; Wong, M-C

2011-08-30

Retinal microvasculature changes are associated with vascular events including stroke in healthy populations. It is not known whether retinal microvascular changes predict recurrent vascular events after ischemic stroke. We examined the relationship between retinal microvascular signs and subsequent vascular events in a prospective cohort of 652 acute ischemic stroke patients admitted to a tertiary hospital in Singapore from 2005 to 2007. Retinal photographs taken within 1 week of stroke onset were assessed in a masked manner for quantitative and qualitative measures. Follow-up data over 2-4 years were obtained by standardized telephone interview and then were verified from medical records. Predictors of recurrent vascular events (cerebrovascular, coronary, vascular death, and composite vascular events) were determined using Cox regression models. Follow-up data over a median of 29 months were obtained for 89% (652 patients) of the cohort. After adjustment for covariates including traditional risk factors and index stroke etiology, patients with severe arteriovenous nicking (AVN) were more likely to have a recurrent cerebrovascular event (hazard ratio [HR] 2.28, 95% confidence interval [CI] 1.20-4.33) compared with those without AVN. Patients with severe focal arteriolar narrowing (FAN) were more likely to have a recurrent cerebrovascular event (HR 2.75, 95% CI 1.14-6.63) or subsequent composite vascular event (HR 2.77, 95% CI 1.31-5.86) compared to those without FAN. Retinal microvascular changes predicted subsequent vascular events after ischemic stroke, independent of traditional risk factors and stroke subtype. Thus, retinal imaging has a potential role in predicting the risk of recurrent vascular events after ischemic stroke and in understanding novel vascular risk factors.

KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces intrauterine growth restriction in mice.

PubMed

Abe, Naomichi; Nakahara, Tsutomu; Morita, Akane; Wada, Yoshiko; Mori, Asami; Sakamoto, Kenji; Nagamitsu, Tohru; Ishii, Kunio

2013-08-01

We previously reported that treatment with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, during mid-pregnancy caused intrauterine growth restriction resulting from impairment of blood vessel growth in the labyrinthine zone of the placenta and fetal organs. However, the relative sensitivities of blood vessels in the placenta and fetal organs to vascular endothelial growth factor (VEGF) inhibitors have not been determined. In this study, we aimed to examine the effects of KRN633 on the vasculatures of organs in mother mice and their newborn pups by immunohistochemical analysis. Pregnant mice were treated daily with KRN633 (5 mg/kg) either from embryonic day 13.5 (E13.5) to E17.5 or from E13.5 to the day of delivery. The weights of the pups of KRN633-treated mice were lower than those of the pups of vehicle-treated mothers. However, no significant difference in body weight was observed between the vehicle- and KRN633-treated mice. The vascular development in the organs (the pancreas, kidney, and intestine) and intestinal lymphatic formation of the pups of KRN633-treated mothers was markedly impaired. In contrast, the KRN633 treatment showed no significant effect on the vascular beds in the organs, including the labyrinthine zone of the placenta, of the mother mice. These results suggest that blood vessels in fetal organs are likely to be more sensitive to reduced VEGF signaling than those in the mother. A partial loss of VEGF function during pregnancy could suppress vascular growth in the fetus without affecting the vasculature in the mother mouse, thereby increasing the risk of intrauterine growth restriction. © 2013 Wiley Periodicals, Inc.

The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis.

PubMed

Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

2016-10-15

Cardiovascular disease (CVD) due to atherosclerosis is the main cause of death in both the elderly and patients with metabolic diseases, including diabetes. Aging processes contribute to the pathogenesis of atherosclerosis. Calorie restriction (CR) is recognized as a dietary intervention for promoting longevity and delaying age-related diseases, including atherosclerosis. Sirt1, an NAD + -dependent deacetylase, is considered an anti-aging molecule and is induced during CR. Sirt1 deacetylates target proteins and is linked to cellular metabolism, the redox state and survival pathways. Sirt1 expression/activation is decreased in vascular tissue undergoing senescence. Sirt1 deficiency in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and monocytes/macrophages contributes to increased oxidative stress, inflammation, foam cell formation, senescences impaired nitric oxide production and autophagy, thereby promoting vascular aging and atherosclerosis. Endothelial dysfunction, activation of monocytes/macrophages, and the functional and phenotypical plasticity of VSMCs are critically implicated in the pathogenesis of atherosclerosis through multiple mechanisms. Therefore, the activation of Sirt1 in vascular tissue, which includes ECs, monocytes/macrophages and VSMCs, may be a new therapeutic strategy against atherosclerosis and the increasing resistance to the metabolic disorder-related causal factors of CVD. In this review, we discuss the protective role of Sirt1 in the pathophysiology of vascular aging and atherosclerosis.

The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis

PubMed Central

Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

2016-01-01

Cardiovascular disease (CVD) due to atherosclerosis is the main cause of death in both the elderly and patients with metabolic diseases, including diabetes. Aging processes contribute to the pathogenesis of atherosclerosis. Calorie restriction (CR) is recognized as a dietary intervention for promoting longevity and delaying age-related diseases, including atherosclerosis. Sirt1, an NAD+-dependent deacetylase, is considered an anti-aging molecule and is induced during CR. Sirt1 deacetylates target proteins and is linked to cellular metabolism, the redox state and survival pathways. Sirt1 expression/activation is decreased in vascular tissue undergoing senescence. Sirt1 deficiency in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and monocytes/macrophages contributes to increased oxidative stress, inflammation, foam cell formation, senescences impaired nitric oxide production and autophagy, thereby promoting vascular aging and atherosclerosis. Endothelial dysfunction, activation of monocytes/macrophages, and the functional and phenotypical plasticity of VSMCs are critically implicated in the pathogenesis of atherosclerosis through multiple mechanisms. Therefore, the activation of Sirt1 in vascular tissue, which includes ECs, monocytes/macrophages and VSMCs, may be a new therapeutic strategy against atherosclerosis and the increasing resistance to the metabolic disorder-related causal factors of CVD. In this review, we discuss the protective role of Sirt1 in the pathophysiology of vascular aging and atherosclerosis. PMID:27744418

Aerobic Exercise and Other Healthy Lifestyle Factors That Influence Vascular Aging

ERIC Educational Resources Information Center

Santos-Parker, Jessica R.; LaRocca, Thomas J.; Seals, Douglas R

2014-01-01

Cardiovascular diseases (CVDs) remain the leading cause of death in the United States and other modern societies. Advancing age is the major risk factor for CVD, primarily due to stiffening of the large elastic arteries and the development of vascular endothelial dysfunction. In contrast, regular aerobic exercise protects against the development…

Evidence for a role of macrophage migration inhibitory factor in vascular disease.

PubMed

Chen, Zhiping; Sakuma, Masashi; Zago, Alexandre C; Zhang, Xiaobin; Shi, Can; Leng, Lin; Mizue, Yuka; Bucala, Richard; Simon, Daniel

2004-04-01

Inflammation plays an essential role in atherosclerosis and restenosis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is widely expressed in vascular cells. However, there is no in vivo evidence that MIF participates directly in vascular injury and repair. Therefore, we investigated the effect of MIF blockade on the response to experimental angioplasty in atherosclerosis-susceptible mice. Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDL receptor-deficient mice treated with a neutralizing anti-MIF or isotype control monoclonal antibody. After 7 days and 28 days, intimal and medial sizes were measured and intima/media area ratio (I/M) was calculated. Intimal thickening and I/M were reduced significantly by anti-MIF compared with control antibody. Vascular injury was accompanied by progressive vessel enlargement or "positive remodeling" that was comparable in both treatment groups. MIF blockade was associated with reduced inflammation and cellular proliferation and increased apoptosis after injury. Neutralizing MIF bioactivity after experimental angioplasty in atherosclerosis-susceptible mice reduces vascular inflammation, cellular proliferation, and neointimal thickening. Although the molecular mechanisms responsible for these effects are not yet established, these data prompt further research directed at understanding the role of MIF in vascular disease and suggest novel therapeutic interventions for preventing atherosclerosis and restenosis.

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

PubMed

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

2012-01-01

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

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

Vascular Consequences of Aldosterone Excess and Mineralocorticoid Receptor Antagonism.

PubMed

Chrissobolis, Sophocles

2017-01-01

Aldosterone binds to mineralocorticoid receptors (MRs) on renal epithelial cells to regulate sodium and water reabsorption, and therefore blood pressure. Recently, the actions of aldosterone outside the kidney have been extensively investigated, with numerous reports of aldosterone having detrimental actions, including in the vasculature. Notably, elevated aldosterone levels are an independent cardiovascular risk factor, and in addition to causing an increase in blood pressure, aldosterone can have blood pressure-dependent and -independent effects commonly manifested in the vasculature in cardiovascular diseases, including oxidative stress, endothelial dysfunction, inflammation, remodeling, stiffening, and plaque formation. Receptor-dependent mechanisms mediating these actions include the MR expressed on vascular endothelial and smooth muscle cells, but also include the angiotensin II type 1 receptor, epidermal growth factor receptor and vascular endothelial growth factor receptor 1, with downstream mechanisms including NADPH oxidase, cyclooxygenase, glucose-6-phosphate dehydrogenase, poly-(ADP ribose) polymerase and placental growth factor. The beneficial actions of MR antagonism in experimental hypertension include improved endothelial function, reduced hypertrophy and remodeling, and in atherosclerosis beneficial actions include reduced plaque area, inflammation, oxidative stress and endothelial dysfunction. Aldosterone excess is detrimental and MR antagonism is beneficial in humans also. The emerging concept of the contribution of aldosterone/MR-induced immunity to vascular pathology will also be discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Potential Therapeutics for Vascular Cognitive Impairment and Dementia.

PubMed

Sun, Miao-Kun

2017-10-16

As the human lifespan increases, the number of people affected by age-related dementia is growing at an epidemic pace. Vascular pathology dramatically affects cognitive profiles, resulting in dementia and cognitive impairment. While vascular dementia itself constitutes a medical challenge, hypoperfusion/vascular risk factors enhance amyloid toxicity and other memory-damaging factors and hasten Alzheimer's disease (AD) and other memory disorders' progression, as well as negatively affect treatment outcome. Few therapeutic options are, however, currently available to improve the prognosis of patients with vascular dementia and cognitive impairment, mixed AD dementia with vascular pathology, or other memory disorders. Emerging evidence, however, indicates that, like AD and other memory disorders, synaptic impairment underlies much of the memory impairment in the cognitive decline of vascular cognitive impairment and vascular dementia. Effective rescues of the memory functions might be achieved through synaptic and memory therapeutics, targeting distinct molecular signaling pathways that support the formation of new synapses and maintaining their connections. Potential therapeutic agents include: 1) memory therapeutic agents that rescue synaptic and memory functions after the brain insults; 2) anti-pathologic therapeutics and an effective management of vascular risk factors; and 3) preventative therapeutic agents that achieve memory therapy through functional enhancement. Their development and potential as clinically effective memory therapeutics for vascular cognitive impairment and dementia are discussed in this review. These therapeutic agents are also likely to benefit patients with AD and/or other types of memory disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Vascular dysfunction in women with a history of preeclampsia and intrauterine growth restriction: insights into future vascular risk.

PubMed

Yinon, Yoav; Kingdom, John C P; Odutayo, Ayodele; Moineddin, Rahim; Drewlo, Sascha; Lai, Vesta; Cherney, David Z I; Hladunewich, Michelle A

2010-11-02

Women with a history of placental disease are at increased risk for the future development of vascular disease. It is unknown whether preexisting endothelial dysfunction underlies both the predisposition to placental disease and the later development of vascular disease. The aim of this study was to assess vascular function in postpartum women and to determine whether differences emerged depending on the presentation of placental disease. Women with a history of early-onset preeclampsia (n=15), late-onset preeclampsia (n=9), intrauterine growth restriction without preeclampsia (n=9), and prior normal pregnancy (n=16) were studied 6 to 24 months postpartum. Flow-mediated vasodilatation and flow-independent (glyceryl trinitrate-induced) vasodilatation were studied through the use of high-resolution vascular ultrasound examination of the brachial artery. Arterial stiffness was assessed by pulse-wave analysis (augmentation index). Laboratory assessment included circulating angiogenic factors (vascular endothelial growth factor, soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin). Flow-mediated vasodilatation was significantly reduced in women with previous early-onset preeclampsia and intrauterine growth restriction compared with women with previous late-onset preeclampsia and control subjects (3.2±2.7% and 2.1±1.2% versus 7.9±3.8% and 9.1±3.5%, respectively; P<0.0001). Flow-independent vasodilatation was similar among all groups. Similarly, the radial augmentation index was significantly increased among women with previous early-onset preeclampsia and intrauterine growth restriction, but not among late preeclamptic women and control subjects (P=0.0105). Circulating angiogenic factors were similar in all groups. Only women with a history of early-onset preeclampsia or intrauterine growth restriction without preeclampsia exhibit impaired vascular function, which might explain their predisposition to placental disease and their higher

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) expression in colorectal cancer.

PubMed

Nagano, Hideki; Goi, Takanori; Koneri, Kenji; Hirono, Yasuo; Katayama, Kanji; Yamaguchi, Akio

2007-12-01

Vascular endothelial growth factor (VEGF) is known as an important factor in the growth and metastasis of cancer cells. In 2001, a novel angiogenesis factor, endocrine gland-derived vascular endothelial growth factor (EG-VEGF), was cloned. In this study, we investigated the expression of EG-VEGF in colorectal cancer, the relationship between its expression and clinicopathological factors, and the in vitro activity of EG-VEGF transfectants. We determined expression levels of EG-VEGF in 113 advanced colorectal cancers resected in our hospital by quantitative PCR, and compared the expression levels and clinicopathological findings by multivariate analyses. The expression of EG-VEGF mRNA was positive in 31 cancers and negative in 82 cancers. We found that compared with the negative expression of the EG-VEGF gene, its positive expression was more frequently associated with hematogenous metastasis, and was associated with a poorer survival rate. In addition, EG-VEGF transfectants showed a higher degree of in vitro tubular formation than control cells. We speculate that, in colorectal cancers, the EG-VEGF gene functions as an important factor in angiogenesis in primary and metastatic lesions, and consider that it is useful as a novel prognostic factor. EG-VEGF molecule-targeted therapy has the potential for improving survival rates.

Tristetraprolin Inhibits Ras-dependent Tumor Vascularization by Inducing Vascular Endothelial Growth Factor mRNA Degradation

PubMed Central

Essafi-Benkhadir, Khadija; Onesto, Cercina; Stebe, Emmanuelle; Moroni, Christoph

2007-01-01

Vascular endothelial growth factor (VEGF) is one of the most important regulators of physiological and pathological angiogenesis. Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and overexpression of VEGF are common denominators of tumors from different origins. We have established a new link between these two fundamental observations converging on VEGF mRNA stability. In this complex phenomenon, tristetraprolin (TTP), an adenylate and uridylate-rich element-associated protein that binds to VEGF mRNA 3′-untranslated region, plays a key role by inducing VEGF mRNA degradation, thus maintaining basal VEGF mRNA amounts in normal cells. ERKs activation results in the accumulation of TTP mRNA. However, ERKs reduce the VEGF mRNA-destabilizing effect of TTP, leading to an increase in VEGF expression that favors the angiogenic switch. Moreover, TTP decreases RasVal12-dependent VEGF expression and development of vascularized tumors in nude mice. As a consequence, TTP might represent a novel antiangiogenic and antitumor agent acting through its destabilizing activity on VEGF mRNA. Determination of TTP and ERKs status would provide useful information for the evaluation of the angiogenic potential in human tumors. PMID:17855506

East-West gradient in cardio-vascular mortality in Austria: how much can we explain by following the pattern of risk factors?

PubMed Central

2011-01-01

Background Various studies show major regional differences in the prevalence of cardio-vascular disease morbidity and mortality, both in Europe and within European countries. In Austria, these differences are documented by an East-West gradient with declining morbidity and mortality rates when moving from the East to the West of the country. It was the aim of this study to analyse if, and to what extent, socio-demographic and socio-economic determinants, social resources and health behaviour can contribute to the clarification of this East-West gradient by conducting secondary analyses of an existing Austrian health dataset. Results The data were analysed using bivariate analyses, as well as univariate and multivariate logistic regression models. These analyses revealed significant East-West gradients for various risk factors, as well as socio-demographic and socio-economic health determinants. There was a gradual decrease of hypertension, diabetes mellitus, obesity, and psycho-social discomfort in both sexes, with the highest prevalences in those Austrian regions with the highest cardio-vascular mortality and a stepwise decrease to the regions with the lowest cardio-vascular mortality. Controlling for educational level significantly raised the odds for diabetes, hypertension and obesity. In the results of the multivariate analyses, factors that significantly and independently predicted diabetes mellitus were geographic location, psycho-social discomfort, lack of physical exercise, and age in both sexes. For women these factors additionally included a low educational level, lack of social support, and being born abroad. Conclusions Our study shows a clear gradual decline of cardio-vascular mortality and some of its risk factors from East to West in Austria. Concerning these risk factors, the geographic region and psycho-social discomfort showed the greatest association with diabetes mellitus, hypertension, and obesity. Hence, they contribute to the explanation of

Efficacy of intravitreal injection of anti-vascular endothelial growth factor agents for stage 4 retinopathy of prematurity.

PubMed

Cheng, Hui-Chen; Lee, Shui-Mei; Hsieh, Yi-Ting; Lin, Po-Kang

2015-04-01

To investigate the efficacy of intravitreal injection of anti-vascular endothelial growth factor agents for Stage 4 retinopathy of prematurity. Retrospective case series study. The medical records of patients receiving intravitreal injection of anti-vascular endothelial growth factor agents for Stage 4 retinopathy of prematurity from January 2007 to May 2012 in Taipei Veterans General Hospital were reviewed. A total of 13 eyes of 7 patients (3 boys and 4 girls) with Stage 4 retinopathy of prematurity were included. The mean gestational age and birth weight were 27.6 ± 2.6 weeks (range, 24.5-30.5 weeks) and 893.1 ± 293.2 g (range, 550-1422 g), respectively. The mean age at the time of injection was 38.2 ± 1.9 weeks (range, 36.0-41.5 weeks) postmenstrual age, and the mean follow-up period was 37.8 ± 19.5 months (range, 11.0-67.5 months). The active neovascularization regressed rapidly, and the anatomical outcomes were favorable in all patients. One eye developed recurrent retinal hemorrhage with localized retinal detachment 21 weeks after initial treatment, which resolved after a second injection. There were no ocular or systemic complications in these patients. Intravitreal injection of anti-vascular endothelial growth factor agents may be effective as monotherapy or as supplement to failed laser treatment for patients with Stage 4 retinopathy of prematurity without additional surgical intervention. Further randomized controlled trials are necessary to compare the clinical efficacy and safety with other conventional interventions.

Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases

PubMed Central

Lesslie, D P; Summy, J M; Parikh, N U; Fan, F; Trevino, J G; Sawyer, T K; Metcalf, C A; Shakespeare, W C; Hicklin, D J; Ellis, L M; Gallick, G E

2006-01-01

Vascular endothelial growth factor (VEGF) is the predominant pro-angiogenic cytokine in human malignancy, and its expression correlates with disease recurrence and poor outcomes in patients with colorectal cancer. Recently, expression of vascular endothelial growth factor receptors (VEGFRs) has been observed on tumours of epithelial origin, including those arising in the colon, but the molecular mechanisms governing potential VEGF-driven biologic functioning in these tumours are not well characterised. In this report, we investigated the role of Src family kinases (SFKs) in VEGF-mediated signalling in human colorectal carcinoma (CRC) cell lines. Vascular endothelial growth factor specifically activated SFKs in HT29 and KM12L4 CRC cell lines. Further, VEGF stimulation resulted in enhanced cellular migration, which was effectively blocked by pharmacologic inhibition of VEGFR-1 or Src kinase. Correspondingly, migration studies using siRNA clones with reduced Src expression confirmed the requirement for Src in VEGF-induced migration in these cells. Furthermore, VEGF treatment enhanced VEGFR-1/SFK complex formation and increased tyrosine phosphorylation of focal adhesion kinase, p130 cas and paxillin. Finally, we demonstrate that VEGF-induced migration is not due, at least in part, to VEGF acting as a mitogen. These results suggest that VEGFR-1 promotes migration of tumour cells through a Src-dependent pathway linked to activation of focal adhesion components that regulate this process. PMID:16685275

Lipidomics in vascular health: current perspectives.

PubMed

Kolovou, Genovefa; Kolovou, Vana; Mavrogeni, Sophie

2015-01-01

Identifying the mechanisms that convert a healthy vascular wall to an atherosclerotic wall is of major importance since the consequences may lead to a shortened lifespan. Classical risk factors (age, smoking, obesity, diabetes mellitus, hypertension, and dyslipidemia) may result in the progression of atherosclerotic lesions by processes including inflammation and lipid accumulation. Thus, the evaluation of blood lipids and the full lipid complement produced by cells, organisms, or tissues (lipidomics) is an issue of importance. In this review, we shall describe the recent progress in vascular health research using lipidomic advances. We will begin with an overview of vascular wall biology and lipids, followed by a short analysis of lipidomics. Finally, we shall focus on the clinical implications of lipidomics and studies that have examined lipidomic approaches and vascular health.

Neural guidance molecules regulate vascular remodeling and vessel navigation.

PubMed

Eichmann, Anne; Makinen, Taija; Alitalo, Kari

2005-05-01

The development of the embryonic blood vascular and lymphatic systems requires the coordinated action of several transcription factors and growth factors that target endothelial and periendothelial cells. However, according to recent studies, the precise "wiring" of the vascular system does not occur without an ordered series of guidance decisions involving several molecules initially discovered for axons in the nervous system, including ephrins, netrins, slits, and semaphorins. Here, we summarize the new advances in our understanding of the roles of these axonal pathfinding molecules in vascular remodeling and vessel guidance, indicating that neuronal axons and vessel sprouts use common molecular mechanisms for navigation in the body.

Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity

PubMed Central

Velez-Montoya, Raul; Clapp, Carmen; Rivera, Jose Carlos; Garcia-Aguirre, Gerardo; Morales-Cantón, Virgilio; Fromow-Guerra, Jans; Guerrero-Naranjo, Jose Luis; Quiroz-Mercado, Hugo

2010-01-01

Purpose: To measure vitreous, aqueous, subretinal fluid and plasma levels of vascular endothelial growth factor in late stages of retinopathy of prematurity. Methods: Interventional study. We enrolled patients with clinical diagnoses of bilateral stage V retinopathy of prematurity, confirmed by b-scan ultrasound and programmed for vitrectomy. During surgery we took samples from blood, aqueous, vitreous, and subretinal fluids. The vascular endothelial growth factor concentration in each sample was measured by ELISA reaction. A control sample of aqueous, vitreous and blood was taken from patients with congenital cataract programmed for phacoemulsification. For statistical analysis, a Mann–Whitney and a Wilcoxon W test was done with a significant P value of 0.05. Results: We took samples of 16 consecutive patients who met the inclusion criteria. The vascular endothelial growth factor levels in the study group were: aqueous, 76.81 ± 61.89 pg/mL; vitreous, 118.53 ± 65.87 pg/mL; subretinal fluid, 1636.58 ± 356.47 pg/mL; and plasma, 74.64 ± 43.94 pg/mL. There was a statistical difference between the study and the control group (P < 0.001) in the aqueous and vitreous samples. Conclusion: Stage 5 retinopathy of prematurity has elevated intraocular levels of vascular endothelial growth factor, which remains high despite severe retinal lesion. There was no statistical difference in plasma levels of the molecule between the control and study group. PMID:20856587

Vascular endothelial growth factor-C (VEGF-C) expression predicts lymph node metastasis of transitional cell carcinoma of the bladder.

PubMed

Suzuki, Kazumi; Morita, Tatsuo; Tokue, Akihiko

2005-02-01

It has been found that expression of vascular endothelial growth factor-C (VEGF-C) in several carcinomas is significantly associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis. However, VEGF-C expression in bladder transitional cell carcinoma (TCC) has not yet been reported. To elucidate the role of VEGF-C in bladder TCC, we examined VEGF-C expression in bladder TCC and pelvic lymph node metastasis specimens obtained from patients who underwent radical cystectomy. Eighty-seven patients who underwent radical cystectomy for clinically organ-confined TCC of the bladder were enrolled in the present study. No neoadjuvant treatments, except transurethral resection of the tumor, were given to these patients. The VEGF-C expressions of 87 bladder tumors and 20 pelvic lymph node metastasis specimens were examined immunohistochemically and the association between VEGF-C expression and clinicopathological factors, including angiogenesis as evaluated by microvessel density (MVD), was also examined. Vascular endothelial growth factor-C expression was found in the cytoplasm of tumor cells, but not in the normal transitional epithelium. Vascular endothelial growth factor-C expression was significantly associated with the pathological T stage (P = 0.0289), pelvic lymph node metastasis (P < 0.0001), lymphatic involvement (P = 0.0008), venous involvement (P = 0.0002) and high MVD (P = 0.0043). The multivariate analysis demonstrated that VEGF-C expression and high MVD in bladder TCC were independent risk factors influencing the pelvic lymph node metastasis. Moreover, the patients with VEGF-C-positive tumors had significantly poorer prognoses than those with the VEGF-C-negative tumors (P = 0.0087) in the univariate analysis. The multivariate analysis based on Cox proportional hazard model showed that the independent prognostic factors were patient age (P = 0.0132) and pelvic lymph node metastasis (P = 0.0333). The present study suggests that VEGF

Additive Manufacturing of Vascular Grafts and Vascularized Tissue Constructs.

PubMed

Elomaa, Laura; Yang, Yunzhi Peter

2017-10-01

There is a great need for engineered vascular grafts among patients with cardiovascular diseases who are in need of bypass therapy and lack autologous healthy blood vessels. In addition, because of the severe worldwide shortage of organ donors, there is an increasing need for engineered vascularized tissue constructs as an alternative to organ transplants. Additive manufacturing (AM) offers great advantages and flexibility of fabrication of cell-laden, multimaterial, and anatomically shaped vascular grafts and vascularized tissue constructs. Various inkjet-, extrusion-, and photocrosslinking-based AM techniques have been applied to the fabrication of both self-standing vascular grafts and porous, vascularized tissue constructs. This review discusses the state-of-the-art research on the use of AM for vascular applications and the key criteria for biomaterials in the AM of both acellular and cellular constructs. We envision that new smart printing materials that can adapt to their environment and encourage rapid endothelialization and remodeling will be the key factor in the future for the successful AM of personalized and dynamic vascular tissue applications.

Connective Tissue Growth Factor Is Involved in Structural Retinal Vascular Changes in Long-Term Experimental Diabetes

PubMed Central

Van Geest, Rob J.; Leeuwis, Jan Willem; Dendooven, Amélie; Pfister, Frederick; Bosch, Klazien; Hoeben, Kees A.; Vogels, Ilse M.C.; Van der Giezen, Dionne M.; Dietrich, Nadine; Hammes, Hans-Peter; Goldschmeding, Roel; Klaassen, Ingeborg; Van Noorden, Cornelis J.F.

2014-01-01

Early retinal vascular changes in the development of diabetic retinopathy (DR) include capillary basal lamina (BL) thickening, pericyte loss and the development of acellular capillaries. Expression of the CCN (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family member CCN2 or connective tissue growth factor (CTGF), a potent inducer of the expression of BL components, is upregulated early in diabetes. Diabetic mice lacking one functional CTGF allele (CTGF+/−) do not show this BL thickening. As early events in DR may be interrelated, we hypothesized that CTGF plays a role in the pathological changes of retinal capillaries other than BL thickening. We studied the effects of long-term (6-8 months) streptozotocin-induced diabetes on retinal capillary BL thickness, numbers of pericytes and the development of acellular capillaries in wild type and CTGF+/− mice. Our results show that an absence of BL thickening of retinal capillaries in long-term diabetic CTGF+/− mice is associated with reduced pericyte dropout and reduced formation of acellular capillaries. We conclude that CTGF is involved in structural retinal vascular changes in diabetic rodents. Inhibition of CTGF in the eye may therefore be protective against the development of DR. PMID:24217924

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

PubMed Central

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

2012-01-01

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

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

PubMed

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

2012-02-01

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

The 2006 William Feinberg lecture: shifting the paradigm from stroke to global vascular risk estimation.

PubMed

Sacco, Ralph L

2007-06-01

By the year 2010, it is estimated that 18.1 million people worldwide will die annually because of cardiovascular diseases and stroke. "Global vascular risk" more broadly includes the multiple overlapping disease silos of stroke, myocardial infarction, peripheral arterial disease, and vascular death. Estimation of global vascular risk requires consideration of a variety of variables including demographics, environmental behaviors, and risk factors. Data from multiple studies suggest continuous linear relationships between the physiological vascular risk modulators of blood pressure, lipids, and blood glucose rather than treating these conditions as categorical risk factors. Constellations of risk factors may be more relevant than individual categorical components. Exciting work with novel risk factors may also have predictive value in estimates of global vascular risk. Advances in imaging have led to the measurement of subclinical conditions such as carotid intima-media thickness and subclinical brain conditions such as white matter hyperintensities and silent infarcts. These subclinical measurements may be intermediate stages in the transition from asymptomatic to symptomatic vascular events, appear to be associated with the fundamental vascular risk factors, and represent opportunities to more precisely quantitate disease progression. The expansion of studies in molecular epidemiology and detection of genetic markers underlying vascular risks also promises to extend our precision of global vascular risk estimation. Global vascular risk estimation will require quantitative methods that bundle these multi-dimensional data into more precise estimates of future risk. The power of genetic information coupled with data on demographics, risk-inducing behaviors, vascular risk modulators, biomarkers, and measures of subclinical conditions should provide the most realistic approximation of an individual's future global vascular risk. The ultimate public health benefit

Demographic Risk Factors for Vascular Lesions as Etiology of Intraventricular Hemorrhage in Prospectively Screened Cases

PubMed Central

Fam, Maged; Pang, Alice; Zeineddine, Hussein A.; Mayo, Steven; Stadnik, Agnieszka; Jesselson, Michael; Zhang, Lingjiao; Dlugash, Rachel; Ziai, Wendy; Hanley, Daniel; Awad, Issam A.

2017-01-01

years of age (OR 0.28 CI 0.20–0.40), African-American (OR 0.23 CI 0.18–0.31) or male (OR 0.48 CI 0.38–0.60), and more likely to present with primary IVH (OR 1.85 CI 1.37–2.51) compared to those with no vascular etiology (p<0.001). Other demographic factors were associated with specific vascular lesion etiologies. A combination of demographic features increases the association with the absence of vascular lesion, but not with absolute reliability (OR 0.1, CI 0.06–0.17, p<0.001). Conclusion An underlying vascular lesion as etiology of intraventricular hemorrhage cannot be excluded solely by demographic parameters in any patient. Some form of vascular imaging is necessary in screening patients before contemplating interventions like intraventricular fibrinolysis, where safety may be impacted by the presence of vascular lesion. PMID:28245439

Vascular endothelial growth factor signaling regulates the segregation of artery and vein via ERK activity during vascular development

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

Kim, Se-Hee; Schmitt, Christopher E.; Woolls, Melissa J.

Highlights: ► VEGF-A signaling regulates the segregation of axial vessels. ► VEGF-A signaling is mediated by PKC and ERK in this process. ► Ectopic activation of ERK is sufficient to rescue defects in vessel segregation. -- Abstract: Segregation of two axial vessels, the dorsal aorta and caudal vein, is one of the earliest patterning events occur during development of vasculature. Despite the importance of this process and recent advances in our understanding on vascular patterning during development, molecular mechanisms that coordinate the segregation of axial vessels remain largely elusive. In this report, we find that vascular endothelial growth factor-A (Vegf-A)more » signaling regulates the segregation of dorsal aorta and axial vein during development. Inhibition of Vegf-A pathway components including ligand Vegf-A and its cognate receptor Kdrl, caused failure in segregation of axial vessels in zebrafish embryos. Similarly, chemical inhibition of Mitogen-activated protein kinase kinase (Map2k1)/Extracellular-signal-regulated kinases (Erk) and phosphatidylinositol 3-kinases (PI3 K), which are downstream effectors of Vegf-A signaling pathway, led to the fusion of two axial vessels. Moreover, we find that restoring Erk activity by over-expression of constitutively active MEK in embryos with a reduced level of Vegf-A signaling can rescue the defects in axial vessel segregation. Taken together, our data show that segregation of axial vessels requires the function of Vegf-A signaling, and Erk may function as the major downstream effector in this process.« less

POOLED ESTIMATES OF INCIDENCE OF ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTION OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS WITH AND WITHOUT TOPICAL ANTIBIOTIC PROPHYLAXIS.

PubMed

Reibaldi, Michele; Pulvirenti, Alfredo; Avitabile, Teresio; Bonfiglio, Vincenza; Russo, Andrea; Mariotti, Cesare; Bucolo, Claudio; Mastropasqua, Rodolfo; Parisi, Guglielmo; Longo, Antonio

2018-01-01

To assess the effect of topical antibiotic prophylaxis on postoperative endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. A systematic literature search was performed from inception to March 2016 using PubMed, Medline, Web of Science, Embase, and the Cochrane Library, to identify articles that reported cases of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. We used a pooled analysis to estimate the incidence of cases of endophthalmitis who developed after injections performed with and without topical antibiotic prophylaxis. We used regression analysis to explore the effects of study characteristics on heterogeneity. From our search of electronic databases, we identified and screened 4,561 unique records. We judged 60 articles to have reported findings for cohorts of patients who met our inclusion criteria, (12 arms of randomized clinical trials, 11 prospective cohort studies, and 37 retrospective cohort studies), which included 244 cases of endophthalmitis and 639,391 intravitreal injections of anti-vascular endothelial growth factor agents. The final pooled estimate endophthalmitis proportions were 9/10,000 (95% confidence interval, 7/10,000-12/10,000) in the antibiotic-treated group and 3/10,000 (95% confidence interval, 2/10,000-5/10,000) in the untreated group. The estimated incidence of endophthalmitis with topical antibiotic prophylaxis was approximated three times the incidence without prophylaxis. Random effects regression showed that none of the study characteristics significantly affected the effect size in either group. Topical antibiotic after intravitreal injection of anti-vascular endothelial growth factor agents is associated with a higher risk of endophthalmitis.

Geraniol Suppresses Angiogenesis by Downregulating Vascular Endothelial Growth Factor (VEGF)/VEGFR-2 Signaling.

PubMed

Wittig, Christine; Scheuer, Claudia; Parakenings, Julia; Menger, Michael D; Laschke, Matthias W

2015-01-01

Geraniol exerts several direct pharmacological effects on tumor cells and, thus, has been suggested as a promising anti-cancer compound. Because vascularization is a major precondition for tumor growth, we analyzed in this study the anti-angiogenic action of geraniol. In vitro, geraniol reduced the migratory activity of endothelial-like eEND2 cells. Western blot analyses further revealed that geraniol downregulates proliferating cell nuclear antigen (PCNA) and upregulates cleaved caspase-3 (Casp-3) expression in eEND2 cells. Moreover, geraniol blocked vascular endothelial growth factor (VEGF)/VEGFR-2 signal transduction, resulting in a suppression of downstream AKT and ERK signaling pathways. In addition, geraniol significantly reduced vascular sprout formation in a rat aortic ring assay. In vivo, geraniol inhibited the vascularization of CT26 tumors in dorsal skinfold chambers of BALB/c mice, which was associated with a smaller tumor size when compared to vehicle-treated controls. Immunohistochemical analyses confirmed a decreased number of Ki67-positive cells and CD31-positive microvessels with reduced VEGFR-2 expression within geraniol-treated tumors. Taken together, these findings indicate that geraniol targets multiple angiogenic mechanisms and, therefore, is an attractive candidate for the anti-angiogenic treatment of tumors.

Role of vascular endothelial cell growth factor in Ovarian Hyperstimulation Syndrome.

PubMed Central

Levin, E R; Rosen, G F; Cassidenti, D L; Yee, B; Meldrum, D; Wisot, A; Pedram, A

1998-01-01

Controlled ovarian hyperstimulation with gonadotropins is followed by Ovarian Hyperstimulation Syndrome (OHSS) in some women. An unidentified capillary permeability factor from the ovary has been implicated, and vascular endothelial cell growth/permeability factor (VEGF) is a candidate protein. Follicular fluids (FF) from 80 women who received hormonal induction for infertility were studied. FFs were grouped according to oocyte production, from group I (0-7 oocytes) through group IV (23-31 oocytes). Group IV was comprised of four women with the most severe symptoms of OHSS. Endothelial cell (EC) permeability induced by the individual FF was highly correlated to oocytes produced (r2 = 0.73, P < 0.001). Group IV FF stimulated a 63+/-4% greater permeability than FF from group I patients (P < 0. 01), reversed 98% by anti-VEGF antibody. Group IV fluids contained the VEGF165 isoform and significantly greater concentrations of VEGF as compared with group I (1,105+/-87 pg/ml vs. 353+/-28 pg/ml, P < 0. 05). Significant cytoskeletal rearrangement of F-actin into stress fibers and a destruction of ZO-1 tight junction protein alignment was caused by group IV FF, mediated in part by nitric oxide. These mechanisms, which lead to increased EC permeability, were reversed by the VEGF antibody. Our results indicate that VEGF is the FF factor responsible for increased vascular permeability, thereby contributing to the pathogenesis of OHSS. PMID:9835623

Binding affinities of vascular endothelial growth factor (VEGF) for heparin-derived oligosaccharides

PubMed Central

Zhao, Wenjing; McCallum, Scott A.; Xiao, Zhongping; Zhang, Fuming; Linhardt, Robert J.

2011-01-01

Heparin and heparan sulphate (HS) exert their wide range of biological activities by interacting with extracellular protein ligands. Among these important protein ligands are various angiogenic growth factors and cytokines. HS-binding to vascular endothelial growth factor (VEGF) regulates multiple aspects of vascular development and function through its specific interaction with HS. Many studies have focused on HS-derived or HS-mimicking structures for the characterization of VEGF165 interaction with HS. Using a heparinase 1-prepared small library of heparin-derived oligosaccharides ranging from hexasaccharide to octadecasaccharide, we systematically investigated the heparin-specific structural features required for VEGF binding. We report the apparent affinities for the association between the heparin-derived oligosaccharides with both VEGF165 and VEGF55, a peptide construct encompassing exclusively the heparin-binding domain of VEGF165. An octasaccharide was the minimum size of oligosaccharide within the library to efficiently bind to both forms of VEGF and that a tetradecasaccharide displayed an effective binding affinity to VEGF165 comparable to unfractionated heparin. The range of relative apparent binding affinities among VEGF and the panel of heparin-derived oligosaccharides demonstrate that VEGF binding affinity likely depends on the specific structural features of these oligosaccharides including their degree of sulphation and sugar ring stereochemistry and conformation. Notably, the unique 3-O-sulpho group found within the specific antithrombin binding site of heparin is not required for VEGF165 binding. These findings afford new insight into the inherent kinetics and affinities for VEGF association with heparin and heparin-derived oligosaccharides with key residue specific modifications and may potentially benefit the future design of oligosaccharide-based anti-angiogenesis drugs. PMID:21658003

Synthetic E-selectin prevents postoperative vascular restenosis by inhibiting nuclear factor κB in rats

PubMed Central

Liu, Jiangang; Liu, Zhongjie; Hu, Xiaohui; Zhang, Yuan; Zhang, Shiming

2018-01-01

During the development of postoperative vascular restenosis, the aberrant proliferation of vascular smooth muscle cells (VSMCs) is a critical event resulting in intimal hyperplasia. Inflammatory responses involving the activation of nuclear factor (NF)-κB are among the major molecular processes underlying restenosis. The present study aimed to investigate the roles of NF-κB in VSMC proliferation and restenosis following vascular anastomosis, as well as to evaluate the potential of synthetic E-selectin to downregulate NF-κB and thus inhibit vascular hyperplasia. A total of 72 adult male Sprague-Dawley rats were randomly assigned to three groups: Control, operation and treatment groups. Rats in the operation and treatment groups received longitudinal incisions in the right carotid arteries, which were closed using interrupted sutures. Following vascular anastomosis, synthetic E-selectin (10 mg/kg), or an equal volume of saline, was immediately injected into the right femoral vein of rats in the treatment and operation groups, respectively. Following surgery, the mRNA and protein expression levels of NF-κB at the site of anastomosis, the levels of tumor necrosis factor-α and interleukin-6 in the serum, NF-κB binding activity, and the presence of proliferating cell nuclear antigen (PCNA)-positive cells were evaluated by western blotting, reverse transcription-quantitative polymerase chain reaction, ELISA, electrophoretic mobility shift assay and immunofluorescence staining. The present results demonstrated that following treatment with synthetic E-selectin, the levels of NF-κB and the inflammatory response, as well as the presence of PCNA-positive cells, were significantly reduced (P<0.01). In conclusion, the results of the present study suggested that synthetic E-selectin may exert anti-inflammatory and anti-restenotic effects following vascular anastomosis in vivo. PMID:29393453

Involvement of Vascular Endothelial Growth Factor in Kaposi's Sarcoma Associated with Acquired Immunodeficiency Syndrome

PubMed Central

Sakurada, Shinsaku; Kato, Tetsuji; Mashiba, Kohichi; Mori, Shigeo

1996-01-01

To examine the role of vascular endothelial growth factor (VEGF) in the development of edema associated with Kaposi's sarcoma (KS) in acquired immunodeficiency syndrome (AIDS), we exploited animal model systems to detect the activity that induces vascular hyper‐permeability (VHP) using cultured AIDS‐KS spindle cells. Cultured AIDS‐KS spindle cells and conditioned medium (AIDS‐KS‐CM) that had been semi‐purified through a heparin affinity column were tested for the ability to induce VHP in animals. The AIDS‐KS spindle cells and AIDS‐KS‐CM induced VHP that was histamine‐independent. The VHP‐inducing activity was detected in the 0.5 M NaCl fraction from the heparin affinity column and was blocked by anti‐VEGF neutralizing antibody. In addition, the production of VEGF was demonstrated in fresh AIDS‐KS tissue as well as in cultured AIDS‐KS cells, while control cells were negative for VEGF production. From these observations, we concluded that AIDS‐KS cells produce a factor(s) that promotes VHP, and this factor could be VEGF. PMID:9045943

Vascular cognitive impairment and dementia.

PubMed

Gorelick, Philip B; Counts, Scott E; Nyenhuis, David

2016-05-01

Vascular contributions to cognitive impairment are receiving heightened attention as potentially modifiable factors for dementias of later life. These factors have now been linked not only to vascular cognitive disorders but also Alzheimer's disease. In this chapter we review 3 related topics that address vascular contributions to cognitive impairment: 1. vascular pathogenesis and mechanisms; 2. neuropsychological and neuroimaging phenotypic manifestations of cerebrovascular disease; and 3. prospects for prevention of cognitive impairment of later life based on cardiovascular and stroke risk modification. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. Copyright © 2015 Elsevier B.V. All rights reserved.

Cost-effectiveness of a nurse-led internet-based vascular risk factor management programme: economic evaluation alongside a randomised controlled clinical trial.

PubMed

Greving, J P; Kaasjager, H A H; Vernooij, J W P; Hovens, M M C; Wierdsma, J; Grandjean, H M H; van der Graaf, Y; de Wit, G A; Visseren, F L J

2015-05-20

To assess the cost-effectiveness of an internet-based, nurse-led vascular risk factor management programme in addition to usual care compared with usual care alone in patients with a clinical manifestation of a vascular disease. Cost-effectiveness analysis alongside a randomised controlled trial (the Internet-based vascular Risk factor Intervention and Self-management (IRIS) study). Multicentre trial in a secondary and tertiary healthcare setting. 330 patients with a recent clinical manifestation of atherosclerosis in the coronary, cerebral, or peripheral arteries and with ≥2 treatable vascular risk factors not at goal. The intervention consisted of a personalised website with an overview and actual status of patients' vascular risk factors, and mail communication with a nurse practitioner via the website for 12 months. The intervention combined self-management support, monitoring of disease control and pharmacotherapy. Societal costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness. Patients experienced equal health benefits, that is, 0.86 vs 0.85 QALY (intervention vs usual care) at 1 year. Adjusting for baseline differences, the incremental QALY difference was -0.014 (95% CI -0.034 to 0.007). The intervention was associated with lower total costs (€4859 vs €5078, difference €219, 95% CI -€2301 to €1825). The probability that the intervention is cost-effective at a threshold value of €20,000/QALY, is 65%. At mean annual cost of €220 per patient, the intervention is relatively cheap. An internet-based, nurse-led intervention in addition to usual care to improve vascular risk factors in patients with a clinical manifestation of a vascular disease does not result in a QALY gain at 1 year, but has a small effect on vascular risk factors and is associated with lower costs. NCT00785031. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Cost-effectiveness of a nurse-led internet-based vascular risk factor management programme: economic evaluation alongside a randomised controlled clinical trial

PubMed Central

Greving, J P; Kaasjager, H A H; Vernooij, J W P; Hovens, M M C; Wierdsma, J; Grandjean, H M H; van der Graaf, Y; de Wit, G A; Visseren, F L J

2015-01-01

Objective To assess the cost-effectiveness of an internet-based, nurse-led vascular risk factor management programme in addition to usual care compared with usual care alone in patients with a clinical manifestation of a vascular disease. Design Cost-effectiveness analysis alongside a randomised controlled trial (the Internet-based vascular Risk factor Intervention and Self-management (IRIS) study). Setting Multicentre trial in a secondary and tertiary healthcare setting. Participants 330 patients with a recent clinical manifestation of atherosclerosis in the coronary, cerebral, or peripheral arteries and with ≥2 treatable vascular risk factors not at goal. Intervention The intervention consisted of a personalised website with an overview and actual status of patients’ vascular risk factors, and mail communication with a nurse practitioner via the website for 12 months. The intervention combined self-management support, monitoring of disease control and pharmacotherapy. Main outcome measures Societal costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness. Results Patients experienced equal health benefits, that is, 0.86 vs 0.85 QALY (intervention vs usual care) at 1 year. Adjusting for baseline differences, the incremental QALY difference was −0.014 (95% CI −0.034 to 0.007). The intervention was associated with lower total costs (€4859 vs €5078, difference €219, 95% CI −€2301 to €1825). The probability that the intervention is cost-effective at a threshold value of €20 000/QALY, is 65%. At mean annual cost of €220 per patient, the intervention is relatively cheap. Conclusions An internet-based, nurse-led intervention in addition to usual care to improve vascular risk factors in patients with a clinical manifestation of a vascular disease does not result in a QALY gain at 1 year, but has a small effect on vascular risk factors and is associated with lower costs. Trial registration number NCT00785031. PMID

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

The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease.

PubMed

Hohman, Timothy J; Bell, Susan P; Jefferson, Angela L

2015-05-01

A subset of older adults present post mortem with Alzheimer disease (AD) pathologic features but without any significant clinical manifestation of dementia. Vascular endothelial growth factor (VEGF) has been implicated in staving off AD-related neurodegeneration. To evaluate whether VEGF levels are associated with brain aging outcomes (hippocampal volume and cognition) and to further evaluate whether VEGF modifies relations between AD biomarkers and brain aging outcomes. Biomarker analysis using neuroimaging and neuropsychological outcomes from the Alzheimer's Disease Neuroimaging Initiative. This prospective longitudinal study across North America included individuals with normal cognition (n = 90), mild cognitive impairment (n = 130), and AD (n = 59) and began in October 2004, with follow-up ongoing. Cerebrospinal fluid VEGF was cross-sectionally related to brain aging outcomes (hippocampal volume, episodic memory, and executive function) using a general linear model and longitudinally using mixed-effects regression. Alzheimer disease biomarker (cerebrospinal fluid β-amyloid 42 and total tau)-by-VEGF interactions evaluated the effect of VEGF on brain aging outcomes in the presence of enhanced AD biomarkers. Vascular endothelial growth factor was associated with baseline hippocampal volume (t277 = 2.62; P = .009), longitudinal hippocampal atrophy (t858 = 2.48; P = .01), and longitudinal decline in memory (t1629 = 4.09; P < .001) and executive function (t1616 = 3.00; P = .003). Vascular endothelial growth factor interacted with tau in predicting longitudinal hippocampal atrophy (t845 = 4.17; P < .001), memory decline (t1610 = 2.49; P = .01), and executive function decline (t1597 = 3.71; P < .001). Vascular endothelial growth factor interacted with β-amyloid 42 in predicting longitudinal memory decline (t1618 = -2.53; P = .01). Elevated cerebrospinal fluid VEGF was associated with more optimal brain aging in vivo. The neuroprotective effect appeared

Engineering clinically relevant volumes of vascularized bone.

PubMed

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

2015-05-01

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. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Mechanisms of integrin-vascular endothelial growth factor receptor cross-activation in angiogenesis.

PubMed

Mahabeleshwar, Ganapati H; Feng, Weiyi; Reddy, Kumar; Plow, Edward F; Byzova, Tatiana V

2007-09-14

The functional responses of endothelial cells are dependent on signaling from peptide growth factors and the cellular adhesion receptors, integrins. These include cell adhesion, migration, and proliferation, which, in turn, are essential for more complex processes such as formation of the endothelial tube network during angiogenesis. This study identifies the molecular requirements for the cross-activation between beta3 integrin and tyrosine kinase receptor 2 for vascular endothelial growth factor (VEGF) receptor (VEGFR-2) on endothelium. The relationship between VEGFR-2 and beta3 integrin appears to be synergistic, because VEGFR-2 activation induces beta3 integrin tyrosine phosphorylation, which, in turn, is crucial for VEGF-induced tyrosine phosphorylation of VEGFR-2. We demonstrate here that adhesion- and growth factor-induced beta3 integrin tyrosine phosphorylation are directly mediated by c-Src. VEGF-stimulated recruitment and activation of c-Src and subsequent beta3 integrin tyrosine phosphorylation are critical for interaction between VEGFR-2 and beta3 integrin. Moreover, c-Src mediates growth factor-induced beta3 integrin activation, ligand binding, beta3 integrin-dependent cell adhesion, directional migration of endothelial cells, and initiation of angiogenic programming in endothelial cells. Thus, the present study determines the molecular mechanisms and consequences of the synergism between 2 cell surface receptor systems, growth factor receptor and integrins, and opens new avenues for the development of pro- and antiangiogenic strategies.

Management of Major Vascular Injury During Endoscopic Endonasal Skull Base Surgery.

PubMed

Gardner, Paul A; Snyderman, Carl H; Fernandez-Miranda, Juan C; Jankowitz, Brian T

2016-06-01

A major vascular injury is the most feared complication of endoscopic sinus and skull base surgery. Risk factors for vascular injury are discussed, and an algorithm for management of a major vascular injury is presented. A team of surgeons (otolaryngology and neurosurgery) is important for identification and control of a major vascular injury applying basic principles of vascular control. A variety of techniques can be used to control a major injury, including coagulation, a muscle patch, sacrifice of the artery, and angiographic stenting. Immediate and close angiographic follow-up is critical to prevent and manage subsequent complications of vascular injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Angiogenesis and expression of vascular endothelial growth factor, tumour necrosis factor-α and hypoxia inducible factor-1α in canine renal cell carcinoma.

PubMed

Yhee, J Y; Yu, C H; Kim, J H; Im, K S; Kim, N H; Brodersen, B W; Doster, A R; Sur, J-H

2012-01-01

The aim of the present study was to determine the distribution and characteristics of microvessels in various histological types of canine renal cell carcinoma (RCC). The study compared microvessel density (MVD) and distribution of blood vessels according to histological type and evaluated the presence of angiogenesis-related proteins. Nine archival samples of canine RCC were studied. MVD was calculated as the mean number of blood vessels per mm(2). The diameter of blood vessels was calculated by determining either the length of the long axis of blood vessels (diameter(max)) or the mean distance from the centre of each blood vessel to the tunica adventia (diameter(mean)). A significant difference in MVD was evident between RCCs and normal kidneys (46.6 ± 28.0 versus 8.4 ± 2.2 microvessels/mm(2)). Diameter(max) in canine RCCs (34.1 ± 14.7 μm) was also significantly different from normal canine kidney (23.2 ± 3.4 μm). Vascular endothelial growth factor (VEGF) was expressed by tumour cells and vascular endothelial cells and tumour necrosis factor (TNF)-α expression was observed in vascular endothelial cells in both neoplastic and normal kidney. Although VEGF is involved in angiogenesis and correlates with tumour stage of development, no correlation was found between VEGF expression and MVD. Tumour-associated macrophages expressing TNF-α and hypoxia inducible factor 1α were identified in peritumoural tissue and may play an important role in angiogenesis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Vascular disease and risk factors are associated with cognitive decline in the alzheimer disease spectrum.

PubMed

Lorius, Natacha; Locascio, Joseph J; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Viswanathan, Anand; Marshall, Gad A

2015-01-01

We investigated the relationship between vascular disease and risk factors versus cognitive decline cross-sectionally and longitudinally in normal older control, mild cognitive impairment, and mild Alzheimer disease (AD) dementia subjects. A total of 812 participants (229 normal older control, 395 mild cognitive impairment, 188 AD) underwent cognitive testing, brain magnetic resonance imaging, and clinical evaluations at baseline and over a period of 3 years. General linear, longitudinal mixed-effects, and Cox proportional hazards models were used. Greater homocysteine level and white matter hyperintensity volume were associated with processing speed impairment (homocysteine: P=0.02; white matter hyperintensity: P<0.0001); greater Vascular Index score was associated with memory impairment (P=0.007); and greater number of apolipoprotein E ε4 (APOE4) alleles was associated with global cognitive impairment (P=0.007) at baseline. Apolipoprotein E ε4 was associated with greater rate of increase in global cognitive impairment (P=0.002) and processing speed impairment (P=0.001) over time, whereas higher total cholesterol was associated with greater rate of increase in global cognitive impairment (P=0.02) and memory impairment (P=0.06) over time. These results suggest a significant association of increased vascular disease and risk factors with cognitive impairment at baseline and over time in the AD spectrum in a sample that was selected to have low vascular burden at baseline.

Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs.

PubMed

Syed, Mansoor A; Choo-Wing, Rayman; Homer, Robert J; Bhandari, Vineet

2016-01-01

The role of vascular endothelial growth factor (VEGF)-induced 3 different nitric oxide synthase (NOS) isoforms in lung development and injury in the newborn (NB) lung are not known. We hypothesized that VEGF-induced specific NOS pathways are critical regulators of lung development and injury. We studied NB wild type (WT), lung epithelial cell-targeted VEGF165 doxycycline-inducible overexpressing transgenic (VEGFTG), VEGFTG treated with a NOS1 inhibitor (L-NIO), VEGFTG x NOS2-/- and VEGFTG x NOS3+/- mice in room air (RA) for 7 postnatal (PN) days. Lung morphometry (chord length), vascular markers (Ang1, Ang2, Notch2, vWF, CD31 and VE-cadherin), cell proliferation (Ki67), vascular permeability, injury and oxidative stress markers (hemosiderin, nitrotyrosine and 8-OHdG) were evaluated. VEGF overexpression in RA led to increased chord length and vascular markers at PN7, which were significantly decreased to control values in VEGFTG x NOS2-/- and VEGFTG x NOS3+/- lungs. However, we found no noticeable effect on chord length and vascular markers in the VEGFTG / NOS1 inhibited group. In the NB VEGFTG mouse model, we found VEGF-induced vascular permeability in the NB murine lung was partially dependent on NOS2 and NOS3-signaling pathways. In addition, the inhibition of NOS2 and NOS3 resulted in a significant decrease in VEGF-induced hemosiderin, nitrotyrosine- and 8-OHdG positive cells at PN7. NOS1 inhibition had no significant effect. Our data showed that the complete absence of NOS2 and partial deficiency of NOS3 confers protection against VEGF-induced pathologic lung vascular and alveolar developmental changes, as well as injury markers. Inhibition of NOS1 does not have any modulating role on VEGF-induced changes in the NB lung. Overall, our data suggests that there is a significant differential regulation in the NOS-mediated effects of VEGF overexpression in the developing mouse lung.

Geraniol Suppresses Angiogenesis by Downregulating Vascular Endothelial Growth Factor (VEGF)/VEGFR-2 Signaling

PubMed Central

Wittig, Christine; Scheuer, Claudia; Parakenings, Julia; Menger, Michael D.; Laschke, Matthias W.

2015-01-01

Geraniol exerts several direct pharmacological effects on tumor cells and, thus, has been suggested as a promising anti-cancer compound. Because vascularization is a major precondition for tumor growth, we analyzed in this study the anti-angiogenic action of geraniol. In vitro, geraniol reduced the migratory activity of endothelial-like eEND2 cells. Western blot analyses further revealed that geraniol downregulates proliferating cell nuclear antigen (PCNA) and upregulates cleaved caspase-3 (Casp-3) expression in eEND2 cells. Moreover, geraniol blocked vascular endothelial growth factor (VEGF)/VEGFR-2 signal transduction, resulting in a suppression of downstream AKT and ERK signaling pathways. In addition, geraniol significantly reduced vascular sprout formation in a rat aortic ring assay. In vivo, geraniol inhibited the vascularization of CT26 tumors in dorsal skinfold chambers of BALB/c mice, which was associated with a smaller tumor size when compared to vehicle-treated controls. Immunohistochemical analyses confirmed a decreased number of Ki67-positive cells and CD31-positive microvessels with reduced VEGFR-2 expression within geraniol-treated tumors. Taken together, these findings indicate that geraniol targets multiple angiogenic mechanisms and, therefore, is an attractive candidate for the anti-angiogenic treatment of tumors. PMID:26154255

Maternal obesity and overnutrition alter fetal growth rate and cotyledonary vascularity and angiogenic factor expression in the ewe.

PubMed

Ma, Yan; Zhu, Mei J; Zhang, Liren; Hein, Sarah M; Nathanielsz, Peter W; Ford, Stephen P

2010-07-01

In pregnant sheep, maternal:fetal exchange occurs across placentomes composed of placental cotyledonary and uterine caruncular tissues. Recently, we reported that fetal weights of obese (OB) ewes [fed a diet of 150% of National Research Council (NRC) recommendations] were approximately 30% greater than those of control (C) ewes (fed a diet 100% of NRC recommendations) at midgestation (MG), but fetal weights were similar in late gestation (LG). Transplacental nutrient exchange is dependent on placental blood flow, which itself is dependent on placental vascularity. The current study investigated whether the observed initial faster and subsequent slower fetal growth rate of OB compared with C was associated with changes in cotyledonary vascularity and expression of angiogenic factors (vascular endothelial growth factor, fibroblast growth factor-2, placental growth factor, angiopoietin-1 and -2). Cotyledonary arteriole diameters were markedly greater (P < 0.05) in OB than C ewes at MG, but while arteriole diameter of C ewes increased (P < 0.05) from MG to LG, they remained unchanged in OB ewes. Cotyledonary arterial angiogenic factors mRNA and protein expression were lower (P < 0.05) in OB than C ewes at MG and remained low from MG to LG. In contrast, mRNA levels of angiogenic factors in C ewes declined from high levels at MG to reach those of OB ewes by LG. The increase in cotyledonary arteriole diameter in early to MG may function to accelerate fetal growth rate in OB ewes, while the decreased cotyledonary arterial angiogenic factors from MG-LG may function to protect the fetus from excessive placental vascular development, increased maternal nutrient delivery, and excessive weight gain.

Maternal obesity and overnutrition alter fetal growth rate and cotyledonary vascularity and angiogenic factor expression in the ewe

PubMed Central

Ma, Yan; Zhu, Mei J.; Zhang, Liren; Hein, Sarah M.; Nathanielsz, Peter W.

2010-01-01

In pregnant sheep, maternal:fetal exchange occurs across placentomes composed of placental cotyledonary and uterine caruncular tissues. Recently, we reported that fetal weights of obese (OB) ewes [fed a diet of 150% of National Research Council (NRC) recommendations] were ∼30% greater than those of control (C) ewes (fed a diet 100% of NRC recommendations) at midgestation (MG), but fetal weights were similar in late gestation (LG). Transplacental nutrient exchange is dependent on placental blood flow, which itself is dependent on placental vascularity. The current study investigated whether the observed initial faster and subsequent slower fetal growth rate of OB compared with C was associated with changes in cotyledonary vascularity and expression of angiogenic factors (vascular endothelial growth factor, fibroblast growth factor-2, placental growth factor, angiopoietin-1 and -2). Cotyledonary arteriole diameters were markedly greater (P < 0.05) in OB than C ewes at MG, but while arteriole diameter of C ewes increased (P < 0.05) from MG to LG, they remained unchanged in OB ewes. Cotyledonary arterial angiogenic factors mRNA and protein expression were lower (P < 0.05) in OB than C ewes at MG and remained low from MG to LG. In contrast, mRNA levels of angiogenic factors in C ewes declined from high levels at MG to reach those of OB ewes by LG. The increase in cotyledonary arteriole diameter in early to MG may function to accelerate fetal growth rate in OB ewes, while the decreased cotyledonary arterial angiogenic factors from MG-LG may function to protect the fetus from excessive placental vascular development, increased maternal nutrient delivery, and excessive weight gain. PMID:20427725

Social network composition of vascular patients and its associations with health behavior and clinical risk factors.

PubMed

Heijmans, Naomi; van Lieshout, Jan; Wensing, Michel

2017-01-01

This study aimed to explore linkages of patients' social network composition with health behaviors and clinical risk factors. This observational study was embedded in a project aimed at improving cardiovascular risk management (CRVM) in primary care. 657 vascular patients (227 with cardiovascular disease, 380 at high vascular risk), mean age 72.4 (SD 9.4) years, were recruited as were individuals patients considered important for dealing with their disease, so called alters (n = 487). Network composition was measured with structured patient questionnaires. Both patients and alters completed questionnaires to measure health behavior (habits for physical activity, diet, and smoking). Clinical risk factors (systolic blood pressure, LDL cholesterol level, and body mass index) were extracted from patients' medical records. Six logistic regression analyses, using generalized estimating equations, were used to test three hypothesized effects of network composition (having alters with healthful behaviors, without depression, and with specialized knowledge) on six outcomes, adjusted for demographic, personal and psychological characteristics. Having alters with overall healthful behavior was related to healthful patient diet (OR 2.14, 95%CI: 1.52-3.02). Having non-smoking alters in networks was related to reduced odds for patient smoking (OR 0.17, 95%CI: 0.05-0.60). No effects of presence of non-depressed alters were found. Presence of alters with specialized knowledge on CVRM was inversely related to healthful diet habits of patients (OR 0.47, 95%CI 0.24-0.89). No significant associations between social network composition and clinical risk factors were found. Diet and smoking, but not physical exercise and clinical risk factors, were associated with social network composition of patients with vascular conditions. In this study of vascular patients, controlling for both personal and psychological factors, fewer network influences were found compared to previous research

Social network composition of vascular patients and its associations with health behavior and clinical risk factors

PubMed Central

Heijmans, Naomi; van Lieshout, Jan; Wensing, Michel

2017-01-01

Background This study aimed to explore linkages of patients’ social network composition with health behaviors and clinical risk factors. Methods/Design This observational study was embedded in a project aimed at improving cardiovascular risk management (CRVM) in primary care. 657 vascular patients (227 with cardiovascular disease, 380 at high vascular risk), mean age 72.4 (SD 9.4) years, were recruited as were individuals patients considered important for dealing with their disease, so called alters (n = 487). Network composition was measured with structured patient questionnaires. Both patients and alters completed questionnaires to measure health behavior (habits for physical activity, diet, and smoking). Clinical risk factors (systolic blood pressure, LDL cholesterol level, and body mass index) were extracted from patients’ medical records. Six logistic regression analyses, using generalized estimating equations, were used to test three hypothesized effects of network composition (having alters with healthful behaviors, without depression, and with specialized knowledge) on six outcomes, adjusted for demographic, personal and psychological characteristics. Results Having alters with overall healthful behavior was related to healthful patient diet (OR 2.14, 95%CI: 1.52–3.02). Having non-smoking alters in networks was related to reduced odds for patient smoking (OR 0.17, 95%CI: 0.05–0.60). No effects of presence of non-depressed alters were found. Presence of alters with specialized knowledge on CVRM was inversely related to healthful diet habits of patients (OR 0.47, 95%CI 0.24–0.89). No significant associations between social network composition and clinical risk factors were found. Discussion Diet and smoking, but not physical exercise and clinical risk factors, were associated with social network composition of patients with vascular conditions. In this study of vascular patients, controlling for both personal and psychological factors, fewer network

The pathobiology of vascular dementia

PubMed Central

Iadecola, Costantino

2013-01-01

Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer’s disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that links inextricably the well being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer’s disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia. PMID:24267647

Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

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

Yang, Bin; Li, Wei; Zheng, Qichang

Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negativemore » effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation.« less

Notch Signaling in Vascular Smooth Muscle Cells

PubMed Central

Baeten, J.T.; Lilly, B.

2018-01-01

The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, associated with degeneration of the smooth muscle layer in cerebral arteries. Like most signaling pathways, the Notch signaling axis is influenced by complex interactions with mediators of other signaling pathways. This complexity is also compounded by different members of the Notch family having both overlapping and unique functions. Thus, it is vital to fully understand the roles and interactions of each Notch family member in order to effectively and specifically target their exact contributions to vascular disease. In this chapter, we will review the Notch signaling pathway in vascular smooth muscle cells as it relates to vascular development and human disease. PMID:28212801

Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis.

PubMed

Rosmorduc, O; Wendum, D; Corpechot, C; Galy, B; Sebbagh, N; Raleigh, J; Housset, C; Poupon, R

1999-10-01

We tested the potential role of vascular endothelial growth factor (VEGF) and of fibroblast growth factor-2 (FGF-2) in the angiogenesis associated with experimental liver fibrogenesis induced by common bile duct ligation in Sprague-Dawley rats. In normal rats, VEGF and FGF-2 immunoreactivities were restricted to less than 3% of hepatocytes. One week after bile duct ligation, hypoxia was demonstrated by the immunodetection of pimonidazole adducts unevenly distributed throughout the lobule. After 2 weeks, hypoxia and VEGF expression were detected in >95% of hepatocytes and coexisted with an increase in periportal vascular endothelial cell proliferation, as ascertained by Ki67 immunolabeling. Subsequently, at 3 weeks the density of von Willebrand-labeled vascular section in fibrotic areas significantly increased. Semiquantitative reverse transcription polymerase chain reaction showed that VEGF(120) and VEGF(164) transcripts, that correspond to secreted isoforms, increased within 2 weeks, while VEGF(188) transcripts remained unchanged. FGF-2 mainly consisting of a 22-kd isoform, according to Western blot, was identified by immunohistochemistry in 49% and 100% of hepatocytes at 3 and 7 weeks, respectively. Our data provide evidence that in biliary-type liver fibrogenesis, angiogenesis is stimulated primarily by VEGF in response to hepatocellular hypoxia while FGF-2 likely contributes to the maintenance of angiogenesis at later stages.

No causal impact of serum vascular endothelial growth factor level on temporal changes in body mass index in Japanese male workers: a five-year longitudinal study.

PubMed

Imatoh, Takuya; Kamimura, Seiichiro; Miyazaki, Motonobu

2017-03-01

It has been reported that adipocytes secrete vascular endothelial growth factor. Therefore, we conducted a 5-year longitudinal epidemiological study to further elucidate the association between vascular endothelial growth factor levels and temporal changes in body mass index. Our study subjects were Japanese male workers, who had regular health check-ups. Vascular endothelial growth factor levels were measured at baseline. To examine the association between vascular endothelial growth factor levels and overweight, we calculated the odds ratio using a multivariate logistic regression model. Moreover, linear mixed effect models were used to assess the association between vascular endothelial growth factor level and temporal changes in body mass index during the 5-year follow-up period. Vascular endothelial growth factor levels were marginally higher in subjects with a body mass index greater than 25 kg/m 2 compared with in those with a body mass index less than 25 kg/m 2 (505.4 vs. 465.5 pg/mL, P = 0.1) and were weakly correlated with leptin levels (β: 0.05, P = 0.07). In multivariate logistic regression, subjects in the highest vascular endothelial growth factor quantile were significantly associated with an increased risk for overweight compared with those in the lowest quantile (odds ratio 1.65, 95 % confidential interval: 1.10-2.50). Moreover P for trend was significant (P for trend = 0.003). However, the linear mixed effect model revealed that vascular endothelial growth factor levels were not associated with changes in body mass index over a 5-year period (quantile 2, β: 0.06, P = 0.46; quantile 3, β: -0.06, P = 0.45; quantile 4, β: -0.10, P = 0.22; quantile 1 as reference). Our results suggested that high vascular endothelial growth factor levels were significantly associated with overweight in Japanese males but high vascular endothelial growth factor levels did not necessarily cause obesity.

[A cohort study on the predictive value of factors influencing cardio-cerebro vascular death among people over 40 years of age].

PubMed

Yang, Jian-min; Lu, Fang-hong; Jin, Shi-kuan; Sun, Shang-wen; Zhao, Ying-xin; Wang, Shu-jian; Zhou, Xiao-hong

2007-02-01

To explore the factors influencing cardio-cerebro vascular death events among people over 40 years of age in Shandong area, China. Baseline survey was carried out in 1991. A total number of 11,008 adults over 40 years old had been studied in Shandong province. Data on cardiocerebro death was collected. The correlation between influencing factors and cardio-cerebro vascular death events was analyzed by Cox regression model. Totally, 434 cardio-cerebro death events occurred among the 11,008 subjects during the 8-year follow-up study. Cardio-cerebro death events were related to systolic blood pressure, diastolic blood pressure, smoking, stroke history and age. Data from Cox regression analysis showed that the relative risk (RR) for cardio-cerebro vascular death events increased by 2.862 [95% confidence interval (CI): 1.976-4.144] times for those people having stroke history. When systolic blood pressure, diastolic blood pressure increased by every 10 mm Hg, the relative risk for cardio-cerebro vascular death events increased by 1.171 (95% CI: 1.033-1.328), 1.214 (95% CI: 1.044-1.413) respectively. it was found that a 1.239 (95% CI: 1.088-1.553) times higher in smokers than non-smokers on relative risk for cardio-cerebro vascular death events. However, the predictive values of the influencing factors for cardio-cerebro vascular death were different among population of different years of age. The relative risk for cardio-cerebro vascular death events increased by 1.366 (95% CI: 1.102-1.678) times for each 10 mm Hg increase of diastolic blood pressure in 40-59 years old population. However, the effect was taken place by systolic blood pressure in 60-74 years old population,with a relative risk of 1.201 (95% CI: 1.017-1.418) for each 10 mm Hg increase. Age seemed the only significant factor for cardio-cerebro vascular death events on population aged more than 75 years old. Conclusion The predictive values of the risk factors were different among age groups. The different

Successful treatment of refractory TAFRO syndrome with elevated vascular endothelial growth factor using thyroxine supplements.

PubMed

Oka, Satoko; Ono, Kazuo; Nohgawa, Masaharu

2018-04-01

Although the clinical significance of hypothyroidism in TAFRO syndrome is unknown, vascular endothelial growth factor (VEGF) levels decreased with improvements in the condition of our refractory TAFRO cases after thyroxine supplement therapy. Our results indicate that elevated VEGF levels are a potential factor in the pathogenesis and anasarca of TAFRO syndrome with hypothyroidism.

Hyaline-Vascular Type Castleman's Disease, Sarcoidosis, and Crohns Disease.

PubMed

Gupta, Arjun; Ayyar, Balaji; Zia, Hamid; Chen, Weina; Harris, Samar; Naina, Harris V

2016-06-01

Sarcoidosis and Crohns disease have been associated with increased long term risk of lymphoproliferative disorders, including lymphomas. Newly developed lymphadenopathy in a patient with these disorders should prompt pathological evaluation. Castleman's disease is a lymphoproliferative disorder characterized by enlarged hyperplastic lymph nodes with regressed follicles surrounded by expanded mantle zones of small lymphocytes, and interfollicular vascular proliferation in the hyaline-vascular type. Similar to sarcoidosis and Crohns disease, its etiology is incompletely understood, although immune dysregulation, genetic factors and infectious and environmental factors are thought to play a role in all three diseases. Interleukin-6 is a possible pathological common factor between these three disease processed. Unicentric, hyaline-vascular type Castleman's disease can be treated successfully with complete surgical resection. We report a patient with long history of sarcoidosis and Crohns disease with newly developed lymphadenopathy which was found to be due to Castleman's disease.

Can vascular risk factors influence number and size of cerebral metastases? A 3D-MRI study in patients with different tumor entities.

PubMed

Nagel, Sandra; Berk, Benjamin-Andreas; Kortmann, Rolf-Dieter; Hoffmann, Karl-Titus; Seidel, Clemens

2018-02-01

There is increasing evidence that cerebral microangiopathy reduces number of brain metastases. Aim of this study was to analyse if vascular risk factors (arterial hypertension, diabetes mellitus, smoking, and hypercholesterolemia) or the presence of peripheral arterial occlusive disease (PAOD) can have an impact on number or size of brain metastases. 200 patients with pre-therapeutic 3D-brain MRI and available clinical data were analyzed retrospectively. Mean number of metastases (NoM) and mean diameter of metastases (mDM) were compared between patients with/without vascular risk factors (vasRF). No general correlation of vascular risk factors with brain metastases was found in this monocentric analysis of a patient cohort with several tumor types. Arterial hypertension, diabetes mellitus, hypercholesterolemia and smoking did not show an effect in uni- and multivariate analysis. In patients with PAOD the number of BM was lower than without PAOD. This was the case independent from cerebral microangiopathy but did not persist in multivariate analysis. From this first screening approach vascular risk factors do not appear to strongly influence brain metastasation. However, larger prospective multi-centric studies with better characterized severity of vascular risk are needed to more accurately detect effects of individual factors. Copyright © 2018 Elsevier B.V. All rights reserved.

Serum vascular endothelial growth factor in dogs with haemangiosarcoma and haematoma.

PubMed

Frenz, Meike; Kaup, Franz-Josef; Neumann, Stephan

2014-10-01

Splenic haemangiosarcomas are frequently seen in dogs. Because of their bad prognosis differentiation from other benign splenic lesions are of prognostic importance. However, because haemangiosarcoma is a tumour of the vascular system, it was hypothesised that vascular endothelial growth factor (VEGF) might play a major role in tumour growth and might thus be increased in the blood of affected dogs. The aim of this study was to investigate the clinical relevance of differences in serum VEGF concentrations between dogs with splenic haemangiosarcomas and those with non-malignant splenic lesions (haematomas) and healthy subjects using a canine ELISA. Serum VEGF levels were significantly higher in dogs with splenic masses compared with healthy dogs, but did not differ significantly between dogs with haemangiosarcomas and haematomas. VEGF has a potential clinical utility as a diagnostic marker for dogs with splenic lesions but may not be useful to differentiate among the various splenic lesions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pharmacogenetics of Vascular Risk Factors in Alzheimer's Disease.

PubMed

Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan C; Cacabelos, Pablo; Teijido, Óscar

2018-01-03

Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic ( APOE-APOB-APOC3-CETP-LPL ) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE , NOS3 , ACE , AGT , and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.

Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells.

PubMed

Lachgar, S; Charveron, M; Gall, Y; Bonafe, J L

1998-03-01

The hair follicle dermal papilla which controls hair growth, is characterized in the anagen phase by a highly developed vascular network. We have demonstrated in a previous study that the expression of an angiogenic growth factor called vascular endothelial growth factor (VEGF) mRNA varied during the hair cycle. VEGF mRNA is strongly expressed in dermal papilla cells (DPC) in the anagen phase, but during the catagen and telogen phases. VEGF mRNA is less strongly expressed. This involvement of VEGF during the hair cycle allowed us to determine whether VEGF mRNA expression by DPC was regulated by minoxidil. In addition, the effect of minoxidil on VEGF protein synthesis in both cell extracts and DPC-conditioned medium, was investigated immunoenzymatically. Both VEGF mRNA and protein were significantly elevated in treated DPC compared with controls. DPC incubated with increasing minoxidil concentrations (0.2, 2, 6, 12 and 24 mumol/L) induced a dose-dependent expression of VEGF mRNA. Quantification of transcripts showed that DPC stimulated with 24 mumol/L minoxidil express six times more VEGF mRNA than controls. Similarly, VEGF protein production increases in cell extracts and conditioned media following minoxidil stimulation. These studies strongly support the likely involvement of minoxidil in the development of dermal papilla vascularization via a stimulation of VEGF expression, and support the hypothesis that minoxidil has a physiological role in maintaining a good vascularization of hair follicles in androgenetic alopecia.

RS3PE syndrome presenting as vascular endothelial growth factor associated disorder

PubMed Central

Arima, K; Origuchi, T; Tamai, M; Iwanaga, N; Izumi, Y; Huang, M; Tanaka, F; Kamachi, M; Aratake, K; Nakamura, H; Ida, H; Uetani, M; Kawakami, A; Eguchi, K

2005-01-01

Methods: Vascular endothelial growth factor165 (VEGF165), tumour necrosis factor α (TNFα), and interleukin 1ß (IL1ß) were measured by enzyme linked immunosorbent assay (ELISA) in serum samples from three patients with RS3PE syndrome. As controls, serum samples from 26 healthy volunteers, 12 patients with rheumatoid arthritis, 10 patients with systemic lupus erythematosus, 13 patients with polymyositis/dermatomyositis, 13 patients with vasculitis syndrome, and 6 patients with mixed connective tissue disease were also analysed. Synovial hypervascularity of patients with RS3PE syndrome was estimated by rate of enhancement (E-rate) in a dynamic MRI study. Results: Serum concentrations of VEGF165 (mean (SD) 2223.3 (156.3) pg/ml) were significantly higher in patients with active RS3PE syndrome than in controls before corticosteroid treatment. TNFα and IL1ß levels were similar in patients and controls. Synovial hypervascularity in affected joints and subcutaneous oedema decreased during corticosteroid treatment, in parallel with the fall in serum VEGF165. Conclusions: VEGF promotes synovial inflammation and vascular permeability in patients with RS3PE syndrome, suggesting that RS3PE can be classified as a VEGF associated disorder. PMID:16227418

Brain vascular lesions: a clinicopathologic, immunohistochemistry, and ultrastructural approach.

PubMed

Navarrete, Marisol Galván; Hernández, Alma Dalia; Collado-Ortiz, Miguel Angel; Salinas-Lara, Citlaltepetl; Tena-Suck, Martha Lilia

2014-08-01

Brain vascular malformations are relatively common lesions that cause serious neurologic disability or death in a significant proportion of individuals bearing them. The purpose of this study was to analyze the clinicopathologic and immunohistochemistry these lesions, looking for common antibodies expressed such as CD31, CD34, CD15, factor VIII, nestin, vimentin, vascular endothelial grow factor (VEGF), vascular endothelial grow factor receptor-2 (VEGF-R2), glial fibrillar acidic protien (GFAP), and fibroblastic grow factor β (β-FGF) and ultrastructure in endothelial cells as well as in vessel walls. Fifty cases of vascular lesions were included in this study: 29 (58%) of them were arteriovenous malformations and 21 (52%) were brain cavernomas. Twenty-six (52%) patients were women and 24 (48%) men. The age range was from 13 to 68 years (mean age, 35.86 ± 15.19 years). The size of the lesions ranged between 1 and 8 cm (3 ± 1.65 cm), and parieto-occipital lesions had a bigger size. Evolution time varied from 1 month to 1 year (mean, 7.5 months). There was a significant statistical correlation between age and sex (P = -035), rupture of lesion (P = .015), brain hemorrhage (P = .033), necrosis (P = .011), hemosiderin deposit (P = .042), VEGF (P = .015), and VEGFR (P = .037), as well as localization of rupture (P = .017), loss of consciousness (P = .000), visual deficit (P = .026), hyaline vessels (P = .000), and CD31 (.009). Interactions between endothelial cells and mural cells (pericytes and vascular smooth muscle cells) in blood vessel walls have recently come into focus as central processes in the regulation of vascular formation, stabilization, remodeling, and function in brain vascular lesions. However, the molecular mechanisms that underlie the formation and growth of brain arteriovenous malformations are still poorly understood. Copyright © 2014 Elsevier Inc. All rights reserved.

Glutathione regulation of redox-sensitive signals in tumor necrosis factor-{alpha}-induced vascular endothelial dysfunction

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

Tsou, T.-C.; Yeh, S.C.; Tsai, F.-Y.

2007-06-01

We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-{alpha})-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-{alpha} induces various biological effects on vascular cells, TNF-{alpha} dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-{alpha} concentrations, we adopted the lower TNF-{alpha} (0.2 ng/ml) to rule out the possible involvement of other TNF-{alpha}-induced biological effects. Inhibition of glutathione synthesis by L-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-{alpha}-induced adhesion molecule expression and monocyte-endothelial monolayermore » binding. BSO attenuated the TNF-{alpha}-induced nuclear factor-kappaB (NF-{kappa}B) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-{alpha}. Inhibition of ERK, JNK, or NF-{kappa}B attenuates TNF-{alpha}-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-{alpha} induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-{kappa}B in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-{alpha}. Although AP-1 activation by the lower TNF-{alpha} was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-{alpha}-induced adhesion molecule expression.« less

Disparities in stroke type and vascular risk factors between 2 Hispanic populations in Miami and Mexico city.

PubMed

Romano, Jose G; Arauz, Antonio; Koch, Sebastian; Dong, Chuanhui; Marquez, Juan M; Artigas, Carol; Merlos, Marlon; Hernandez, Bernardo; Roa, Luis F; Rundek, Tatjana; Sacco, Ralph L

2013-08-01

The heterogeneous nature and determinants of stroke among different Hispanic groups was examined by comparing hospitalized Hispanic stroke patients in Miami, where the Hispanic population is largely of Caribbean origin, to a Mestizo population in Mexico City. Consecutive Hispanic patients who were admitted with stroke or transient ischemic attack (TIA) and included in the prospective stroke registries of 2 tertiary care teaching hospitals were studied. Demographic factors, stroke subtypes, vascular risk factors, stroke severity, and outcomes were compared. Vascular risk factor definitions were standardized. A total of 928 patients (520 Mexicans and 408 Miami Hispanics) were analyzed. Mexicans were younger, with a greater proportion of women. More cerebral venous thromboses (CVTs) were admitted in Mexico, while TIA and stroke mimics were more commonly admitted in Miami; cardioembolic strokes were more commonly ascertained in Miami, and more cryptogenic strokes in Mexico. Stroke severity was similar for intracerebral hemorrhages, but more severe ischemic strokes and CVTs were included in the Mexican registry. Outcome at 1 and 3 months was similar in both registries after adjusting for age and baseline stroke severity. After adjusting for age and sex, hypertension, dyslipidemia, and atrial fibrillation were more frequent, and diabetes mellitus was less frequent, among Miami Hispanics compared to Mexicans. We found significant differences in the frequency of hypertension, diabetes, dyslipidemia, and atrial fibrillation in Miami Hispanics and Mexican stroke patients, highlighting the heterogeneity of the Hispanic ethnic group. Future studies are needed to clarify the relative contribution of genetic and environmental disparities amongst Mexican and Caribbean Hispanic stroke patients. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Inhibition of intimal thickening after vascular injury with a cocktail of vascular endothelial growth factor and cyclic Arg-Gly-Asp peptide.

PubMed

Li, Yue; McRobb, Lucinda S; Khachigian, Levon M

2016-10-01

Percutaneous coronary intervention is widely used for the treatment of coronary artery disease; however, significant challenges such as restenosis remain. Key to solving these problems is to inhibit smooth muscle cell activation while enhancing re-endothelialization. Early growth response-1 (Egr-1) is a transcription factor that regulates vascular smooth muscle cell (SMC) proliferation and migration through its control of an array of downstream genes. A "cocktail" of vascular endothelial growth factor (VEGF)-A, VEGF-D and cyclic RGD was tested for its ability to inhibit neointima formation and accelerate re-endothelialization following balloon injury to carotid arteries of rats. In vitro, the cocktail stimulated endothelial cell growth yet inhibited smooth muscle cell growth. In vivo, cocktail-treated injured arteries exhibited reduced intimal thickening by >50% (P<0.05). It increased both re-endothelialization and endothelial nitric oxide synthase (NOS) expression. Cocktail reduced Egr-1 expression, an effect blocked by the NOS inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) that also prevented cocktail inhibition of neointima inhibition. This combination may potentially be useful for the treatment of restenosis with concomitant stimulation of revascularization. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

New Insights into Dialysis Vascular Access: What Is the Optimal Vascular Access Type and Timing of Access Creation in CKD and Dialysis Patients?

PubMed

Woo, Karen; Lok, Charmaine E

2016-08-08

Optimal vascular access planning begins when the patient is in the predialysis stages of CKD. The choice of optimal vascular access for an individual patient and determining timing of access creation are dependent on a multitude of factors that can vary widely with each patient, including demographics, comorbidities, anatomy, and personal preferences. It is important to consider every patient's ESRD life plan (hence, their overall dialysis access life plan for every vascular access creation or placement). Optimal access type and timing of access creation are also influenced by factors external to the patient, such as surgeon experience and processes of care. In this review, we will discuss the key determinants in optimal access type and timing of access creation for upper extremity arteriovenous fistulas and grafts. Copyright © 2016 by the American Society of Nephrology.

Vector-based RNA interference against vascular endothelial growth factor-A significantly limits vascularization and growth of prostate cancer in vivo.

PubMed

Wannenes, Francesca; Ciafré, Silvia Anna; Niola, Francesco; Frajese, Gaetano; Farace, Maria Giulia

2005-12-01

RNA interference technology is emerging as a very potent tool to obtain a cellular knockdown of a desired gene. In this work we used vector-based RNA interference to inhibit vascular endothelial growth factor (VEGF) expression in prostate cancer in vitro and in vivo. We demonstrated that transduction with a plasmid carrying a small interfering RNA targeting all isoforms of VEGF, dramatically impairs the expression of this growth factor in the human prostate cancer cell line PC3. As a consequence, PC3 cells loose their ability to induce one of the fundamental steps of angiogenesis, namely the formation of a tube-like network in vitro. Most importantly, our "therapeutic" vector is able to impair tumor growth rate and vascularization in vivo. We show that a single injection of naked plasmid in developing neoplastic mass significantly decreases microvessel density in an androgen-refractory prostate xenograft and is able to sustain a long-term slowing down of tumor growth. In conclusion, our results confirm the basic role of VEGF in the angiogenic development of prostate carcinoma, and suggest that the use of our vector-based RNA interference approach to inhibit angiogenesis could be an effective tool in view of future gene therapy applications for prostate cancer.

Bone marrow vascular endothelial growth factor level per platelet count might be a significant predictor for the treatment outcomes of patients with diffuse large B-cell lymphomas.

PubMed

Kim, Jung Sun; Gang, Ga Won; Lee, Se Ryun; Sung, Hwa Jung; Park, Young; Kim, Dae Sik; Choi, Chul Won; Kim, Byung Soo

2015-10-01

Developing a parameter to predict bone marrow invasion by non-Hodgkin's lymphoma is an important unmet medical need for treatment decisions. This study aimed to confirm the validity of the hypothesis that bone marrow plasma vascular endothelial growth factor level might be correlated with the risk of bone marrow involvement and the prognosis of patients with diffuse large B-cell non-Hodgkin's lymphoma. Forty-nine diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone regimen were enrolled. Vascular endothelial growth factor level was measured with enzyme-linked immunosorbent assay. The validity of bone marrow plasma vascular endothelial growth factor level and bone marrow vascular endothelial growth factor level per platelet count for predicting treatment response and survival after initial rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone combined chemotherapy was assessed. Bone marrow plasma vascular endothelial growth factor level per platelet count was significantly associated with old age (≥ 65 years), poor performance score (≥ 2), high International prognosis index (≥ 3) and bone marrow invasion. The patients with high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) showed a significantly lower complete response rate than the others. On Kaplan-Meier survival curves, the patients with high bone marrow plasma vascular endothelial growth factor levels (≥ 655 pg/ml) or high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) demonstrated a significantly shorter overall survival and progression-free survival than the others. In the patients without bone marrow involvement, bone marrow plasma vascular endothelial growth factor level per platelet count had a significant relationship with overall survival and progression-free survival. Multivariate analysis revealed that the patients without

VEGF signaling inside vascular endothelial cells and beyond

PubMed Central

Eichmann, Anne; Simons, Michael

2014-01-01

Vascular endothelial growth factor-A (VEGF-A) has long been recognized as the key regulator of vascular development and function in health and disease. VEGF is a secreted polypeptide that binds to transmembrane tyrosine kinase VEGF receptors on the plasma membrane, inducing their dimerization, activation and assembly of a membrane-proximal signaling complex. Recent studies have revealed that many key events of VEGFR signaling occur inside the endothelial cell and are regulated by endosomal receptor trafficking. Plasma membrane VEGFR interacting molecules, including vascular guidance receptors Neuropilins and Ephrins also regulate VEGFR endocytosis and trafficking. VEGF signaling is increasingly recognized for its roles outside of the vascular system, notably during neural development, and blood vessels regulate epithelial branching morphogenesis. We review here recent advances in our understanding of VEGF signaling and its biological roles. PMID:22366328

Emerging vascular endothelial growth factor antagonists to treat neovascular age-related macular degeneration.

PubMed

Hussain, Rehan M; Ciulla, Thomas A

2017-09-01

Evolving anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration (nAMD) include long acting agents, combination strategies involving new pathways, topical agents, sustained-release, and genetic therapy strategies. Areas covered: Brolucizumab and abicipar pegol have smaller molecular size, facilitating higher concentrations and potentially longer duration than current anti-VEGF agents. Agents being combined with anti-VEGFs include OPT-302 (to inhibit VEGF-C and VEGF-D); pegpleranib and rinucumab (to inhibit platelet derived growth factor, PDGF - but both failed to show consistently improved visual outcomes compared to anti-VEGF monotherapy); and RG7716, ARP-1536 and nesvacumab (to activate the Tie-2 tyrosine kinase receptor, which reduces permeability). X-82 is an oral anti-VEGF and anti-PDGF being tested in phase 2 studies. Topical anti-VEGF ± anti-PDGF drugs under study include pazopanib, PAN-90806, squalamine lactate, regorafinib, and LHA510. Sustained-release anti-VEGF delivery treatments, such as the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305 aim to reduce the burden of frequent injections. Gene therapies with new viral vectors hold the potential to induce sustained expression of anti-angiogenic proteins via the retina's cellular apparatus, and include AVA-101/201, ADVM-202/302, AAV2-sFLT01, RGX314, and Retinostat. Expert opinion: There are many emerging anti-VEGF treatments that aim to improve visual outcomes and reduce the treatment burden of nAMD.

[Vascular aging, arterial hypertension and physical activity].

PubMed

Schmidt-Trucksäss, A; Weisser, B

2011-11-01

The present review delineates the significance of intima-media-thickness, arterial stiffness and endothelial function for vascular aging. There is profound evidence for an increase in intima-media-thickness and vascular stiffness not only during healthy aging but induced also by cardiovascular risk factors. There is a central role of arterial hypertension for this progression in both structural factors. In addition, both parameters are strongly associated with cardiovascular risk. Endothelial function measured as postischemic flow-mediated vasodilatation is a functional parameter which is decreased both in healthy aging and by cardiovascular risk factors. Physical activity modifies the influence of aging and risk factors on endothelial function. A positive influence of endurance exercise on vascular stiffness and endothelial function has been demonstrated in numerous studies. In long-term studies, regular physical activity has been shown to reduce the progression of intima-media-thickness. Thus, arterial hypertension accelerates vascular aging, while physical activity has a positive influence on a variety of vascular parameters associated with vascular aging. © Georg Thieme Verlag KG Stuttgart · New York.

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

PubMed

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

2018-06-01

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

Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors

PubMed Central

Kalaria, Raj N; Maestre, Gladys E; Arizaga, Raul; Friedland, Robert P; Galasko, Doug; Hall, Kathleen; Luchsinger, José A; Ogunniyi, Adesola; Perry, Elaine K; Potocnik, Felix; Prince, Martin; Stewart, Robert; Wimo, Anders; Zhang, Zhen-Xin; Antuono, Piero

2010-01-01

Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population. Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (≥5%) in certain Asian and Latin American countries, but consistently low (1–3%) in India and sub-Saharan Africa; Alzheimer's disease accounts for 60% whereas vascular dementia accounts for ∼30% of the prevalence. Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa. Illiteracy remains a risk factor for dementia. The APOE ε4 allele does not influence dementia progression in sub-Saharan Africans. Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia. Use of traditional diets and medicinal plant extracts might aid prevention and treatment. Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions. PMID:18667359

Up-regulation of proproliferative genes and the ligand/receptor pair placental growth factor and vascular endothelial growth factor receptor 1 in hepatitis C cirrhosis.

PubMed

Huang, Xiao X; McCaughan, Geoffrey W; Shackel, Nicholas A; Gorrell, Mark D

2007-09-01

Cirrhosis can lead to hepatocellular carcinoma (HCC). Non-diseased liver and hepatitis C virus (HCV)-associated cirrhosis with or without HCC were compared. Proliferation pathway genes, immune response genes and oncogenes were analysed by a quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunostaining. Real-time RT-PCR showed up-regulation of genes in HCV cirrhosis including the proliferation-associated genes bone morphogenetic protein 3 (BMP3), placental growth factor 3 (PGF3), vascular endothelial growth factor receptor 1 (VEGFR1) and soluble VEGFR1, the oncogene FYN, and the immune response-associated genes toll-like receptor 9 (TLR9) and natural killer cell transcript 4 (NK4). Expressions of TLR2 and the oncogenes B-cell CLL/lymphoma 9 (BCL9) and PIM2 were decreased in HCV cirrhosis. In addition, PIM2 and TLR2 were increased in HCV cirrhosis with HCC compared with HCV cirrhosis. The ligand/receptor pair PGF and VEGFR1 was intensely expressed by the portal tract vascular endothelium. VEGFR1 was expressed in reactive biliary epithelial structures in fibrotic septum and in some stellate cells and macrophages. PGF and VEGFR1 may have an important role in the pathogenesis of the neovascular response in cirrhosis.

Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors

PubMed Central

Butler, Jason M.; Kobayashi, Hideki; Rafii, Shahin

2010-01-01

The precise mechanisms whereby anti-angiogenesis therapy blocks tumour growth or causes vascular toxicity are unknown. We propose that endothelial cells establish a vascular niche that promotes tumour growth and tissue repair not only by delivering nutrients and O2 but also through an ‘angiocrine’ mechanism by producing stem and progenitor cell-active trophogens. Identification of endothelial-derived instructive angiocrine factors will allow direct tumour targeting, while diminishing the unwanted side effects associated with the use of anti-angiogenic agents. PMID:20094048

Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors.

PubMed

Butler, Jason M; Kobayashi, Hideki; Rafii, Shahin

2010-02-01

The precise mechanisms whereby anti-angiogenesis therapy blocks tumour growth or causes vascular toxicity are unknown. We propose that endothelial cells establish a vascular niche that promotes tumour growth and tissue repair not only by delivering nutrients and O2 but also through an 'angiocrine' mechanism by producing stem and progenitor cell-active trophogens. Identification of endothelial-derived instructive angiocrine factors will allow direct tumour targeting, while diminishing the unwanted side effects associated with the use of anti-angiogenic agents.

Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.

PubMed

Khalil, Raouf A

2013-12-15

Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. Copyright © 2013 Elsevier Inc. All rights reserved.

Estrogen, Vascular Estrogen Receptor and Hormone Therapy in Postmenopausal Vascular Disease

PubMed Central

Khalil, Raouf A.

2013-01-01

Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women’s Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject’s age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. PMID:24099797

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

PubMed

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

2015-01-01

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

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

PubMed Central

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

2015-01-01

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

Stroke injury, cognitive impairment and vascular dementia☆

PubMed Central

Kalaria, Raj N.; Akinyemi, Rufus; Ihara, Masafumi

2016-01-01

The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25–30% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood–brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26806700

Factors Affecting Choroidal Vascular Density in Normal Eyes: Quantification Using En Face Swept-Source Optical Coherence Tomography.

PubMed

Fujiwara, Atsushi; Morizane, Yuki; Hosokawa, Mio; Kimura, Shuhei; Kumase, Fumiaki; Shiode, Yusuke; Doi, Shinichiro; Hirano, Masayuki; Toshima, Shinji; Hosogi, Mika; Shiraga, Fumio

2016-10-01

To quantify the vascular density of the choroid of normal eyes and to identify the influencing factors using en face images obtained with swept-source optical coherence tomography (SS OCT). Prospective cross-sectional study. One hundred and sixty-three eyes of 163 healthy volunteers (83 female; mean age 42.2 ± 22.6 years) with a corrected visual acuity of ≥1.0 were investigated. En face SS OCT images of the choroid were used for quantitative assessment of the vascular density in the large choroid vessel layer. Relationships between vascular density of the choroid and age, sex, refractive error (RE), axial length (AL), and subfoveal choroidal thickness (SCT) were also investigated. There was a significant negative relationship between vascular density of the choroid and subject age (P < .001). Analysis according to age showed a significant correlation in the group aged >30 years (P < .001), but not in the group aged ≤30 years (P = .225). SCT had a significant positive relationship with vascular density of the choroid (P < .001). However, a significant correlation was not observed between sex, RE, or AL and vascular density of the choroid (P = .981, P = .292, and P = .216, respectively). Multivariable regression analysis with vascular density of the choroid as the dependent variable and age, sex, RE, AL, and SCT as independent variables showed that age and SCT are important determinants of vascular density of the choroid (P < .001). Age and SCT affect vascular density of the choroid. Copyright © 2016 Elsevier Inc. All rights reserved.

The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1

PubMed Central

Qin, Liuliang; Zhao, Dezheng; Xu, Jianfeng; Ren, Xianghui; Terwilliger, Ernest F.; Parangi, Sareh; Lawler, Jack; Dvorak, Harold F.

2013-01-01

Angiogenesis plays an important role in cancer and in many other human diseases. Vascular endothelial growth factor-A (VEGF-A), the best known angiogenic factor, was originally discovered as a potent vascular permeability factor (VPF), suggesting that other vascular permeabilizing agents, such as histamine and serotonin, might also have angiogenic activity. We recently demonstrated that, like VEGF-A, histamine and serotonin up-regulate the orphan nuclear receptor and transcription factor TR3 (mouse homolog Nur77) and that TR3/Nur77 is essential for their vascular permeabilizing activities. We now report that histamine and serotonin are also angiogenic factors that, at low micromolar concentrations, induce endothelial cell proliferation, migration and tube formation in vitro, and angiogenesis in vivo. All of these responses are mediated through specific histamine and serotonin receptors, are independent of VEGF-A, and are directly dependent on TR3/Nur77. Initially, the angiogenic response closely resembled that induced by VEGF-A, with generation of “mother” vessels. However, after ∼10 days, mother vessels began to regress as histamine and serotonin, unlike VEGF-A, up-regulated the potent angiogenesis inhibitor thrombospondin-1, thereby triggering a negative feedback loop. Thus, histamine and serotonin induce an angiogenic response that fits the time scale of acute inflammation. PMID:23315169

Pathogenesis of vascular leak in dengue virus infection.

PubMed

Malavige, Gathsaurie Neelika; Ogg, Graham S

2017-07-01

Endothelial dysfunction leading to vascular leak is the hallmark of severe dengue. Vascular leak typically becomes clinically evident 3-6 days after the onset of illness, which is known as the critical phase. This critical phase follows the period of peak viraemia, and lasts for 24-48 hr and usually shows rapid and complete reversal, suggesting that it is likely to occur as a result of inflammatory mediators, rather than infection of the endothelium. Cytokines such as tumour necrosis factor-α, which are known to be elevated in the critical phase of dengue, are likely to be contributing factors. Dengue NS1, a soluble viral protein, has also been shown to disrupt the endothelial glycocalyx and thus contribute to vascular leak, although there appears to be a discordance between the timing of NS1 antigenaemia and occurrence of vascular leak. In addition, many inflammatory lipid mediators are elevated in acute dengue viral infection such as platelet activating factor (PAF) and leukotrienes. Furthermore, many other inflammatory mediators such as vascular endothelial growth factor and angiopoietin-2 have been shown to be elevated in patients with dengue haemorrhagic fever, exerting their action in part by inducing the activity of phospholipases, which have diverse inflammatory effects including generation of PAF. Platelets have also been shown to significantly contribute to endothelial dysfunction by production of interleukin-1β through activation of the NLRP3 inflammasome and also by inducing production of inflammatory cytokines by monocytes. Drugs that block down-stream immunological mediator pathways such as PAF may also be beneficial in the treatment of severe disease. © 2017 John Wiley & Sons Ltd.

Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion.

PubMed

Gorin, Caroline; Rochefort, Gael Y; Bascetin, Rumeyza; Ying, Hanru; Lesieur, Julie; Sadoine, Jérémy; Beckouche, Nathan; Berndt, Sarah; Novais, Anita; Lesage, Matthieu; Hosten, Benoit; Vercellino, Laetitia; Merlet, Pascal; Le-Denmat, Dominique; Marchiol, Carmen; Letourneur, Didier; Nicoletti, Antonino; Vital, Sibylle Opsahl; Poliard, Anne; Salmon, Benjamin; Muller, Laurent; Chaussain, Catherine; Germain, Stéphane

2016-03-01

Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF. ©AlphaMed Press.

Production of Experimental Malignant Pleural Effusions Is Dependent on Invasion of the Pleura and Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor by Human Lung Cancer Cells

PubMed Central

Yano, Seiji; Shinohara, Hisashi; Herbst, Roy S.; Kuniyasu, Hiroki; Bucana, Corazon D.; Ellis, Lee M.; Fidler, Isaiah J.

2000-01-01

We determined the molecular mechanisms that regulate the pathogenesis of malignant pleural effusion (PE) associated with advanced stage of human, non-small-cell lung cancer. Intravenous injection of human PC14 and PC14PE6 (adenocarcinoma) or H226 (squamous cell carcinoma) cells into nude mice yielded numerous lung lesions. PC14 and PC14PE6 lung lesions invaded the pleura and produced PE containing a high level of vascular endothelial growth factor (VEGF)-localized vascular hyperpermeability. Lung lesions produced by H226 cells were confined to the lung parenchyma with no PE. The level of expression of VEGF mRNA and protein by the cell lines directly correlated with extent of PE formation. Transfection of PC14PE6 cells with antisense VEGF165 gene did not inhibit invasion into the pleural space but reduced PE formation. H226 cells transfected with either sense VEGF 165 or sense VEGF 121 genes induced localized vascular hyperpermeability and produced PE only after direct implantation into the thoracic cavity. The production of PE was thus associated with the ability of tumor cells to invade the pleura, a property associated with expression of high levels of urokinase-type plasminogen activator and low levels of TIMP-2. Collectively, the data demonstrate that the production of malignant PE requires tumor cells to invade the pleura and express high levels of VEGF/VPF. PMID:11106562

Sphingosine-1-phosphate: a novel nonhypoxic activator of hypoxia-inducible factor-1 in vascular cells.

PubMed

Michaud, Maude D; Robitaille, Geneviève A; Gratton, Jean-Philippe; Richard, Darren E

2009-06-01

Sphingosine-1-phosphate (S1P) is a potent bioactive phospholipid responsible for a variety of vascular cell responses. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of genes essential for adaptation to low oxygen. S1P and HIF-1 are both important mediators of vascular cell responses such as migation, proliferation, and survival. Studies have shown that nonhypoxic stimuli can activate HIF-1 in oxygenated conditions. Here, we attempt to determine whether S1P can modulate the vascular activation of HIF-1. We show that in vascular endothelial and smooth muscle cells, activation of the S1P type-2 receptor by S1P strongly increases HIF-1 alpha protein levels, the active subunit of HIF-1. This is achieved through pVHL-independent stabilization of HIF-1 alpha. We demonstrate that the HIF-1 nuclear complex, formed on S1P stimulation, is transcriptionally active and specifically binds to a hypoxia-responsive elements. Moreover, S1P activates the expression of genes known to be closely regulated by HIF-1. Our results identify S1P as a novel and potent nonhypoxic activator of HIF-1. We believe that understanding the role played by HIF-1 in S1P gene regulation will have a strong impact on different aspects of vascular biology.

VEGF signaling inside vascular endothelial cells and beyond.

PubMed

Eichmann, Anne; Simons, Michael

2012-04-01

Vascular endothelial growth factor-A (VEGF-A) has long been recognized as the key regulator of vascular development and function in health and disease. VEGF is a secreted polypeptide that binds to transmembrane tyrosine kinase VEGF receptors on the plasma membrane, inducing their dimerization, activation and assembly of a membrane-proximal signaling complex. Recent studies have revealed that many key events of VEGFR signaling occur inside the endothelial cell and are regulated by endosomal receptor trafficking. Plasma membrane VEGFR interacting molecules, including vascular guidance receptors Neuropilins and Ephrins also regulate VEGFR endocytosis and trafficking. VEGF signaling is increasingly recognized for its roles outside of the vascular system, notably during neural development, and blood vessels regulate epithelial branching morphogenesis. We review here recent advances in our understanding of VEGF signaling and its biological roles. Copyright © 2012 Elsevier Ltd. All rights reserved.

Capture of endothelial cells under flow using immobilized vascular endothelial growth factor

PubMed Central

Smith, Randall J.; Koobatian, Maxwell T.; Shahini, Aref; Swartz, Daniel D.; Andreadis, Stelios T.

2015-01-01

We demonstrate the ability of immobilized vascular endothelial growth factor (VEGF) to capture endothelial cells (EC) with high specificity under fluid flow. To this end, we engineered a surface consisting of heparin bound to poly-L-lysine to permit immobilization of VEGF through the C-terminal heparin-binding domain. The immobilized growth factor retained its biological activity as shown by proliferation of EC and prolonged activation of KDR signaling. Using a microfluidic device we assessed the ability to capture EC under a range of shear stresses from low (0.5 dyne/cm2) to physiological (15 dyne/cm2). Capture was significant for all shear stresses tested. Immobilized VEGF was highly selective for EC as evidenced by significant capture of human umbilical vein and ovine pulmonary artery EC but no capture of human dermal fibroblasts, human hair follicle derived mesenchymal stem cells, or mouse fibroblasts. Further, VEGF could capture EC from mixtures with non-EC under low and high shear conditions as well as from complex fluids like whole human blood under high shear. Our findings may have far reaching implications, as they suggest that VEGF could be used to promote endothelialization of vascular grafts or neovascularization of implanted tissues by rare but continuously circulating EC. PMID:25771020

Vascular signaling abnormalities in Alzheimer disease.

PubMed

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

2011-08-01

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

Vinpocetine Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

PubMed Central

Chen, Xiu-Juan; Wang, Na; Yi, Peng-Fei; Song, Min; Zhang, Bo; Wang, Yu-Zhong; Liang, Qiu-Hua

2016-01-01

Vascular calcification is an active process of osteoblastic differentiation of vascular smooth muscle cells; however, its definite mechanism remains unknown. Vinpocetine, a derivative of the alkaloid vincamine, has been demonstrated to inhibit the high glucose-induced proliferation of vascular smooth muscle cells; however, it remains unknown whether vinpocetine can affect the osteoblastic differentiation of vascular smooth muscle cells. We hereby investigated the effect of vinpocetine on vascular calcification using a beta-glycerophosphate-induced cell model. Our results showed that vinpocetine significantly reduced the osteoblast-like phenotypes of vascular smooth muscle cells including ALP activity, osteocalcin, collagen type I, Runx2 and BMP-2 expression as well as the formation of mineralized nodule. Vinpocetine, binding to translocation protein, induced phosphorylation of extracellular signal-related kinase and Akt and thus inhibited the translocation of nuclear factor-kappa B into the nucleus. Silencing of translocator protein significantly attenuated the inhibitory effect of vinpocetine on osteoblastic differentiation of vascular smooth muscle cells. Taken together, vinpocetine may be a promising candidate for the clinical therapy of vascular calcification. PMID:27589055

Vinpocetine Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells.

PubMed

Ma, Yun-Yun; Sun, Lin; Chen, Xiu-Juan; Wang, Na; Yi, Peng-Fei; Song, Min; Zhang, Bo; Wang, Yu-Zhong; Liang, Qiu-Hua

2016-01-01

Vascular calcification is an active process of osteoblastic differentiation of vascular smooth muscle cells; however, its definite mechanism remains unknown. Vinpocetine, a derivative of the alkaloid vincamine, has been demonstrated to inhibit the high glucose-induced proliferation of vascular smooth muscle cells; however, it remains unknown whether vinpocetine can affect the osteoblastic differentiation of vascular smooth muscle cells. We hereby investigated the effect of vinpocetine on vascular calcification using a beta-glycerophosphate-induced cell model. Our results showed that vinpocetine significantly reduced the osteoblast-like phenotypes of vascular smooth muscle cells including ALP activity, osteocalcin, collagen type I, Runx2 and BMP-2 expression as well as the formation of mineralized nodule. Vinpocetine, binding to translocation protein, induced phosphorylation of extracellular signal-related kinase and Akt and thus inhibited the translocation of nuclear factor-kappa B into the nucleus. Silencing of translocator protein significantly attenuated the inhibitory effect of vinpocetine on osteoblastic differentiation of vascular smooth muscle cells. Taken together, vinpocetine may be a promising candidate for the clinical therapy of vascular calcification.

Immunohistochemical expression of vascular endothelial growth factor in canine oral squamous cell carcinomas.

PubMed

Martano, Manuela; Restucci, Brunella; Ceccarelli, Dora Maria; Lo Muzio, Lorenzo; Maiolino, Paola

2016-01-01

Angiogenesis is crucial for the growth and metastasis of malignant tumours, and various proangiogenic factors promote this process. One of these factors is vascular endothelial growth factor (VEGF), which appears to play a key role in tumour angiogenesis. The aim of the present study was to assess whether VEGF expression is associated with angiogenesis, disease progression and neoplastic proliferation in canine oral squamous cell carcinoma (OSCC) tissue. VEGF immunoreactivity was quantified by immunohistochemistry in 30 specimens, including normal oral mucosa and OSCC tissues graded as well, moderately or poorly differentiated. VEGF expression was correlated with tumour cell proliferation, as assessed using the proliferating cell nuclear antigen (PCNA) marker and microvessel density (data already published). The present results revealed that VEGF and PCNA expression increased significantly between normal oral tissue and neoplastic tissue, and between well and moderately/poorly differentiated tumours. In addition, VEGF expression was strongly correlated with PCNA expression and microvessel density. It was concluded that VEGF may promote angiogenesis through a paracrine pathway, stimulating endothelial cell proliferation and, similarly, may induce tumour cell proliferation through an autocrine pathway. The present results suggest that the evaluation of VEGF may be a useful additional criterion for estimating malignancy and growth potential in canine OSCCs.

Cloning of a cancer cell-producing hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 from gastric cancer cells.

PubMed

Iwai, Mineko; Matsuda, Masahiko; Iwai, Yoshiaki

2003-01-01

A cell colony (IM95m) that produces hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) was cloned from gastric cancer cells (IM95 cell line). In culture medium, the highest levels of HGF, VEGF, and IL-8 were about 1.1, 0.9, and 0.17 ng/ml culture medium at 3 d from 10(5) cells. IM95m may be useful in elucidating the role of tumor cells in angiogenesis.

Risk factors associated with surgical site infection and the development of short-term complications in macaques undergoing indwelling vascular access port placement.

PubMed

Graham, M L; Rieke, E F; Wijkstrom, M; Dunning, M; Aasheim, T C; Graczyk, M J; Pilon, K J; Hering, B J

2008-08-01

Risk factors associated with surgical site infection (SSI) and the development of short-term complications in macaques undergoing vascular access port (VAP) placement are evaluated in this study. Records from 80 macaques with VAPs were retrospectively reviewed. Logistic regression was used to identify factors associated with short-term post-operative complications. The primary outcome was SSI, which occurred in 21.6% (52.6% in the first 12 months vs. 13% thereafter) of procedures. SSI was associated with major secondary complications including VAP removal (11.4%), wound dehiscence (5.7%), and mechanical catheter occlusion (5.7%). In multivariate modeling, only surgical program progress was a statistically significant predictor of SSI, while animal compliance had a slightly protective effect. Vascular access ports have a moderate risk of complications, provided the surgical program optimizes best practices. Under complex experimental conditions, VAPs represent an important refinement, both improving animals' overall well-being and environment and reducing stress.

Dysexecutive versus amnestic Alzheimer disease subgroups: analysis of demographic, genetic, and vascular factors.

PubMed

Mez, Jesse; Cosentino, Stephanie; Brickman, Adam M; Huey, Edward D; Manly, Jennifer J; Mayeux, Richard

2013-01-01

The objective of this study was to compare the demographic and vascular characteristics and APOE genotypes of a dysexecutive subgroup of Alzheimer disease (AD) with an amnestic subgroup of AD early in the disease course. A total of 2224 participants from the National Alzheimer's Coordinating Center database who carried a diagnosis of mild cognitive impairment (n=1188) or mild AD (clinical dementia rating ≤1) (n=1036) were included in this study. A subset of the mild cognitive impairment (n=61) and mild AD (n=79) participants underwent an autopsy. A dysexecutive subgroup (n=587) was defined as having executive performance >1 SD worse than memory performance, and an amnestic subgroup (n=549) was defined conversely. Among the autopsy subset, the odds of an AD pathologic diagnosis were compared in the 2 subgroups. The demographics, APOE[Latin Small Letter Open E]4 status, and vascular risk factors were compared in the 2 subgroups. Among the autopsy subset, the odds of having an AD pathologic diagnosis did not differ between the dysexecutive and amnestic subgroups. Under an additive model, participants in the dysexecutive subgroup possessed the APOE[Latin Small Letter Open E]4 allele less frequently compared with those in the amnestic subgroup. The dysexecutive subgroup had a history of hypertension less frequently compared with the amnestic subgroup. These distinct characteristics add to accumulating evidence that a dysexecutive subgroup of AD may have a unique underlying pathophysiology.

Targeting vascular (endothelial) dysfunction

PubMed Central

Steven, Sebastian; Weber, Alina; Shuvaev, Vladimir V.; Muzykantov, Vladimir R.; Laher, Ismail; Li, Huige; Lamas, Santiago

2016-01-01

Abstract Cardiovascular diseases are major contributors to global deaths and disability‐adjusted life years, with hypertension a significant risk factor for all causes of death. The endothelium that lines the inner wall of the vasculature regulates essential haemostatic functions, such as vascular tone, circulation of blood cells, inflammation and platelet activity. Endothelial dysfunction is an early predictor of atherosclerosis and future cardiovascular events. We review the prognostic value of obtaining measurements of endothelial function, the clinical techniques for its determination, the mechanisms leading to endothelial dysfunction and the therapeutic treatment of endothelial dysfunction. Since vascular oxidative stress and inflammation are major determinants of endothelial function, we have also addressed current antioxidant and anti‐inflammatory therapies. In the light of recent data that dispute the prognostic value of endothelial function in healthy human cohorts, we also discuss alternative diagnostic parameters such as vascular stiffness index and intima/media thickness ratio. We also suggest that assessing vascular function, including that of smooth muscle and even perivascular adipose tissue, may be an appropriate parameter for clinical investigations. Linked Articles This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc PMID:27187006

Altering dietary lysine:arginine ratio has little effect on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults

PubMed Central

Vega-López, Sonia; Matthan, Nirupa R.; Ausman, Lynne M.; Harding, Scott V.; Rideout, Todd C.; Ai, Masumi; Otokozawa, Seiko; Freed, Alicia; Kuvin, Jeffrey T; Jones, Peter J; Schaefer, Ernst J; Lichtenstein, Alice H.

2010-01-01

Background Information is scarce regarding the effect of dietary protein type, with specific focus on the lysine to arginine (Lys:Arg) ratio, on cardiovascular risk factors and vascular reactivity in humans. Objective Determine effect of dietary Lys:Arg ratio on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults. Design Randomized cross-over design of two 35-day diet phases; thirty adults (21 females and 9 males, ≥50 y, LDL cholesterol ≥120 mg/dL). Diets had 20% energy (E) protein, 30%E fat, 50%E carbohydrate and were designed to have low (0.7) or high (1.4) Lys:Arg ratio. Measures included fasting and postprandial lipid, lipoprotein, apolipoprotein concentrations; fasting high sensitivity C-reactive protein (hsCRP), small dense LDL (sdLDL)-cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities; cholesterol fractional synthesis rate (FSR); and flow mediated dilation (FMD) and peripheral artery tonometry (PAT). Results No differences were observed in fasting and/or postprandial total, LDL, HDL and sdLDL cholesterol, RemLC, Lp(a) or apo B concentrations, LCAT and CETP activities, FSR, glycated albumin, immunoreactive insulin, FMD or PAT. The low, relative to the high, Lys:Arg ratio diet resulted in lower postprandial VLDL cholesterol (−24%, P=0.001) and triglycerides (−23%, P=0.001), and small but significant differences in fasting (−3%, P=0.003) and postprandial (−3%, P=0.018) apo AI, and fasting adiponectin concentrations (+7%, P=0.035). Fasting and postprandial hsCRP concentrations were 23% lower after the low Lys:Arg ratio diet (P=0.020 for both). Conclusions Diets differing in Lys:Arg ratios had no or small effects on cardiovascular risk factors and vascular reactivity. PMID:20042191

Vascular Endothelial Growth Factor in Eye Disease

PubMed Central

Penn, J.S.; Madan, A.; Caldwell, R.B.; Bartoli, M.; Caldwell, R.W.; Hartnett, M.E.

2012-01-01

Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis. PMID:18653375

Decreased Plasma Brain-Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Concentrations during Military Training

PubMed Central

Nibuya, Masashi; Ishida, Toru; Yamamoto, Tetsuo; Mukai, Yasuo; Mitani, Keiji; Tsumatori, Gentaro; Scott, Daniel; Shimizu, Kunio

2014-01-01

Decreased concentrations of plasma brain-derived neurotrophic factor (BDNF) and serum BDNF have been proposed to be a state marker of depression and a biological indicator of loaded psychosocial stress. Stress evaluations of participants in military mission are critically important and appropriate objective biological parameters that evaluate stress are needed. In military circumstances, there are several problems to adopt plasma BDNF concentration as a stress biomarker. First, in addition to psychosocial stress, military missions inevitably involve physical exercise that increases plasma BDNF concentrations. Second, most participants in the mission do not have adequate quality or quantity of sleep, and sleep deprivation has also been reported to increase plasma BDNF concentration. We evaluated plasma BDNF concentrations in 52 participants on a 9-week military mission. The present study revealed that plasma BDNF concentration significantly decreased despite elevated serum enzymes that escaped from muscle and decreased quantity and quality of sleep, as detected by a wearable watch-type sensor. In addition, we observed a significant decrease in plasma vascular endothelial growth factor (VEGF) during the mission. VEGF is also neurotrophic and its expression in the brain has been reported to be up-regulated by antidepressive treatments and down-regulated by stress. This is the first report of decreased plasma VEGF concentrations by stress. We conclude that decreased plasma concentrations of neurotrophins can be candidates for mental stress indicators in actual stressful environments that include physical exercise and limited sleep. PMID:24586790

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

PubMed

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

2014-06-01

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

Vascular endothelial growth factor (VEGF-634G/C) polymorphism and retinopathy of prematurity: a meta-analysis

PubMed Central

Malik, Manzoor Ahmad; Shukla, Swati; Azad, Shorya Vardhan; Kaur, Jasbir

2014-01-01

Purpose Vascular endothelial growth factor polymorphism (VEGF-634G/C, rs 2010963) has been considered a risk factor for the development of retinopathy of prematurity (ROP). However, the results remain controversial. Therefore, the aim of the present meta-analysis was to determine the association between VEGF-634G/C polymorphism and ROP risk. Methods Published literature from PubMed and other databases were retrieved. All studies evaluating the association between VEGF-634G/C polymorphism and ROP risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random or fixed effects model. A total of six case-control studies including 355 cases and 471 controls were included. Results By pooling all the studies, we found that VEGF-634G/C polymorphism was not associated with ROP risk at co-dominant and allele levels and no association was also found in dominant and recessive models. While stratifying on ethnicity level no association was observed in Caucasian and Asian population. Discussion This meta-analysis suggests that VEGF-634G/C polymorphism may not be associated with ROP risk, the association between single VEGF-634G/C polymorphism and ROP risk awaits further investigation. PMID:25473347

Assessment of risk of peripheral vascular disease and vascular care capacity in low- and middle-income countries.

PubMed

Gyedu, A; Stewart, B T; Nakua, E; Quansah, R; Donkor, P; Mock, C; Hardy, M; Yangni-Angate, K H

2016-01-01

This study aimed to describe national peripheral vascular disease (PVD) risk and health burden, and vascular care capacity in Ghana. The gap between PVD burden and vascular care capacity in low- and middle-income countries was defined, and capacity improvement priorities were identified. Data to estimate PVD risk factor burden were obtained from the World Health Organization Study on Global Ageing and Adult Health (SAGE), Ghana, and the Institute of Health Metrics and Evaluation Global Burden of Disease (IHME GBD) database. In addition, a novel nationwide assessment of vascular care capacity was performed, with 20 vascular care items assessed at 40 hospitals in Ghana. Factors contributing to specific item deficiency were described. From the SAGE database, there were 4305 respondents aged at least 50 years with data to estimate PVD risk. Of these, 57·4 per cent were at moderate to risk high of PVD with at least three risk factors; extrapolating nationally, the estimate was 1 654 557 people. Based on IHME GBD data, the estimated disability-adjusted life-years incurred from PVD increased fivefold from 1990 to 2010 (from 6·3 to 31·7 per 100 000 persons respectively). Vascular care capacity assessment demonstrated marked deficiencies in items for diagnosis, and in perioperative and vascular surgical care. Deficiencies were most often due to absence of equipment, lack of training and technology breakage. Risk factor reduction and management as well as optimization of current resources are paramount to avoid the large burden of PVD falling on healthcare systems in low- and middle-income countries. These countries are not well equipped to handle vascular surgical care, and rapid development of such capacity would be difficult and expensive. © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.

The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis

PubMed Central

Smith, Gina A.; Fearnley, Gareth W.; Tomlinson, Darren C.; Harrison, Michael A.; Ponnambalam, Sreenivasan

2015-01-01

VEGFs (vascular endothelial growth factors) are a family of conserved disulfide-linked soluble secretory glycoproteins found in higher eukaryotes. VEGFs mediate a wide range of responses in different tissues including metabolic homoeostasis, cell proliferation, migration and tubulogenesis. Such responses are initiated by VEGF binding to soluble and membrane-bound VEGFRs (VEGF receptor tyrosine kinases) and co-receptors. VEGF and receptor splice isoform diversity further enhances complexity of membrane protein assembly and function in signal transduction pathways that control multiple cellular responses. Different signal transduction pathways are simultaneously activated by VEGFR–VEGF complexes with membrane trafficking along the endosome–lysosome network further modulating signal output from multiple enzymatic events associated with such pathways. Balancing VEGFR–VEGF signal transduction with trafficking and proteolysis is essential in controlling the intensity and duration of different intracellular signalling events. Dysfunction in VEGF-regulated signal transduction is important in chronic disease states including cancer, atherosclerosis and blindness. This family of growth factors and receptors is an important model system for understanding human disease pathology and developing new therapeutics for treating such ailments. PMID:26285805

Changes in Fundus Autofluorescence after Anti-vascular Endothelial Growth Factor According to the Type of Choroidal Neovascularization in Age-related Macular Degeneration.

PubMed

Lee, Ji Young; Chung, Hyewon; Kim, Hyung Chan

2016-02-01

To describe the changes of fundus autofluorescence (FAF) in patients with age-related macular degeneration before and after intravitreal injection of anti-vascular endothelial growth factor according to the type of choroidal neovascularization (CNV) and to evaluate the correlation of FAF with spectral domain optical coherence tomography (SD-OCT) parameters and vision. This was a retrospective study. Twenty-one treatment-naïve patients with neovascular age-related macular degeneration were included. Study eyes were divided into two groups according to the type of CNV. Fourteen eyes were type 1 CNV and seven eyes were type 2 CNV. All eyes underwent a complete ophthalmologic examination, including an assessment of best-corrected visual acuity, SD-OCT, fluorescein angiography, and FAF imaging, before and 3 months after intravitreal anti-vascular endothelial growth factor injection. Gray scales of FAF image for CNV areas, delineated as in fluorescein angiography, were analyzed using the ImageJ program, which were adjusted by comparison with normal background areas. Correlation of changes in FAF with changes in SD-OCT parameters, including CNV thickness, photoreceptor inner and outer segment junction disruption length, external limiting membrane disruption length, central macular thickness, subretinal fluid, and intraretinal fluid were analyzed. Eyes with both type 1 and type 2 CNV showed reduced FAF before treatment. The mean gray scales (%) of type 1 and type 2 CNV were 52.20% and 42.55%, respectively. The background values were 106.72 and 96.86. After treatment, the mean gray scales (%) of type 1 CNV and type 2 CNV were changed to 57.61% (p = 0.005) and 57.93% (p = 0.008), respectively. After treatment, CNV thickness, central macular thickness, and inner and outer segment junction disruption length were decreased while FAF increased. FAF was noted to be reduced in eyes with newly diagnosed wet age-related macular degeneration, but increased after anti-vascular

Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

PubMed Central

Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan C.; Cacabelos, Pablo; Teijido, Óscar

2018-01-01

Alzheimer’s disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders. PMID:29301387

Inhibition of Vascular Endothelial Growth Factor Receptor Signal Transduction Blocks Follicle Progression but Does Not Necessarily Disrupt Vascular Development in Perinatal Rat Ovaries1

PubMed Central

McFee, Renee M.; Artac, Robin A.; McFee, Ryann M.; Clopton, Debra T.; Smith, Robyn A. Longfellow; Rozell, Timothy G.; Cupp, Andrea S.

2009-01-01

We hypothesized that vascular endothelial growth factor A (VEGFA) angiogenic isoforms and their receptors, FLT1 and KDR, regulate follicular progression in the perinatal rat ovary. Each VEGFA angiogenic isoform has unique functions (based on its exons) that affect diffusibility, cell migration, branching, and development of large vessels. The Vegfa angiogenic isoforms (Vegfa_120, Vegfa_164, and Vegfa_188) were detected in developing rat ovaries, and quantitative RT-PCR determined that Vegfa_120 and Vegfa_164 mRNA was more abundant after birth, while Vegfa_188 mRNA was highest at Embryonic Day 16. VEGFA and its receptors were localized to pregranulosa and granulosa cells of all follicle stages and to theca cells of advanced-stage follicles. To determine the role of VEGFA in developing ovaries, Postnatal Day 3/4 rat ovaries were cultured with 8 μM VEGFR-TKI, a tyrosine kinase inhibitor that blocks FLT1 and KDR. Ovaries treated with VEGFR-TKI had vascular development reduced by 94% (P < 0.0001), with more primordial follicles (stage 0), fewer early primary, transitional, and secondary follicles (stages 1, 3, and 4, respectively), and greater total follicle numbers compared with control ovaries (P < 0.005). V1, an inhibitor specific for KDR, was utilized to determine the effects of only KDR inhibition. Treatment with 30 μM V1 had no effect on vascular density; however, treated ovaries had fewer early primary, transitional, and secondary follicles and more primary follicles (stage 2) compared with control ovaries (P < 0.05). We conclude that VEGFA may be involved in primordial follicle activation and in follicle maturation and survival, which are regulated through vascular-dependent and vascular-independent mechanisms. PMID:19605787

Determinants of impaired renal and vascular function are associated with elevated levels of procoagulant factors in the general population.

PubMed

Dekkers, I A; de Mutsert, R; de Vries, A P J; Rosendaal, F R; Cannegieter, S C; Jukema, J W; le Cessie, S; Rabelink, T J; Lamb, H J; Lijfering, W M

2018-03-01

Essentials Why venous thrombosis is more prevalent in chronic kidney disease is unclear. We investigated whether renal and vascular function are associated with hypercoagulability. Coagulation factors showed a procoagulant shift with impaired renal and vascular function. This suggests that renal and vascular function play a role in the etiology of thrombosis. Background Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear. Objectives We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state. Methods In this cross-sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n = 6536), and PWV was assessed in a random subset (n = 2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (> 50 th [reference] to < 1st) and UACR (< 50 th [reference] to > 99th), and per four categories (< 50 th [reference] to > 95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C-reactive protein (CRP) and vitamin K antagonists use (FIX). Results Mean age was 55.6 years, mean eGFR 86.0 (12SD) mL 1.73 m - ² and median UACR 0.4 mg mmol -1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22 IU dL -1 (95% CI, 13-32) higher in the eGFR < 1st percentile compared with the > 50th percentile, and FVIII was 12 IU dL -1 (95% CI, 3-22) higher in the UACR > 99th percentile compared with the < 50th percentile. PWV was positively associated with coagulation factors FIX and FXI in continuous analysis; per m/s difference in PWV, FIX was 2.0 IU dL -1 (95% CI, 0.70-3.2) higher

Effect of Intravitreal Anti-Vascular Endothelial Growth Factor Therapy on the Risk of Arterial Thromboembolic Events: A Meta-Analysis

PubMed Central

Lu, Guo-Cai; Wei, Rui-Li

2012-01-01

Background Intravitreal anti-vascular endothelial growth factor (VEGF) monoclonal antibodies are used in ocular neovascular diseases. A consensus has emerged that intravenous anti-VEGF can increase the risk of arterial thromboembolic events. However, the role of intravitreal anti-VEGF in arterial thromboembolism is controversial. Therefore, we did a systematic review and meta-analysis to investigate the effects of intravitreal anti-VEGF on the risk of arterial thromboembolic events. Methods Electronic databases were searched to identify relevant randomized clinical trials comparing intravitreal anti-VEGF with controls. Criteria for inclusion in our meta-analysis included a study duration of no less than 12 months, the use of a randomized control group not receiving any intravitreal active agent, and the availability of outcome data for arterial thromboembolic events, myocardial infarction, cerebrovascular accidents, and vascular death. The risk ratios and 95% CIs were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. Results A total of 4942 patients with a variety of ocular neovascular diseases from 13 randomized controlled trials were identified and included for analysis. There was no significant difference between intravitreal anti-VEGF and control in the risk of all events, with risk ratios of 0.87 (95% CI, 0.64 to 1.19) for arterial thromboembolic events, 0.96 (95% CI, 0.55–1.68) for cerebrovascular accidents, 0.69 (95% CI 0.40–1.21) for myocardial infarctions, and 0.68 (95% CI, 0.37–1.27) for vascular death. Conclusions The strength evidence suggests that the intravitreal use of anti-VEGF antibodies is not associated with an increased risk of arterial thromboembolic events. PMID:22829940

Birt-Hogg-Dubé syndrome and intracranial vascular pathologies.

PubMed

Kapoor, Rahul; Evins, Alexander I; Steitieh, Diala; Bernardo, Antonio; Stieg, Philip E

2015-12-01

Birt-Hogg-Dubé syndrome, first described in 1977, is a rare autosomal dominant condition that commonly presents with skin lesions, including fibrofolliculomas and trichodiscomas; pulmonary cysts; spontaneous pneumothoraces; and renal cancer. We present the only known cases of intracranial vascular pathologies in patients with Birt-Hogg-Dubé syndrome. We present three cases (three female; age range 18-50) of intracranial vascular lesions in Birt-Hogg-Dubé patients, including two aneurysms and one arteriovenous malformation, and review one previously reported case of carotid aplasia. Due to the rarity of Birt-Hogg-Dubé syndrome and significant variations in its clinical presentation, it is difficult to assess whether or not Birt-Hogg-Dubé patients are predisposed to intracranial vascular pathologies. We hypothesize that increased transcription of hypoxia-inducible factor 1-alpha, resulting from a mutated form of the protein folliculin transcribed by the Birt-Hogg-Dubé gene, may be associated with vascular pathogenesis in Birt-Hogg-Dubé patients and thus provide a possible molecular basis for a link between these two conditions.

RS3PE syndrome presenting as vascular endothelial growth factor associated disorder.

PubMed

Arima, K; Origuchi, T; Tamai, M; Iwanaga, N; Izumi, Y; Huang, M; Tanaka, F; Kamachi, M; Aratake, K; Nakamura, H; Ida, H; Uetani, M; Kawakami, A; Eguchi, K

2005-11-01

To characterise serum concentrations of various cytokines and detection by magnetic resonance imaging (MRI) of synovial hypervascularity in patients with remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome before and after corticosteroid treatment. Vascular endothelial growth factor(165) (VEGF(165)), tumour necrosis factor alpha (TNFalpha), and interleukin 1beta (IL1beta) were measured by enzyme linked immunosorbent assay (ELISA) in serum samples from three patients with RS3PE syndrome. As controls, serum samples from 26 healthy volunteers, 12 patients with rheumatoid arthritis, 10 patients with systemic lupus erythematosus, 13 patients with polymyositis/dermatomyositis, 13 patients with vasculitis syndrome, and 6 patients with mixed connective tissue disease were also analysed. Synovial hypervascularity of patients with RS3PE syndrome was estimated by rate of enhancement (E-rate) in a dynamic MRI study. Serum concentrations of VEGF(165) (mean (SD) 2223.3 (156.3) pg/ml) were significantly higher in patients with active RS3PE syndrome than in controls before corticosteroid treatment. TNFalpha and IL1beta levels were similar in patients and controls. Synovial hypervascularity in affected joints and subcutaneous oedema decreased during corticosteroid treatment, in parallel with the fall in serum VEGF(165). VEGF promotes synovial inflammation and vascular permeability in patients with RS3PE syndrome, suggesting that RS3PE can be classified as a VEGF associated disorder.

Early life stage trimethyltin exposure induces ADP-ribosylation factor expression and perturbs the vascular system in zebrafish.

PubMed

Chen, Jiangfei; Huang, Changjiang; Truong, Lisa; La Du, Jane; Tilton, Susan C; Waters, Katrina M; Lin, Kuanfei; Tanguay, Robert L; Dong, Qiaoxiang

2012-12-16

Trimethyltin chloride (TMT) is an organotin contaminant, widely detected in aqueous environments, posing potential human and environmental risks. In this study, we utilized the zebrafish model to investigate the impact of transient TMT exposure on developmental progression, angiogenesis, and cardiovascular development. Embryos were waterborne exposed to a wide TMT concentration range from 8 to 96 h post fertilization (hpf). The TMT concentration that led to mortality in 50% of the embryos (LC(50)) at 96 hpf was 8.2 μM; malformations in 50% of the embryos (EC(50)) was 2.8 μM. The predominant response observed in surviving embryos was pericardial edema. Additionally, using the Tg (fli1a: EGFP) y1 transgenic zebrafish line to non-invasively monitor vascular development, TMT exposure led to distinct disarrangements in the vascular system. The most susceptible developmental stage to TMT exposure was between 48 and 72 hpf. High density whole genome microarrays were used to identify the early transcriptional changes following TMT exposure from 48 to 60 hpf or 72 hpf. In total, 459 transcripts were differentially expressed at least 2-fold (P<0.05) by TMT compared to control. Using Ingenuity Pathway Analysis (IPA) tools, it was revealed that the transcripts misregulated by TMT exposure were clustered in numerous categories including metabolic and cardiovascular disease, cellular function, cell death, molecular transport, and physiological development. In situ localization of highly elevated transcripts revealed intense staining of ADP-ribosylation factors arf3 and arf5 in the head, trunk, and tail regions. When arf5 expression was blocked by morpholinos, the zebrafish did not display the prototypical TMT-induced vascular deficits, indicating that the induction of arf5 was necessary for TMT-induced vascular toxicity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Paracrine control of vascularization and neurogenesis by neurotrophins.

PubMed

Emanueli, Costanza; Schratzberger, Peter; Kirchmair, Rudolf; Madeddu, Paolo

2003-10-01

The neuronal system plays a fundamental role in the maturation of primitive embryonic vascular network by providing a paracrine template for blood vessel branching and arterial differentiation. Furthermore, postnatal vascular and neural regeneration cooperate in the healing of damaged tissue. Neurogenesis continues in adulthood although confined to specific brain regions. Following ischaemic insult, neural staminal cells contribute towards the healing process through the stimulation of neurogenesis and vasculogenesis. Evidence indicates that nerves and blood vessels exert a reciprocal control of their own growth by paracrine mechanisms. For instance, guidance factors, including vascular endothelial growth factor A (VEGF-A) and semaphorins, which share the ability of binding neuropilin receptors, play a pivotal role in the tridimensional growth pattern of arterial vessels and nerves. Animal models and clinical studies have demonstrated a role of VEGF-A in the pathogenesis of ischaemic and diabetic neuropathies. Further, supplementation with VEGF-A ameliorates neuronal recovery by exerting protective effects on nerves and stimulating reparative neovascularization. Human tissue kallikrein, a recently discovered angiogenic and arteriogenic factor, accelerates neuronal recovery by stimulating the growth of vasa nervorum. Conversely, the neurotrophin nerve growth factor, known to regulate neuronal survival and differentiation, is now regarded as a stimulator of angiogenesis and arteriogenesis. These results indicate that angiogenesis and neurogenesis are paracrinally regulated by growth factors released by endothelial cells and neurons. Supplementation of these growth factors, alone or in combination, could benefit the treatment of ischaemic diseases and neuropathies.

The Interaction Between IGF-1, Atherosclerosis and Vascular Aging

PubMed Central

Higashi, Yusuke; Quevedo, Henry C.; Tiwari, Summit; Sukhanov, Sergiy; Shai, Shaw-Yung; Anwar, Asif; Delafontaine, Patrice

2014-01-01

The process of vascular aging encompasses alterations in the function of endothelial (EC) and vascular smooth muscle cells (VSMCs) via oxidation, inflammation, cell senescence and epigenetic modifications, increasing the probability of atherosclerosis. Aged vessels exhibit decreased endothelial antithrombogenic properties, increased reactive oxygen species (ROS) generation and inflammatory signaling, increased migration of VSMCs to the subintimal space, impaired angiogenesis and increased elastin degradation. The key initiating step in atherogenesis is subendothelial accumulation of apolipoprotein-B containing low density lipoproteins resulting in activation of endothelial cells and recruitment of monocytes. Activated endothelial cells secrete “chemokines” that interact with cognate chemokine receptors on monocytes and promote directional migration. Recruitment of immune cells establishes a pro-inflammatory status, further causing elevated oxidative stress, which in turn triggers a series of events including apoptotic or necrotic death of vascular and non-vascular cells. Increased oxidative stress is also considered to be a key factor in mechanisms of aging-associated changes in tissue integrity and function. Experimental evidence indicates that insulin-like growth factor-1 (IGF-1) exerts anti-oxidant, anti-inflammatory and pro-survival effects on the vasculature, reducing atherosclerotic plaque burden and promoting features of atherosclerotic plaque stability. PMID:24943302

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

PubMed

Aslan, Mutay; Freeman, Bruce A

2007-12-01

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

Molecular parallels between neural and vascular development.

PubMed

Eichmann, Anne; Thomas, Jean-Léon

2013-01-01

The human central nervous system (CNS) features a network of ~400 miles of blood vessels that receives >20% of the body's cardiac output and uses most of its blood glucose. Many human diseases, including stroke, retinopathy, and cancer, are associated with the biology of CNS blood vessels. These vessels originate from extrinsic cell populations, including endothelial cells and pericytes that colonize the CNS and interact with glia and neurons to establish the blood-brain barrier and control cerebrovascular exchanges. Neurovascular interactions also play important roles in adult neurogenic niches, which harbor a unique population of neural stem cells that are intimately associated with blood vessels. We here review the cellular and molecular mechanisms required to establish the CNS vascular network, with a special focus on neurovascular interactions and the functions of vascular endothelial growth factors.

The pathology and pathophysiology of vascular dementia.

PubMed

Kalaria, Raj N

2017-12-19

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

Role of vascular endothelial growth factor in non‑small cell lung cancer pathogenesis.

PubMed

Krupnova, E V; Shapetska, M N; Mikhalenko, E P; Chebotaryova, N V; Shchayuk, A N; Pissarchik, S N; Prokhorov, A V

2015-09-01

The angiogenesis is an important process in the pathogenesis of malignancies. It is regulated by various growth factors, with the vascular endothelial growth factor (VEGF) playing the central role. The aim of the present study was to evaluate possible associations of functional VEGF -2578C>A, -634G>C, and +936C>T polymorphisms with the risk for occurrence and progression of non-small cell lung cancer (NSCLC) in patients living in Republic of Belarus. A total of 202 patients (147 males and 55 females) diagnosed as having the NSCLC. The control group consisted of 336 individuals (245 males and 91 females) without an oncopathology. The total DNA was isolated from peripheral blood. We investigated the single nucleotide polymorphisms of VEGF (rs 2010963), (rs 699947), (rs 3025039). The genotyping was performed by PCR-RFLP analysis. Our results revealed a marginally significant association of the -2578CC genotype (p=0.002) with a greater degree of tumor spread (Т2-Т4). Heterozygous genotypes -2578СА and +936СT carriers were included into the follow-up group significantly more often (р=0.021 and р=0.012, respectively). Our study demonstrate that VEGF -2578A/C and +936C/T polymorphisms are among the factors determining the individual peculiarities of NSCLC course in this population and can be used for clarifying the prognosis of the disease.

Improvement of insulin sensitivity in response to exercise training in type 2 diabetes mellitus is associated with vascular endothelial growth factor A expression.

PubMed

Wagner, Henrik; Fischer, Helene; Degerblad, Marie; Alvarsson, Michael; Gustafsson, Thomas

2016-09-01

Insulin sensitivity changes in response to exercise training demonstrate a large variation. Vascular endothelial growth factor A could promote increased insulin sensitivity through angiogenesis. We investigated associations between changes in expression of key genes and insulin sensitivity, aerobic capacity and glycaemic control following exercise training in diabetes mellitus type 2. Subjects with diabetes mellitus type 2 underwent 12 weeks of structured exercise. Euglycaemic clamp, exercise test and HbA1c were performed. Muscle biopsies were obtained for mRNA expression. A total of 16 subjects completed the study. Change in vascular endothelial growth factor A expression was positively associated with an increase in insulin sensitivity (p = 0.004) and with a decrease in HbA1c (p = 0.034). Vascular endothelial growth factor A receptor-1 expression showed similar associations. The variation in physical adaptation to exercise training in diabetes mellitus type 2 was associated with changes in expression of vascular endothelial growth factor A in muscle. This difference in induced gene expression could contribute to the variation in exercise training effects on insulin sensitivity. Measures of capillary blood flow need to be assessed in future studies. © The Author(s) 2016.

Vascular risk factor burden, atherosclerosis, and functional dependence in old age: a population-based study.

PubMed

Welmer, Anna-Karin; Liang, Yajun; Angleman, Sara; Santoni, Giola; Yan, Zhongrui; Cai, Chuanzhu; Qiu, Chengxuan

2014-08-01

Vascular risk factors such as hypertension and obesity have been associated with physical limitations among older adults. The purpose of this study is to examine whether individual and aggregated vascular risk factors (VRFs) are associated with functional dependence and to what extent carotid atherosclerosis (CAS) or peripheral artery disease (PAD) may mediate the possible associations of aggregated VRFs with functional dependence. This cross-sectional study included 1,451 community-living participants aged ≥60 years in the Confucius Hometown Aging Project of China. Data on demographic features, hypertension, high total cholesterol, obesity, smoking, physical inactivity, diabetes, CAS, PAD, and cardiovascular diseases (CVDs) were collected through an interview, a clinical examination, and laboratory tests. Functional dependence was defined as being dependent in at least one activity in the personal or instrumental activities of daily living. Data were analyzed using multiple logistic models controlling for potential confounders. We used the mediation model to explore the potential mediating effect of CAS and PAD on the associations of aggregated VRFs with functional dependence. Of the 1,451 participants, 222 (15.3%) had functional dependence. The likelihood of functional dependence increased linearly with increasing number of VRFs (hypertension, high total cholesterol, abdominal obesity, and physical inactivity) (p for trend <0.002). Mediation analysis showed that controlling for demographics and CVDs up to 11% of the total association of functional dependence with clustering VRFs was mediated by CAS and PAD. Aggregation of multiple VRFs is associated with an increased likelihood of functional dependence among Chinese older adults; the association is partially mediated by carotid and peripheral artery atherosclerosis independently of CVDs.

Increased expression of pro-angiogenic factors and vascularization in thyroid hyperfunctioning adenomas with and without TSH receptor activating mutations.

PubMed

Celano, Marilena; Sponziello, Marialuisa; Tallini, Giovanni; Maggisano, Valentina; Bruno, Rocco; Dima, Mariavittoria; Di Oto, Enrico; Redler, Adriano; Durante, Cosimo; Sacco, Rosario; Filetti, Sebastiano; Russo, Diego

2013-02-01

Autonomously functioning thyroid nodules (AFTN) are known to receive an increased blood influx necessary to sustain their high rate of growth and hormone production. Here, we investigated the expression of hematic and lymphatic vases in a series of 20 AFTN compared with the contralateral non-tumor tissues of the same patients, and the transcript levels of proteins involved in the control of vascular proliferation, including the vascular endothelial growth factor (VEGF) and platelet-derived growth factors (PDGF) and their receptors and the endothelial nitric oxide synthase (eNOS). In parallel, the expression of the differentiation markers sodium/iodide symporter (NIS), thyroperoxidase (TPO), thyroglobulin (Tg), and TSH receptor (TSHR) was also investigated. The data were further analyzed comparing subgroups of tumors with or without mutations in the TSHR gene. Analysis by means of CD31 and D2-40 immunostaining showed in AFTN an increased number of hematic, but not lymphatic, vessels in parallel with an enhanced proliferation rate shown by increased Ki67 staining. Quantitative RT-PCR analysis revealed an increase of VEGF, VEGFR1 and 2, PDGF-A, PDGF-B, and eNOS expression in tumor versus normal tissues. Also, higher transcript levels of NIS, TPO, and Tg were detected. Comparison of the two subgroups of samples revealed only few differences in the expression of the genes examined. In conclusion, these data demonstrate an increased expression of angiogenesis-related factors associated with an enhanced proliferation of hematic, but not lymphatic, vessels in AFTNs. In this context, the presence of TSHR mutations may only slightly influence the expression of pro-angiogenic growth factors.

Serum vascular endothelial growth factor and adiponectin levels in patients with benign and malignant gynecological diseases.

PubMed

Lasalandra, Carla; Coviello, Maria; Falco, Gaetano; Divella, Rosa; Trojano, Giuseppe; Laterza, Anna Maria; Quero, Carmela; Pepe, Vito; Zito, Francesco Alfredo; Quaranta, Michele

2010-05-01

One of the most specific and critical regulators of angiogenesis is vascular endothelial growth factor (VEGF), which regulates endothelial proliferation, permeability, and survival. Vascular endothelial growth factor is an angiogenic mediator in tumors and has been implicated in the pathogenesis and progression of cancer. Adipose tissue is a major endocrine and it secretes hormones termed adipokines. These factors are derived from adipocytes and include proteins and metabolites such as adiponectin. Recently, adiponectin was also shown to modulate angiogenesis. This study was designed to determine the serum VEGF and adiponectin levels in patients with benign and malignant gynecological diseases and if there was a correlation between serum VEGF and adiponectin. Serum samples, collected fasting before surgery or intervention, were available for total of 114 female patients recorded between October 2006 and December 2008. Diagnosis of benign and malignant gynaecological diseases was established by biopsy. Serum levels VEGF and adiponectin were using commercially available enzyme linked immunosorbent assay (R&D Systems Inc, Minneapolis, MN), respectively. Statistical analysis was performed by using the SPSS 9.0 software package (SPSS, Inc, Chicago, IL). The correlation between serum VEGF and serum Adiponectin was calculated using the Pearson correlation coefficient. P values of < 0.05 were considered statistically significant. Our results were analyzed on the basis of 2 different parameters: age and benign and malignant gynecological diseases of the patient. Only for serum VEGF levels was a significant difference observed (P = 0.004) between patients with benign and malignant gynecological diseases. A significantly inverse correlation between serum VEGF and adiponectin levels among patients with benign and malignant gynecological diseases was found. Adiponectin level is not correlated with body mass index. This is one of the first report on adiponectin in benign and

Transient global amnesia and transient ischemic attack. Natural history, vascular risk factors, and associated conditions.

PubMed

Zorzon, M; Antonutti, L; Masè, G; Biasutti, E; Vitrani, B; Cazzato, G

1995-09-01

The purpose of the present study was to make an attempt to ascertain the etiology of transient global amnesia (TGA), which is still disputed more than 30 years after the first description of this clinical entity. In a case-control study, we compared the prevalence of vascular risk factors in 64 TGA patients with 64 first-ever transient ischemic attack (TIA) control subjects and 108 normal community-based control subjects matched for age and sex. We prospectively studied the vascular events and mortality rates of the TGA cases and of the TIA control subjects. Then we compared the outcome of the two groups using actuarial analysis based on survival curves. We did not find evidence of an increased risk of TGA associated with any vascular risk factor. In contrast to TIA control subjects, no TGA patient suffered stroke, myocardial infarction, or TIA during the follow-up period. Migraine was more common in TGA patients than in both normal and TIA control subjects. In three patients (4.5%), the TGA was eventually considered to be of epileptic origin. The results of our case-control and longitudinal studies point to the conclusion that TGA and TIA do not share the same etiology. Since half of our patients had a precipitating event in their history, it is reasonable to hypothesize that spreading depression may play a role in TGA. The significant positive association between migraine and TGA may support this hypothesis. Epilepsy may mimic TGA in a minority of cases.

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.

Dietary potassium regulates vascular calcification and arterial stiffness.

PubMed

Sun, Yong; Byon, Chang Hyun; Yang, Youfeng; Bradley, Wayne E; Dell'Italia, Louis J; Sanders, Paul W; Agarwal, Anupam; Wu, Hui; Chen, Yabing

2017-10-05

Vascular calcification is a risk factor that predicts adverse cardiovascular complications of several diseases including atherosclerosis. Reduced dietary potassium intake has been linked to cardiovascular diseases such as hypertension and incidental stroke, although the underlying molecular mechanisms remain largely unknown. Using the ApoE-deficient mouse model, we demonstrated for the first time to our knowledge that reduced dietary potassium (0.3%) promoted atherosclerotic vascular calcification and increased aortic stiffness, compared with normal (0.7%) potassium-fed mice. In contrast, increased dietary potassium (2.1%) attenuated vascular calcification and aortic stiffness. Mechanistically, reduction in the potassium concentration to the lower limit of the physiological range increased intracellular calcium, which activated a cAMP response element-binding protein (CREB) signal that subsequently enhanced autophagy and promoted vascular smooth muscle cell (VSMC) calcification. Inhibition of calcium signals and knockdown of either CREB or ATG7, an autophagy regulator, attenuated VSMC calcification induced by low potassium. Consistently, elevated autophagy and CREB signaling were demonstrated in the calcified arteries from low potassium diet-fed mice as well as aortic arteries exposed to low potassium ex vivo. These studies established a potentially novel causative role of dietary potassium intake in regulating atherosclerotic vascular calcification and stiffness, and uncovered mechanisms that offer opportunities to develop therapeutic strategies to control vascular disease.

The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species.

PubMed

Monaghan-Benson, Elizabeth; Burridge, Keith

2009-09-18

Vascular permeability is a complex process involving the coordinated regulation of multiple signaling pathways in the endothelial cell. It has long been documented that vascular endothelial growth factor (VEGF) greatly enhances microvascular permeability; however, the molecular mechanisms controlling VEGF-induced permeability remain unknown. Treatment of microvascular endothelial cells with VEGF led to an increase in reactive oxygen species (ROS) production. ROS are required for VEGF-induced permeability as treatment with the free radical scavenger, N-acetylcysteine, inhibited this effect. Additionally, treatment with VEGF caused ROS-dependent tyrosine phosphorylation of both vascular-endothelial (VE)-cadherin and beta-catenin. Rac1 was required for the VEGF-induced increase in permeability and adherens junction protein phosphorylation. Knockdown of Rac1 inhibited VEGF-induced ROS production consistent with Rac lying upstream of ROS in this pathway. Collectively, these data suggest that VEGF leads to a Rac-mediated generation of ROS, which, in turn, elevates the tyrosine phosphorylation of VE-cadherin and beta-catenin, ultimately regulating adherens junction integrity.

Visfatin and cardio-cerebro-vascular disease.

PubMed

Wang, Pei; Vanhoutte, Paul M; Miao, Chao-Yu

2012-01-01

Nicotinamide phosphoribosyltransferase is the rate-limiting enzyme that catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide from nicotinamide. This protein was originally cloned as a putative pre-B cell colony-enhancing factor and also found to be a visceral fat-derived adipokine (visfatin). As a multifunctional protein, visfatin plays an important role in immunity, metabolism, aging, inflammation, and responses to stress. Visfatin also participates in several pathophysiological processes contributing to cardio-cerebro-vascular diseases, including hypertension, atherosclerosis, ischemic heart disease, and ischemic stroke. However, whether visfatin is a friend or a foe in these diseases remains uncertain. This brief review focuses on the current understanding of the complex role of visfatin in the cardio-cerebro-vascular system under normal and pathophysiological conditions.

Fibroblast growth factor signaling affects vascular outgrowth and is required for the maintenance of blood vessel integrity.

PubMed

De Smet, Frederik; Tembuyser, Bieke; Lenard, Anna; Claes, Filip; Zhang, Jie; Michielsen, Christof; Van Schepdael, Ann; Herbert, Jean-Marc; Bono, Françoise; Affolter, Markus; Dewerchin, Mieke; Carmeliet, Peter

2014-10-23

Angiogenesis contributes to the development of numerous disorders. Even though fibroblast growth factors (FGFs) were discovered as mediators of angiogenesis more than 30 years ago, their role in developmental angiogenesis still remains elusive. We use a recently described chemical probe, SSR128129E (SSR), that selectively inhibits the action of multiple FGF receptors (FGFRs), in combination with the zebrafish model to examine the role of FGF signaling in vascular development. We observe that while FGFR signaling is less important for vessel guidance, it affects vascular outgrowth and is especially required for the maintenance of blood vessel integrity by ensuring proper cell-cell junctions between endothelial cells. In conclusion, our work illustrates the power of a small molecule probe to reveal insights into blood vessel formation and stabilization and thus of broad interest to the vascular biology community.

Review of gestational diabetes mellitus effects on vascular structure and function.

PubMed

Jensen, Louise A; Chik, Constance L; Ryan, Edmond A

2016-05-01

Vascular dysfunction has been described in women with a history of gestational diabetes mellitus. Furthermore, previous gestational diabetes mellitus increases the risk of developing Type 2 diabetes mellitus, a risk factor for cardiovascular disease. Factors contributing to vascular changes remain uncertain. The aim of this review was to summarize vascular structure and function changes found to occur in women with previous gestational diabetes mellitus and to identify factors that contribute to vascular dysfunction. A systematic search of electronic databases yielded 15 publications from 1998 to March 2014 that met the inclusion criteria. Our review confirmed that previous gestational diabetes mellitus contributes to vascular dysfunction, and the most consistent risk factor associated with previous gestational diabetes mellitus and vascular dysfunction was elevated body mass index. Heterogeneity existed across studies in determining the relationship of glycaemic levels and insulin resistance to vascular dysfunction. © The Author(s) 2016.

Risk factors for vascular complications and treatment patterns at diagnosis of 2389 PV and ET patients: Real-world data from the Swedish MPN Registry.

PubMed

Abdulkarim, Khadija; Samuelsson, Jan; Johansson, Peter; Andréasson, Björn

2017-06-01

The study mainly aimed at investigating possible correlations between peripheral blood counts, erythropoietin (EPO), JAK2 V617F mutation, and vascular complications prior to diagnosis of a population-based cohort of newly diagnosed patients with myeloproliferative neoplasms (MPN). The study comprises 1105 patients with polycythemia vera (PV) and 1284 patients with essential thrombocythemia (ET) registered in the Swedish MPN Registry. Vascular complications, prior to diagnosis, were registered in 37% of PV patients. In multivariate analysis, low hemoglobin was the only significant risk factor (P=.0120). Among ET patients, 35% had encountered a vascular complication. Risk factors for thromboembolic complications in ET were identified as age>65 years, white cell count>12×10 9 /L, and the presence of JAK2 V617F mutation (P=.0004, P=.0038, and P=.0016, respectively). A JAK2 V617F mutation was present in 71% of ET patients with vascular complications, compared to 60% in patients without. A majority of complications were thromboembolic, in both PV and ET. We conclude that vascular complications among newly diagnosed patients had affected more than one-third of our study population. Risk factors for vascular complications prior to diagnosis were lower hemoglobin in PV, and the presence of JAK2 V617F mutation, higher age, and leukocytosis in ET. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Disruptive technological advances in vascular access for dialysis: an overview.

PubMed

Yeo, Wee-Song; Ng, Qin Xiang

2017-11-29

End-stage kidney disease (ESKD), one of the most prevalent diseases in the world and with increasing incidence, is associated with significant morbidity and mortality. Current available modes of renal replacement therapy (RRT) include dialysis and renal transplantation. Though renal transplantation is the preferred and ideal mode of RRT, this modality may not be available to all patients with ESKD. Moreover, renal transplant recipients are constantly at risk of complications associated with immunosuppression and immunosuppressant use, and posttransplant lymphoproliferative disorder. Dialysis may be the only available modality in certain patients. However, dialysis has its limitations, which include issues associated with lack of vascular access, risks of infections and vascular thrombosis, decreased quality of life, and absence of biosynthetic functions of the kidney. In particular, the creation and maintenance of hemodialysis vascular access in children poses a unique set of challenges to the pediatric nephrologist owing to the smaller vessel diameters and vascular hyperreactivity compared with adult patients. Vascular access issues continue to be one of the major limiting factors prohibiting the delivery of adequate dialysis in ESKD patients and is the Achilles' heel of hemodialysis. This review aims to provide a critical overview of disruptive technological advances and innovations for vascular access. Novel strategies in preventing neointimal hyperplasia, novel bioengineered products, grafts and devices for vascular access will be discussed. The potential impact of these solutions on improving the morbidity encountered by dialysis patients will also be examined.

The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice

PubMed Central

Ghanekar, Yashoda; Kaur, Inderjeet

2007-01-01

In the last few years anti-vascular endothelial growth factor (VEGF) therapy has changed the paradigm in the treatment of neovascular age-related macular degeneration (ARMD). Besides, its potential use in the treatment of diabetic retinopathy and other possible proliferative vascular disorders has also shown promise. Clinical trial results have shown tremendous beneficial effect of ranibizumab in ARMD. Off-label use of bevacizumab has also shown similar benefit but long-term and clinical trial results do not exist. Some of the potential questions in the use of anti-VEGF are recurring cost, possible long-term effect on physiological function of VEGF and determination of endpoint of treatment. Overall, the use of anti-VEGF therapy in ocular angiogenesis has proven to be beneficial at least now. PMID:17951902

Disentangling the influence of environmental and anthropogenic factors on the distribution of endemic vascular plants in Sardinia.

PubMed

Fois, Mauro; Fenu, Giuseppe; Cañadas, Eva Maria; Bacchetta, Gianluigi

2017-01-01

Due to the impelling urgency of plant conservation and the increasing availability of high resolution spatially interpolated (e.g. climate variables) and categorical data (e.g. land cover and vegetation type), many recent studies have examined relationships among plant species distributions and a diversified set of explanatory factors; nevertheless, global and regional patterns of endemic plant richness remain in many cases unexplained. One such pattern is the 294 endemic vascular plant taxa recorded on a 1 km resolution grid on the environmentally heterogeneous island of Sardinia. Sixteen predictors, including topographic, geological, climatic and anthropogenic factors, were used to model local (number of taxa inside each 1 km grid cell) Endemic Vascular Plant Richness (EVPR). Generalized Linear Models were used to evaluate how each factor affected the distribution of local EVPR. Significant relationships with local EVPR and topographic, geological, climatic and anthropogenic factors were found. In particular, elevation explained the larger fraction of variation in endemic richness but other environmental factors (e.g. precipitation seasonality and slope) and human-related factors (e.g. the Human Influence Index (HII) and the proportion of anthropogenic land uses) were, respectively, positively and negatively correlated with local EVPR. Regional EVPR (number of endemic taxa inside each 100 m elevation interval) was also measured to compare local and regional EVPR patterns along the elevation gradient. In contrast to local, regional EVPR tended to decrease with altitude partly due to the decreasing area covered along altitude. The contrasting results between local and regional patterns suggest that local richness increases as a result of increased interspecific aggregation along altitude, whereas regional richness may depend on the interaction between area and altitude. This suggests that the shape and magnitude of the species-area relationship might vary with

Factors Associated with Placental Vascularization Measured by 3D Power Doppler Ultrasonographic Sphere Biopsy between 11 and 14 Weeks of Gestation.

PubMed

Demers, Suzanne; Boutin, Amelie; Dembickaja, Regina; Campanero, Mercedes; Nicolaides, Kypros

2018-02-19

 Preeclampsia is associated with placental vascularization disorders. Ultrasonographic sphere biopsy (USSB) of the placenta can estimate the vascularization of the placenta and potentially the risk of preeclampsia. We aimed to explore the factors related to placental vascularization measured with USSB in the first trimester.  A prospective cohort was conducted in women recruited at 11 to 14 weeks. Three-dimensional acquisition of the placenta with power Doppler was undertaken along with crown-rump length (CRL). Using USSB of the full placental thickness at its center, vascularization index, flow index, and vascular flow index were measured. Pearson's correlation coefficients and multivariate linear regression were used to correlate the vascularization indices with CRL and maternal characteristics.  A total of 5,612 women were recruited at a mean gestational age of 12.8 ± 0.6 weeks. We observed that vascularization indices increase with CRL. After adjustment, we observed that maternal age, ethnicity other than Caucasian, and body mass index were associated with lower vascularization indices, while diabetes, smoking, and assisted reproduction technology were not. We observed that parous women without history of preeclampsia had greater vascularization indices compared with nulliparous women.  Placental vascularization indices assessed by USSB fluctuate with gestational age, ethnicity, maternal age, body mass index, and previous pregnancy history. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Molecular Parallels between Neural and Vascular Development

PubMed Central

Eichmann, Anne; Thomas, Jean-Léon

2013-01-01

The human central nervous system (CNS) features a network of ∼400 miles of blood vessels that receives >20% of the body’s cardiac output and uses most of its blood glucose. Many human diseases, including stroke, retinopathy, and cancer, are associated with the biology of CNS blood vessels. These vessels originate from extrinsic cell populations, including endothelial cells and pericytes that colonize the CNS and interact with glia and neurons to establish the blood–brain barrier and control cerebrovascular exchanges. Neurovascular interactions also play important roles in adult neurogenic niches, which harbor a unique population of neural stem cells that are intimately associated with blood vessels. We here review the cellular and molecular mechanisms required to establish the CNS vascular network, with a special focus on neurovascular interactions and the functions of vascular endothelial growth factors. PMID:23024177

Aqueous vascular endothelial growth factor and aflibercept concentrations after bimonthly intravitreal injections of aflibercept for age-related macular degeneration.

PubMed

Sawada, Tomoko; Wang, Xiying; Sawada, Osamu; Saishin, Yoshitsugu; Ohji, Masahito

2018-01-01

Clinical evidence supports the efficacy of bimonthly aflibercept injection for age-related macular degeneration. The study aimed to evaluate aqueous vascular endothelial growth factor and aflibercept concentrations and the efficacy of bimonthly aflibercept in patients with age-related macular degeneration. This study is a prospective, interventional case series. Enrolled were 35 eyes with exudative age-related macular degeneration from 35 patients. Patients received three bimonthly intravitreal aflibercept without loading doses. We collected the aqueous humor just before each injection, measured vascular endothelial growth factor and aflibercept concentrations by enzyme-linked immunosorbent assay and measured best-corrected visual acuity and central retinal subfield thickness before and after the injections. Aqueous vascular endothelial growth factor and aflibercept concentrations were measured. The vascular endothelial growth factor concentration was 135.4 ± 60.5 pg/mL (mean ± standard deviation, range 60.6-323.4) at baseline and below the lowest detectable limit in all eyes at month 2 and in 32 eyes at month 4 (P < 0.001 [month 2] and P < 0.001 [month 4]). The mean aflibercept concentration was 20.3 ng/mL at month 2 and 28.0 ng/mL at month 4. The mean logarithm of the minimum angle of resolution visual acuity improved from 0.50 ± 0.36 at baseline to 0.36 ± 0.40 at month 6 (P < 0.001). The mean central retinal subfield thickness decreased from 353 ± 100 μm at baseline to 236 ± 45 μm at month 6 (P < 0.001). Bimonthly aflibercept injections without loading doses may be considered a treatment option for age-related macular degeneration. © 2017 Royal Australian and New Zealand College of Ophthalmologists.

The evolving integrated vascular surgery residency curriculum.

PubMed

Smith, Brigitte K; Greenberg, Jacob A; Mitchell, Erica L

2014-10-01

Since their introduction several years ago, integrated (0 + 5) vascular surgery residency programs are being increasingly developed across the country. To date, however, there is no defined "universal" curriculum for these programs and each program is responsible for creating its own curriculum. The aim of this study was to review the experiences of current 0 + 5 program directors (PDs) to determine what factors contributed to the curricular development within their institution. Semistructured interviews were conducted with 0 + 5 PDs to explore their experiences with program development, factors influencing the latter, and rationale for current curricula. The interview script was loosely structured to explore several factors including time of incoming residents' first exposure to the vascular surgical service, timing and rationale behind the timing of core surgical rotations throughout the 5 year program, educational value of nonsurgical rotations, opportunities for leadership and scholarly activity, and influence the general surgery program and institutional climate had on curricular structure. All interviews were conducted by a single interviewer. All interviews were qualitatively analyzed using emergent theme analysis. Twenty-six 0 + 5 PDs participated in the study. A total of 69% believed establishing professional identity early reduces resident attrition and recommend starting incoming trainees on vascular surgical services. Sixty-two percent spread core surgical rotations over the first 3 years to optimize general surgical exposure and most of the programs have eliminated specific rotations, as they were not considered valuable to the goals of training. Factors considered most important by PDs in curricular development include building on existing institutional opportunities (96%), avoiding rotations considered unsuccessful by "experienced" programs (92%), and maintaining a good working relationship with general surgery (77%). Fifty-eight percent of

Neural progenitor cell implants modulate vascular endothelial growth factor and brain-derived neurotrophic factor expression in rat axotomized neurons.

PubMed

Talaverón, Rocío; Matarredona, Esperanza R; de la Cruz, Rosa R; Pastor, Angel M

2013-01-01

Axotomy of central neurons leads to functional and structural alterations which largely revert when neural progenitor cells (NPCs) are implanted in the lesion site. The new microenvironment created by NPCs in the host tissue might modulate in the damaged neurons the expression of a high variety of molecules with relevant roles in the repair mechanisms, including neurotrophic factors. In the present work, we aimed to analyze changes in neurotrophic factor expression in axotomized neurons induced by NPC implants. For this purpose, we performed immunofluorescence followed by confocal microscopy analysis for the detection of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) on brainstem sections from rats with axotomy of abducens internuclear neurons that received NPC implants (implanted group) or vehicle injections (axotomized group) in the lesion site. Control abducens internuclear neurons were strongly immunoreactive to VEGF and BDNF but showed a weak staining for NT-3 and NGF. Comparisons between groups revealed that lesioned neurons from animals that received NPC implants showed a significant increase in VEGF content with respect to animals receiving vehicle injections. However, the immunoreactivity for BDNF, which was increased in the axotomized group as compared to control, was not modified in the implanted group. The modifications induced by NPC implants on VEGF and BDNF content were specific for the population of axotomized abducens internuclear neurons since the neighboring abducens motoneurons were not affected. Similar levels of NT-3 and NGF immunolabeling were obtained in injured neurons from axotomized and implanted animals. Among all the analyzed neurotrophic factors, only VEGF was expressed by the implanted cells in the lesion site. Our results point to a role of NPC implants in the modulation of neurotrophic factor expression by lesioned central neurons, which might

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. © 2015 American Heart Association, Inc.

Calcium-Alginate Hydrogel-Encapsulated Fibroblasts Provide Sustained Release of Vascular Endothelial Growth Factor

PubMed Central

Hunt, Nicola C.; Shelton, Richard M.; Henderson, Deborah J.

2013-01-01

Vascularization of engineered or damaged tissues is essential to maintain cell viability and proper tissue function. Revascularization of the left ventricle (LV) of the heart after myocardial infarction is particularly important, since hypoxia can give rise to chronic heart failure due to inappropriate remodeling of the LV after death of cardiomyocytes (CMs). Fibroblasts can express vascular endothelial growth factor (VEGF), which plays a major role in angiogenesis and also acts as a chemoattractant and survival factor for CMs and cardiac progenitors. In this in vitro model study, mouse NIH 3T3 fibroblasts encapsulated in 2% w/v Ca-alginate were shown to remain viable for 150 days. Semiquantitative reverse transcription–polymerase chain reaction and immunohistochemistry demonstrated that over 21 days of encapsulation, fibroblasts continued to express VEGF, while enzyme-linked immunosorbent assay showed that there was sustained release of VEGF from the Ca-alginate during this period. The scaffold degraded gradually over the 21 days, without reduction in volume. Cells released from the Ca-alginate at 7 and 21 days as a result of scaffold degradation were shown to retain viability, to adhere to fibronectin in a normal manner, and continue to express VEGF, demonstrating their potential to further contribute to maintenance of cardiac function after scaffold degradation. This model in vitro study therefore demonstrates that fibroblasts encapsulated in Ca-alginate provide sustained release of VEGF. PMID:23082964

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

PubMed Central

Miao, Chao-Yu; Li, Zhi-Yong

2012-01-01

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

Cognition and Vascular Risk Factors: An Epidemiological Study

PubMed Central

Vicario, Augusto; Del Sueldo, Mildren; Fernández, Ruth A.; Enders, Julio; Zilberman, Judith; Cerezo, Gustavo H.

2012-01-01

We conducted an epidemiological approach to identify the negative impact of the vascular risk factors (such as hypertension, diabetes and hypercholesterolemia) over cognition. The interesting aspect of this study was that the survey was conducted in all age groups through a voluntary call (n = 1365; ≥18 years old, both sexes; age 49 ± 15 y, female 75.7%). Thus, we demonstrated that the use of a Minimum Cognitive Examination (MCE), a brief, simple, and easy managed neuropsychological evaluation, detected a greater number of people with cognitive decline surpassing to the Minimal Mental Statement Examination alone (14.5% of the participants showed MMSE ≤24, 34,6% showed dys-executive function, and 45,8% memory impairment. Out of the 4 studied RF, the only one that was not related to cognitive impairment was dyslipemia. Finally, we noted the importance of cognitive state early detection in all age groups, even in the youngest group. Acting in the middle of the life stages, we can prevent or delay the onset of a disease in adults, nowadays incurable: dementia. PMID:22988488

Phosphate toxicity and vascular mineralization.

PubMed

Razzaque, Mohammed S

2013-01-01

Vascular calcification or mineralization is a major complication seen in patients with advanced stages of chronic kidney disease (CKD), and it is associated with markedly increased morbidity and mortality. Most of the CKD-related vascular mineralization is attributable to abnormal mineral ion metabolism. Elevated serum calcium and phosphate levels, along with increased calcium-phosphorus byproduct, and the use of active vitamin D metabolites are thought to be the predisposing factors for developing vascular mineralization in patients with CKD. Recent experimental studies have shown that vascular mineralization can be suppressed by reducing serum phosphate levels, even in the presence of extremely high serum calcium and 1,25-dihydroxyvitamin D levels, indicating that reducing 'phosphate toxicity' should be the important therapeutic priority in CKD patients for minimizing the risk of developing vascular mineralization and the disease progression. Copyright © 2013 S. Karger AG, Basel.

Dietary potassium regulates vascular calcification and arterial stiffness

PubMed Central

Sun, Yong; Byon, Chang Hyun; Yang, Youfeng; Bradley, Wayne E.; Dell’Italia, Louis J.; Agarwal, Anupam; Wu, Hui

2017-01-01

Vascular calcification is a risk factor that predicts adverse cardiovascular complications of several diseases including atherosclerosis. Reduced dietary potassium intake has been linked to cardiovascular diseases such as hypertension and incidental stroke, although the underlying molecular mechanisms remain largely unknown. Using the ApoE-deficient mouse model, we demonstrated for the first time to our knowledge that reduced dietary potassium (0.3%) promoted atherosclerotic vascular calcification and increased aortic stiffness, compared with normal (0.7%) potassium–fed mice. In contrast, increased dietary potassium (2.1%) attenuated vascular calcification and aortic stiffness. Mechanistically, reduction in the potassium concentration to the lower limit of the physiological range increased intracellular calcium, which activated a cAMP response element–binding protein (CREB) signal that subsequently enhanced autophagy and promoted vascular smooth muscle cell (VSMC) calcification. Inhibition of calcium signals and knockdown of either CREB or ATG7, an autophagy regulator, attenuated VSMC calcification induced by low potassium. Consistently, elevated autophagy and CREB signaling were demonstrated in the calcified arteries from low potassium diet–fed mice as well as aortic arteries exposed to low potassium ex vivo. These studies established a potentially novel causative role of dietary potassium intake in regulating atherosclerotic vascular calcification and stiffness, and uncovered mechanisms that offer opportunities to develop therapeutic strategies to control vascular disease. PMID:28978809

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

Vascular brain-derived neurotrophic factor pathway in rats with adjuvant-induced arthritis: Effect of anti-rheumatic drugs.

PubMed

Pedard, Martin; Quirié, Aurore; Totoson, Perle; Verhoeven, Frank; Garnier, Philippe; Tessier, Anne; Demougeot, Céline; Marie, Christine

2018-05-02

In rheumatoid arthritis, the control of both disease activity and standard cardiovascular (CV) risk factors is expected to attenuate the increased CV risk. Evidence that brain-derived neurotrophic factor (BDNF) plays a role in vascular biology led us to investigate the vascular BDNF pathway in arthritis rats as well as the interaction between endothelial nitric oxide (NO) and BDNF production. The aortic BDNF pathway was studied in rats with adjuvant-induced arthritis, (AIA) using Western blot and immunohistochemical analysis. Control of arthritis score was achieved by administration (for 3 weeks) of an equipotent dosage of etanercept, prednisolone, methotrexate, celecoxib or diclofenac. Aortas were exposed to an NO donor or an NO synthase inhibitor and vasoreactivity experiments were performed using LM22A-4 as a TrkB agonist. Vascular BDNF and full length tropomyosin-related kinase B receptor (TrkB-FL) were higher in AIA than in control rats. These changes coincided with decreased endothelial immunoreactivity in BDNF and pTrkB tyr816 and were disconnected from arthritis score. Among anti-rheumatic drugs, only prednisolone and methotrexate prevented AIA-induced vascular BDNF loss. The effect of AIA on aortic BDNF levels was reversed by an NO donor and reproduced by an NOS inhibitor. Finally, LM22A-4 induced both NO-dependent vasodilation and phosphorylation of endothelial NO synthase at serine 1177. Our study identified changes in the BDNF/TrkB pathway as a disease activity-independent component of AIA-associated changes in endothelial phenotype. It provides new perspectives in the understanding and management of the high CV risk reported in rheumatoid arthritis. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular mechanisms for vascular complications of targeted cancer therapies.

PubMed

Gopal, Srila; Miller, Kenneth B; Jaffe, Iris Z

2016-10-01

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Pathophysiological consequences of VEGF-induced vascular permeability

NASA Astrophysics Data System (ADS)

Weis, Sara M.; Cheresh, David A.

2005-09-01

Although vascular endothelial growth factor (VEGF) induces angiogenesis, it also disrupts vascular barrier function in diseased tissues. Accordingly, VEGF expression in cancer and ischaemic disease has unexpected pathophysiological consequences. By uncoupling endothelial cell-cell junctions VEGF causes vascular permeability and oedema, resulting in extensive injury to ischaemic tissues after stroke or myocardial infarction. In cancer, VEGF-mediated disruption of the vascular barrier may potentiate tumour cell extravasation, leading to widespread metastatic disease. Therefore, by blocking the vascular permeability promoting effects of VEGF it may be feasible to reduce tissue injury after ischaemic disease and minimize the invasive properties of circulating tumour cells.

Vascular Damage and Kidney Transplant Outcomes: An Unfriendly and Harmful Link.

PubMed

Hernández, Domingo; Triñanes, Javier; Armas, Ana María; Ruiz-Esteban, Pedro; Alonso-Titos, Juana; Duarte, Ana; González-Molina, Miguel; Palma, Eulalia; Salido, Eduardo; Torres, Armando

2017-07-01

Kidney transplant (KT) is the treatment of choice for most patients with chronic kidney disease, but this has a high cardiovascular mortality due to traditional and nontraditional risk factors, including vascular calcification. Inflammation could precede the appearance of artery wall lesions, leading to arteriosclerosis and clinical and subclinical atherosclerosis in these patients. Additionally, mineral metabolism disorders and activation of the renin-angiotensin system could contribute to this vascular damage. Thus, understanding the vascular lesions that occur in KT recipients and the pathogenic mechanisms involved in their development could be crucial to optimize the therapeutic management and outcomes in survival of this population. This review focuses on the following issues: (1) epidemiological data framing the problem; (2) atheromatosis in KT patients: subclinical and clinical atheromatosis, involving ischemic heart disease, congestive heart failure, stroke and peripheral vascular disease; (3) arteriosclerosis and vascular calcifications; and (4) potential pathogenic mechanisms and their therapeutic targets. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Predicting vascular complications in percutaneous coronary interventions.

PubMed

Piper, Winthrop D; Malenka, David J; Ryan, Thomas J; Shubrooks, Samuel J; O'Connor, Gerald T; Robb, John F; Farrell, Karen L; Corliss, Mary S; Hearne, Michael J; Kellett, Mirle A; Watkins, Matthew W; Bradley, William A; Hettleman, Bruce D; Silver, Theodore M; McGrath, Paul D; O'Mears, John R; Wennberg, David E

2003-06-01

Using a large, current, regional registry of percutaneous coronary interventions (PCI), we identified risk factors for postprocedure vascular complications and developed a scoring system to estimate individual patient risk. A vascular complication (access-site injury requiring treatment or bleeding requiring transfusion) is a potentially avoidable outcome of PCI. Data were collected on 18,137 consecutive patients undergoing PCI in northern New England from January 1997 to December 1999. Multivariate regression was used to identify characteristics associated with vascular complications and to develop a scoring system to predict risk. The rate of vascular complication was 2.98% (541 cases). Variables associated with increased risk in the multivariate analysis included age >or=70, odds ratio (OR) 2.7, female sex (OR 2.4), body surface area <1.6 m(2) (OR 1.9), history of congestive heart failure (OR 1.4), chronic obstructive pulmonary disease (OR 1.5), renal failure (OR 1.9), lower extremity vascular disease (OR 1.4), bleeding disorder (OR 1.68), emergent priority (OR 2.3), myocardial infarction (OR 1.7), shock (1.86), >or=1 type B2 (OR 1.32) or type C (OR 1.7) lesions, 3-vessel PCI (OR 1.5), use of thienopyridines (OR 1.4) or use of glycoprotein IIb/IIIa receptor inhibitors (OR 1.9). The model performed well in tests for significance, discrimination, and calibration. The scoring system captured 75% of actual vascular complications in its highest quintiles of predicted risk. Predicting the risk of post-PCI vascular complications is feasible. This information may be useful for clinical decision-making and institutional efforts at quality improvement.

Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease

PubMed Central

Wallin, Anders; Román, Gustavo C.; Esiri, Margaret; Kettunen, Petronella; Svensson, Johan; Paraskevas, George P.; Kapaki, Elisabeth

2018-01-01

Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer’s disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder. PMID:29562536

Information entropy-based fitting of the disease trajectory of brain ischemia-induced vascular cognitive impairment.

PubMed

Liu, Lin; Huo, Ju; Zhao, Ying; Tian, Yu

2012-03-25

The present study investigated the disease trajectory of vascular cognitive impairment using the entropy of information in a neural network mathematical simulation based on the free radical and excitatory amino acids theories. Glutamate, malondialdehyde, and inducible nitric oxide synthase content was significantly elevated, but acetylcholine, catalase, superoxide dismutase, glutathione peroxidase and constitutive nitric oxide synthase content was significantly decreased in our vascular cognitive impairment model. The fitting curves for each factor were obtained using Matlab software. Nineteen, 30 and 49 days post ischemia were the main output time frames of the influence of these seven factors. Our results demonstrated that vascular cognitive impairment involves multiple factors. These factors include excitatory amino acid toxicity and nitric oxide toxicity. These toxicities disrupt the dynamic equilibrium of the production and removal of oxygen free radicals after cerebral ischemia, reducing the ability to clear oxygen free radicals and worsening brain injury.

INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT AT 2-MONTH INTERVALS REDUCES FOVEAL AVASCULAR ZONE ENLARGEMENT AND VISION LOSS IN RADIATION MACULOPATHY: A Pilot Study.

PubMed

Daruich, Alejandra; Matet, Alexandre; Schalenbourg, Ann; Zografos, Leonidas

2018-05-03

To evaluate, in eyes with radiation maculopathy, the effect of 2-month-interval anti-vascular endothelial growth factor therapy on best-corrected visual acuity and foveal avascular zone (FAZ) enlargement using optical coherence tomography angiography. Consecutive treatment-naive patients with radiation maculopathy after proton beam irradiation for choroidal melanoma were retrospectively included. Clinical and optical coherence tomography angiography data at baseline and the 6-month visit were recorded. Two independent observers measured FAZ area manually on 3 × 3-mm optical coherence tomography angiography images of the superficial capillary plexus and deep capillary plexus. Patients were encouraged to follow strictly a 2-month-interval intravitreal anti-vascular endothelial growth factor treatment by either bevacizumab or ranibizumab. Findings were analyzed based on the adherence to the treatment scheme. According to the adherence to the bimonthly anti-vascular endothelial growth factor treatment protocol, patients were categorized into 3 groups: treatment protocol (n = 19, strict adherence), variable intervals (n = 11, intervals other than 2 months), and no treatment (n = 11). The estimated radiation dose to the foveola in each group was 49 ± 16, 46 ± 17, and 46 ± 18 cobalt gray equivalent, respectively (P = 0.85). For the entire cohort, best-corrected visual acuity loss (P < 0.02) and FAZ enlargement (P < 0.0001) were observed over 6 months. Best-corrected visual acuity loss was significantly less pronounced in the treatment-protocol group than in the variable-interval and no-treatment groups (P = 0.007 and P = 0.004). The FAZ enlargement was lower in the treatment-protocol group compared with the variable-interval group for both superficial capillary plexus (P = 0.029) and deep capillary plexus (P = 0.03), and to the no-treatment group for the deep capillary plexus only (P = 0.016). Decrease in best-corrected visual acuity and FAZ enlargement on optical

Peripheral vascular calcification in long-haemodialysis patients: associated factors and survival consequences.

PubMed

Jean, Guillaume; Bresson, Eric; Terrat, Jean-Claude; Vanel, Thierry; Hurot, Jean-Marc; Lorriaux, Christie; Mayor, Brice; Chazot, Charles

2009-03-01

Vascular calcifications (VCs) are frequently observed in chronic kidney disease (CKD) and haemodialysis (HD) patients. They have been associated with numerous factors, particularly hyperphosphataemia, excess calcium load, hypertension and increased mortality rate. The purpose of this study is to measure VCs in long-HD patients with good blood pressure and phosphate control, with the occasional use of sevelamer, using a plain radiological score to identify the associated factors and effects on the 1-year survival rate. We studied HD patients from one centre using a semi-quantitative score ranging from 0 to 3 according to the severity and extent of VCs. The following patients' characteristics were compared according to their VC scores: medical history, treatments, blood pressure, standard biological data, fibroblast growth factor (FGF) 23, osteoprotegerin (OPG), whole PTH, beta-crosslaps, bone alkaline phosphatases and bone mineral density scores. One-year survival analyses were also performed. Among the 250 HD patients of the centre, 161 were studied; the mean age was 67.2 +/- 13 years, 45% of the subjects were females, 35% were diabetics, and they had been on dialysis for between 1-486 months (median: 45 months) with a 3 x 5-3 x 8 h dialysis schedule using 1.5 mmol/l dialysate calcium and providing a mean 2.25 +/- 0.5 Kt/V. Only 17% of the patients were free from VCs and 11% had severe VCs. The factors associated with VCs were classified into 'classic' (age, diabetes, male gender, tobacco use, inflammation, more frequent warfarin treatment and peripheral vascular and cardiac diseases) and 'non-traditional' (higher FGF-23 and OPG serum levels, low albumin serum levels and low alfacalcidol and CaCO(3) use). In logistic regression, only age, diabetes and FGF-23 serum levels were associated with VC scores of 2 and 3. The patients with a score of 3 had a higher 1-year mortality rate (RR 2.1; P = 0.01) as compared to patients with a 0 score. A plain radiological score

FGF-dependent metabolic control of vascular development.

PubMed

Yu, Pengchun; Wilhelm, Kerstin; Dubrac, Alexandre; Tung, Joe K; Alves, Tiago C; Fang, Jennifer S; Xie, Yi; Zhu, Jie; Chen, Zehua; De Smet, Frederik; Zhang, Jiasheng; Jin, Suk-Won; Sun, Lele; Sun, Hongye; Kibbey, Richard G; Hirschi, Karen K; Hay, Nissim; Carmeliet, Peter; Chittenden, Thomas W; Eichmann, Anne; Potente, Michael; Simons, Michael

2017-05-11

Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/Fgfr3 double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development.

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.

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

Induction of vascular endothelial growth factor expression in human pulp fibroblasts stimulated with black-pigmented Bacteroides.

PubMed

Yang, L-C; Tsai, C-H; Huang, F-M; Su, Y-F; Lai, C-C; Liu, C-M; Chang, Y-C

2004-09-01

To investigate the effect of black-pigmented Bacteroides on the expression of vascular endothelial growth factor (VEGF) gene in human pulp fibroblasts. The supernatants of Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia were used to evaluate VEGF gene expression in human pulp fibroblasts. The levels of mRNAs were measured by the quantitative reverse-transcriptase polymerase chain reaction analysis. Black-pigmented Bacteroides induced significantly high levels of VEGF mRNA gene expression in human pulp fibroblasts (P < 0.05). In addition, the expression of VEGF depended on the bacteria tested. Black-pigmented Bacteroides may be involved in developing pulpal disease through the stimulation of VEGF production that would lead to the expansion of the vascular network coincident to progression of the inflammation.

Pulmonary vascular dysfunction in ARDS

PubMed Central

2014-01-01

Acute respiratory distress syndrome (ARDS) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension (PH). Multiple factors may contribute to the development of PH in this setting. In this review, we report the results of a systematic search of the available peer-reviewed literature for papers that measured indices of pulmonary haemodynamics in patients with ARDS and reported on mortality in the period 1977 to 2010. There were marked differences between studies, with some reporting strong associations between elevated pulmonary arterial pressure or elevated pulmonary vascular resistance and mortality, whereas others found no such association. In order to discuss the potential reasons for these discrepancies, we review the physiological concepts underlying the measurement of pulmonary haemodynamics and highlight key differences between the concepts of resistance in the pulmonary and systemic circulations. We consider the factors that influence pulmonary arterial pressure, both in normal lungs and in the presence of ARDS, including the important effects of mechanical ventilation. Pulmonary arterial pressure, pulmonary vascular resistance and transpulmonary gradient (TPG) depend not alone on the intrinsic properties of the pulmonary vascular bed but are also strongly influenced by cardiac output, airway pressures and lung volumes. The great variability in management strategies within and between studies means that no unified analysis of these papers was possible. Uniquely, Bull et al. (Am J Respir Crit Care Med 182:1123–1128, 2010) have recently reported that elevated pulmonary vascular resistance (PVR) and TPG were independently associated with increased mortality in ARDS, in a large trial with protocol-defined management strategies and using lung-protective ventilation. We then considered the existing literature to determine whether the relationship between PVR/TPG and outcome might be causal. Although we could identify

Localization and signaling patterns of vascular endothelial growth factors and receptors in human periapical lesions.

PubMed

Virtej, Anca; Løes, Sigbjørn S; Berggreen, Ellen; Bletsa, Athanasia

2013-05-01

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key players in vasculogenesis and are also involved in pathologic conditions with bone destruction. Vasculogenesis is critical for disease progression, and bone resorption is a hallmark of apical periodontitis. However, the localization of VEGFs and VEGFRs and their gene signaling pathways in human apical periodontitis have not been thoroughly investigated. The aim of this study was to localize VEGFs and VEGFRs and analyze their gene expression as well as signaling pathways in human periapical lesions. Tissue was collected after endodontic surgery from patients diagnosed with chronic apical periodontitis. Periodontal ligament samples from extracted healthy wisdom teeth was also collected and used as control tissue. In lesion cryosections, VEGFs/VEGFRs were identified by immunohistochemistry/double immunofluorescence by using specific antibodies. A human VEGF signaling polymerase chain reaction array system was used for gene expression analysis comparing lesions with periodontal ligament samples. The histologic evaluation revealed heterogeneous morphology of the periapical lesions with various degrees of inflammatory infiltrates. In the lesions, all investigated factors and receptors were identified in blood vessels and various immune cells. No lymphatic vessels were detected. Gene expression analysis revealed up-regulation of VEGF-A and VEGFR-3, although not significant. Phosphatidylinositol-3-kinases, protein kinase C, mitogen-activated protein kinases, and phospholipases, all known to be involved in VEGF-mediated angiogenic activity, were significantly up-regulated. The cellular and vascular expressions of VEGFs and VEGFRs in chronic apical periodontitis, along with significant alterations of genes mediating VEGF-induced angiogenic responses, suggest ongoing vascular remodeling in established chronic periapical lesions. Copyright © 2013 American Association of Endodontists. Published by

The Relationship between Vascular Endothelial Growth Factor 1154G/A Polymorphism and Recurrent Implantation Failure

PubMed Central

Vagnini, Laura D.; Nascimento, Adriana M.; Canas, Maria do Carmo T.; Renzi, Adriana; Oliveira-Pelegrin, Gabriela R.; Petersen, Claudia G.; Mauri, Ana L.; Oliveira, João Batista A.; Baruffi, Ricardo L.R.; Cavagna, Mario; Franco, José G.

2015-01-01

Objective The aim of this study was to investigate the relationship between herpesvirus-associated ubiquitin-specific protease (HAUSP A/G, rs1529916), tumor protein p53 (TP53 Arg/Pro, rs1042522), leukemia inhibitory factor (LIF G/T, rs929271), glycoprotein 130 (gp130 A/T, rs1900173) and vascular endothelial growth factor (VEGF G/A, rs1570360) polymorphisms and recurrent implantation failure (RIF) in Brazilian women. Subjects and Methods A total of 120 women with RIF (i.e. those with ≥5 cleaved embryos transferred and a minimum of 2 failed in vitro fertilization/intracytoplasmic sperm injection attempts) were included. The control group involved 89 women who had experienced at least 1 live birth (without any infertility treatment). DNA was extracted from the peripheral blood of all participants, and the abovementioned single-nucleotide polymorphisms (SNPs) were genotyped by real-time polymerase chain reaction. The data were evaluated using Fisher's test. Results A significant difference between the RIF and control groups was found in the VEGF gene where the GG genotype showed a 2.1-fold increased chance of not being included in the RIF group, while the presence of an A allele increased this risk 1.6-fold. No significant differences were found for the other polymorphisms. Conclusion This study showed an association between the VEGF -1154G/A polymorphism and RIF in Brazilian women. PMID:26305668

Vascular endothelial growth factor from Trimeresurus jerdonii venom specifically binds to VEGFR-2.

PubMed

Zhong, Shurong; Wu, Jianbo; Cui, Yunpeng; Li, Rui; Zhu, Shaowen; Rong, Mingqiang; Lu, Qiumin; Lai, Ren

2015-09-01

Vascular endothelial growth factors (VEGFs) play important roles in angiogenesis. In this study, a vascular endothelial growth factor named TjsvVEGF was purified from the venom of Trimeresurus jerdonii by gel filtration, affinity, ion-exchange and high-performance liquid chromatography. TjsvVEGF was a homodimer with an apparent molecular mass of 29 kDa. The cDNA encoding TjsvVEGF was obtained by PCR. The open reading frame of the cloned TjsvVEGF was composed of 432 bp coding for a signal peptide of 24 amino acid residues and a mature protein of 119 amino acid residues. Compared with other snake venom VEGFs, the nucleotide and deduced protein sequences of the cloned TjsvVEGF were conserved. TjsvVEGF showed low heparin binding activity and strong capillary permeability increasing activity. The KD of TjsvVEGF to VEFGR-2 is 413 pM. However, the binding of TjsvVEGF to VEGFR-1 is too weak to detect. Though TjsvVEGF had high sequence identities (about 90%) with Crotalinae VEGFs, the receptor preference of TjsvVEGF was similar to Viperinae VEGFs which had lower sequence identities (about 60%) with it. TjsvVEGF might serve as a useful tool for the study of structure-function relationships of VEGFs and their receptors. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Angiogenesis and Vascular Architecture in Pheochromocytomas

PubMed Central

Favier, Judith; Plouin, Pierre-François; Corvol, Pierre; Gasc, Jean-Marie

2002-01-01

Angiogenesis is a critical step in tumor growth and metastatic invasion. We here report the study of the vascular status of 10 benign and 9 malignant pheochromocytomas. We examined the vascular architecture after immunostaining endothelial cells (CD34) and vascular smooth muscle cells (α-actin) and identified a vascular pattern characteristic of malignant lesions. To define a gene expression profile indicative of the invasive phenotype, we studied by in situ hybridization the expression of genes encoding several pro- and anti-angiogenic factors [hypoxia-inducible factor (HIF-1α), EPAS1, vascular endothelial growth factor (VEGF), VEGF receptors, angiopoietins and their receptor Tie2, five genes of the endothelin system, and thrombospondin 1]. A semiquantitative evaluation of the labeling revealed an induction of genes encoding EPAS1, VEGF, VEGFR-1, VEGFR-2, endothelin receptor, type B (ETB) and endothelin receptor, type A (ETA) in malignant pheochromocytomas as compared to benign tumors. These differences were observed in tumor cells, in endothelial cells, or in both. Quantification by real-time reverse-transcriptase polymerase chain reaction showed an increase of EPAS1, VEGF, and ETB transcripts of 4.5-, 3.5-, and 10-fold, respectively, in malignant versus benign tumors. Furthermore, we observed a strong correlation between the expression of EPAS1 and VEGF in tumoral tissue and between EPAS1 and ETB in endothelial cells. Altogether, our observations show that analysis of angiogenesis provides promising new criteria for the diagnosis of malignant pheochromocytomas. PMID:12368197

Developmental regulation of vascular endothelial growth/permeability factor messenger ribonucleic acid levels in and vascularization of the villous placenta during baboon pregnancy.

PubMed

Hildebrandt, V A; Babischkin, J S; Koos, R D; Pepe, G J; Albrecht, E D

2001-05-01

Vascular endothelial growth/permeability factor (VEG/PF) has an important role in angiogenesis; however, very little is known about the developmental regulation of VEG/PF and the vascular system within the placenta during human pregnancy. In the present study, therefore, a developmental approach was used in the baboon to determine the placental source of VEG/PF and its fms-like tyrosine kinase (flt-1) and kinase-insert domain containing (KDR/flk-1) receptors, and whether the rise in estrogen with advancing pregnancy was associated with a corresponding increase in placental VEG/PF expression and vascularization. VEG/PF messenger RNA (mRNA) levels were determined by competitive RT-PCR in villous cell fractions isolated by Percoll gradient centrifugation from placentas obtained on days 45 and 54 (very early), 60 (early), 100 (mid), and 165-170 (late) of baboon pregnancy (term = 184 days). Maternal peripheral serum estradiol increased from very low concentrations early in gestation (0.15-0.20 ng/ml) to an early surge of over 2.5 ng/ml on days 60-85, and peak levels of 4-6 ng/ml late in baboon pregnancy. VEG/PF mRNA was expressed in low level in the syncytiotrophoblast (<2,000 attomol/microgram total RNA), and values in this fraction did not change significantly with advancing gestation. VEG/PF mRNA expression was slightly greater in the inner villous core cell fraction; however, levels decreased (P < 0.05) between early and late gestation. Cytotrophoblasts were a major source of VEG/PF mRNA and levels increased (P < 0.01) from 3,631 +/- 844 attomol/microgram total RNA on day 45 to 25,807 +/- 5,873 attomol/microgram total RNA on day 170. VEG/PF protein expression determined by immunocytochemistry was abundant in cytotrophoblasts and lower in the syncytiotrophoblast and inner villous core cells. The flt-1 and KDR/flk-1 receptors were expressed in the vascular endothelial cells of the baboon villous placenta. The percentage of villous placenta occupied by blood vessels

Perlecan and vascular endothelial growth factor-encoding DNA-loaded chitosan scaffolds promote angiogenesis and wound healing.

PubMed

Lord, Megan S; Ellis, April L; Farrugia, Brooke L; Whitelock, John M; Grenett, Hernan; Li, Chuanyu; O'Grady, Robert L; DeCarlo, Arthur A

2017-03-28

The repair of dermal wounds, particularly in the diabetic population, poses a significant healthcare burden. The impaired wound healing of diabetic wounds is attributed to low levels of endogenous growth factors, including vascular endothelial growth factor (VEGF), that normally stimulate multiple phases of wound healing. In this study, chitosan scaffolds were prepared via freeze drying and loaded with plasmid DNA encoding perlecan domain I and VEGF189 and analyzed in vivo for their ability to promote dermal wound healing. The plasmid DNA encoding perlecan domain I and VEGF189 loaded scaffolds promoted dermal wound healing in normal and diabetic rats. This treatment resulted in an increase in the number of blood vessels and sub-epithelial connective tissue matrix components within the wound beds compared to wounds treated with chitosan scaffolds containing control DNA or wounded controls. These results suggest that chitosan scaffolds containing plasmid DNA encoding VEGF189 and perlecan domain I have the potential to induce angiogenesis and wound healing. Copyright © 2017 Elsevier B.V. All rights reserved.

Vascular Contributions to Cognitive Impairment and Dementia

PubMed Central

Gorelick, Philip B.; Scuteri, Angelo; Black, Sandra E.; DeCarli, Charles; Greenberg, Steven M.; Iadecola, Costantino; Launer, Lenore J.; Laurent, Stephane; Lopez, Oscar L.; Nyenhuis, David; Petersen, Ronald C.; Schneider, Julie A.; Tzourio, Christophe; Arnett, Donna K.; Bennett, David A.; Chui, Helena C.; Higashida, Randall T.; Lindquist, Ruth; Nilsson, Peter M.; Roman, Gustavo C.; Sellke, Frank W.; Seshadri, Sudha

2013-01-01

dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people. Conclusions Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative

Vascular Induction of a Disintegrin and Metalloprotease 17 by Angiotensin II Through Hypoxia Inducible Factor 1α

PubMed Central

Obama, Takashi; Takayanagi, Takehiko; Kobayashi, Tomonori; Bourne, Allison M.; Elliott, Katherine J.; Charbonneau, Martine; Dubois, Claire M.

2015-01-01

BACKGROUND A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature. METHODS Cultured vascular smooth muscle cells were stimulated with 100nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter–reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II–infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. CONCLUSIONS Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α–dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system. PMID:24871629

[Oral contraception and the vascular risk].

PubMed

Garnier, L F; Gruel, Y

1989-01-01

Vascular risk, mainly thromboembolitic risk, attributed to oral contraceptives (OCs) since 1962, has been primarily linked to ethinyl estradiol (EE). OCs which combine estrogen and have been associated with cerebral vascular accidents. A 1977 study showed a 40% increase of mortality due to cardiovascular complications in women taking OCs. There were of both an arterial and a venous character. The risk of myocardial infarction was 3 times more frequent among OC users. Deep venous thrombosis and pulmonary embolism were more numerous. Some other risk factors include smoking, hypertension, diabetes, and age 35. The risk of heart attack vanishes a few years after stopping OC use. The reduction of EE (and similarly progesterone) dosage from 100-50 mcg also lower the risk of hypertension, cerebral vascular accidents, and venous thrombosis. Prolonged use of OCs causes disorders of hemostasis affecting the walls of blood vessels, modifying the viscosity of blood flow (increase of hematocrits, reduction of venous tonus), modifying plasmatic coagulation (increase of platelets, increase of factors VII and X and plasma fibrinogen, and decrease of antithrombin III activity), and increased fibrinolysis. These anomalies are exclusively associated with high doses of estrogens. 5% of women using OCs develop moderate hypertension of 5-10 mm Hg of systolic pressure 5 years later, but after cessation it is reversed. OCs stimulate the renin-angiotensin-aldosterone system causing accelerated production of angiotensin II with the resultant forceful vasotension. 3 months after quitting OC use, high blood pressure returns to normal. EE can provoke diabetes; it increases very low density lipoprotein (VLDL) and high density lipoprotein (HDL) production, but total cholesterol is hardly affected. The androgenic property of progestogens reduces HDL. Combined OCs are contraindicated for women with hypertension, hyperlipidemia, diabetes, and a family history of vascular accidents.

Enhanced susceptibility of irradiated tumor vessels to vascular endothelial growth factor receptor tyrosine kinase inhibition.

PubMed

Zips, Daniel; Eicheler, Wolfgang; Geyer, Peter; Hessel, Franziska; Dörfler, Annegret; Thames, Howard D; Haberey, Martin; Baumann, Michael

2005-06-15

Previous experiments with PTK787/ZK222584, a specific inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, using irradiated human FaDu squamous cell carcinoma in nude mice, suggested that radiation-damaged tumor vessels are more sensitive to VEGFR inhibition. To test this hypothesis, the tumor transplantation site (i.e., the right hind leg of nude mice) was irradiated 10 days before transplantation of FaDu to induce radiation damage in the host tissue. FaDu tumors vascularized by radiation-damaged blood vessels appeared later, grew at a slower rate, and showed more necrosis and a smaller vessel area per central tumor section than controls. PTK787/ZK222584 at a daily dose of 50 mg/kg body weight had no impact on growth of control tumors. In contrast, tumors vascularized by radiation-damaged vessels responded to PTK787/ZK222584 with longer latency and slower growth rate than controls, and a trend toward further increase in necrosis, indicating that irradiated tumor vessels are more susceptible to VEGFR inhibition than unirradiated vessels. Although not proving causality, expression analysis of VEGF and VEGFR2 shows that enhanced sensitivity of irradiated vessels to a specific inhibitor of VEGFR tyrosine kinases correlates with increased expression of the molecular target.

Expression of epidermal growth factor receptor and vascular endothelial growth factor in malignant canine epithelial nasal tumours.

PubMed

Shiomitsu, K; Johnson, C L; Malarkey, D E; Pruitt, A F; Thrall, D E

2009-06-01

Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) signalling pathways play a role in carcinogenesis. Inhibition of EGF receptor (EGFR) and of VEGF is effective in increasing the radiation responsiveness of neoplastic cells both in vitro and in human trials. In this study, immunohistochemical evaluation was employed to determine and characterize the potential protein expression levels and patterns of EGFR and VEGF in a variety of canine malignant epithelial nasal tumours. Of 24 malignant canine nasal tumours, 13 (54.2%) were positive for EGFR staining and 22 (91.7%) were positive for VEGF staining. The intensity and percentage of immunohistochemically positive neoplastic cells for EGFR varied. These findings indicate that EGFR and VEGF proteins were present in some malignant epithelial nasal tumours in the dogs, and therefore, it may be beneficial to treat canine patients with tumours that overexpress EGFR and VEGF with specific inhibitors in conjunction with radiation.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.

PubMed

Muñoz-García, Begoña; Moreno, Juan Antonio; López-Franco, Oscar; Sanz, Ana Belén; Martín-Ventura, José Luis; Blanco, Julia; Jakubowski, Aniela; Burkly, Linda C; Ortiz, Alberto; Egido, Jesús; Blanco-Colio, Luis Miguel

2009-12-01

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice. ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti-TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF-kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion. Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with

Guidance of vascular development: lessons from the nervous system.

PubMed

Larrivée, Bruno; Freitas, Catarina; Suchting, Steven; Brunet, Isabelle; Eichmann, Anne

2009-02-27

The vascular system of vertebrates consists of an organized, branched network of arteries, veins, and capillaries that penetrates all the tissues of the body. One of the most striking features of the vascular system is that its branching pattern is highly stereotyped, with major and secondary branches forming at specific sites and developing highly conserved organ-specific vascular patterns. The factors controlling vascular patterning are not yet completely understood. Recent studies have highlighted the anatomic and structural similarities between blood vessels and nerves. The 2 networks are often aligned, with nerve fibers and blood vessels following parallel routes. Furthermore, both systems require precise control over their guidance and growth. Several molecules with attractive and repulsive properties have been found to modulate the proper guidance of both nerves and blood vessels. These include the Semaphorins, the Slits, and the Netrins and their receptors. In this review, we describe the molecular mechanisms by which blood vessels and axons achieve proper path finding and the molecular cues that are involved in their guidance.

Sox17 is required for normal pulmonary vascular morphogenesis

PubMed Central

Lange, Alexander W.; Haitchi, Hans Michael; LeCras, Timothy D.; Sridharan, Anusha; Xu, Yan; Wert, Susan E.; James, Jeanne; Udell, Nicholas; Thurner, Philipp J.; Whitsett, Jeffrey A.

2015-01-01

The SRY-box containing transcription factor Sox17 is required for endoderm formation and vascular morphogenesis during embryonic development. In the lung, Sox17 is expressed in mesenchymal progenitors of the embryonic pulmonary vasculature and is restricted to vascular endothelial cells in the mature lung. Conditional deletion of Sox17 in splanchnic mesenchyme-derivatives using Dermo1-Cre resulted in substantial loss of Sox17 from developing pulmonary vascular endothelial cells and caused pulmonary vascular abnormalities before birth, including pulmonary vein varices, enlarged arteries, and decreased perfusion of the microvasculature. While survival of Dermo1-Cre;Sox17Δ/Δ mice (herein termed Sox17Δ/Δ) was unaffected at E18.5, most Sox17Δ/Δ mice died by 3 weeks of age. After birth, the density of the pulmonary microvasculature was decreased in association with alveolar simplification, biventricular cardiac hypertrophy, and valvular regurgitation. The severity of the postnatal cardiac phenotype was correlated with the severity of pulmonary vasculature abnormalities. Sox17 is required for normal formation of the pulmonary vasculature and postnatal cardiovascular homeostasis. PMID:24418654

[Vascular Calcification - Pathological Mechanism and Clinical Application - . Role of vascular smooth muscle cells in vascular calcification].

PubMed

Kurabayashi, Masahiko

2015-05-01

Vascular calcification is commonly seen with aging, chronic kidney disese (CKD), diabetes, and atherosclerosis, and is closely associated with cardiovascular morbidity and mortality. Vascular calcification has long been regarded as the final stage of degeneration and necrosis of arterial wall and a passive, unregulated process. However, it is now known to be an active and tightly regulated process involved with phenotypic transition of vascular smooth muscle cells (VSMC) that resembles bone mineralization. Briefly, calcium deposits of atherosclerotic plaque consist of hydroxyapatite and may appear identical to fully formed lamellar bone. By using a genetic fate mapping strategy, VSMC of the vascular media give rise to the majority of the osteochondrogenic precursor- and chondrocyte-like cells observed in the calcified arterial media of MGP (- / -) mice. Osteogenic differentiation of VSMC is characterized by the expression of bone-related molecules including bone morphogenetic protein (BMP) -2, Msx2 and osteopontin, which are produced by osteoblasts and chondrocytes. Our recent findings are that (i) Runx2 and Notch1 induce osteogenic differentiation, and (ii) advanced glycation end-product (AGE) /receptor for AGE (RAGE) and palmitic acid promote osteogenic differentiation of VSMC. To understand of the molecular mechanisms of vascular calcification is now under intensive research area.

Vascular Diseases

MedlinePlus

... 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.

Cell Based Therapeutic Approach in Vascular Surgery: Application and Review

PubMed Central

Rocca, Aldo; Tafuri, Domenico; Paccone, Marianna; Giuliani, Antonio; Zamboli, Anna Ginevra Immacolata; Surfaro, Giuseppe; Paccone, Andrea; Compagna, Rita; Amato, Maurizo; Serra, Raffaele; Amato, Bruno

2017-01-01

Abstract Multipotent stem cells - such as mesenchymal stem/stromal cells and stem cells derived from different sources like vascular wall are intensely studied to try to rapidly translate their discovered features from bench to bedside. Vascular wall resident stem cells recruitment, differentiation, survival, proliferation, growth factor production, and signaling pathways transduced were analyzed. We studied biological properties of vascular resident stem cells and explored the relationship from several factors as Matrix Metalloproteinases (MMPs) and regulations of biological, translational and clinical features of these cells. In this review we described a translational and clinical approach to Adult Vascular Wall Resident Multipotent Vascular Stem Cells (VW-SCs) and reported their involvement in alternative clinical approach as cells based therapy in vascular disease like arterial aneurysms or peripheral arterial obstructive disease. PMID:29071303

Risk stratification for the development of respiratory adverse events following vascular surgery using the Society of Vascular Surgery's Vascular Quality Initiative.

PubMed

Genovese, Elizabeth A; Fish, Larry; Chaer, Rabih A; Makaroun, Michel S; Baril, Donald T

2017-02-01

Postoperative respiratory adverse events (RAEs) are associated with high rates of morbidity and mortality in general surgery, however, little is known about these complications in the vascular surgery population, a frail subset with multiple comorbidities. The objective of this study was to describe the contemporary incidence of RAEs in vascular surgery patients, the risk factors for this complication, and the overall impact of RAEs on patient outcomes. The Vascular Quality Initiative was queried (2003-2014) for patients who underwent endovascular abdominal aortic repair, open abdominal aortic aneurysm repair, thoracic endovascular aortic repair, suprainguinal bypass, or infrainguinal bypass. A mixed-effects logistic regression model determined the independent risk factors for RAEs. Using a random 85% of the cohort, a risk prediction score for RAEs was created, and the score was validated using the remaining 15% of the cohort, comparing the predicted to the actual incidence of RAE and determining the area under the receiver operating characteristic curve. The independent risk of in-hospital mortality and discharge to a nursing facility associated with RAEs was determined using a mixed-effects logistic regression to control for baseline patient characteristics, operative variables, and other postoperative adverse events. The cohort consisted of 52,562 patients, with a 5.4% incidence of RAEs. The highest rates of RAEs were seen in current smokers (6.1%), recent acute myocardial infarction (10.1%), symptomatic congestive heart failure (9.9%), chronic obstructive pulmonary disease requiring oxygen therapy (11.0%), urgent and emergent procedures (6.4% and 25.9%, respectively), open abdominal aortic aneurysm repairs (17.6%), in situ suprainguinal bypasses (9.68%), and thoracic endovascular aortic repairs (9.6%). The variables included in the risk prediction score were age, body mass index, smoking status, congestive heart failure severity, chronic obstructive pulmonary

[Malignant vascular tumors of the vulva].

PubMed

Chokoeva, A; Tchernev, G

2015-01-01

Due to the increased vascularity as well as the unique anatomical structure, vascular lesions, which occur in the female reproductive system are common observed and diverse by their morphology. The majority of them are benign, including vascular malformations, lesions due to vascular hyperplasia, tumors with significant vascular component and others. Malignant vascular tumors are rare in the area of the vulva accounting about 1% of all vulvar lesions with vascular origin. Kaposi sarcoma, epithelioid hemangioepithelioma and epithelioid angiosarcoma have been reported with vulvar localization. With a view to their rare incidence, nonspecific clinical manifestation and aggressive behavior associated with high mortality, we present the most common malignant tumors of vascular origin arising in the vulva, as we emphasize on their epidemiology and clinical features, differential diagnosis and therapeutic algorithms for this rare type of malignancies.

The skeletal vascular system - Breathing life into bone tissue.

PubMed

Stegen, Steve; Carmeliet, Geert

2017-08-26

During bone development, homeostasis and repair, a dense vascular system provides oxygen and nutrients to highly anabolic skeletal cells. Characteristic for the vascular system in bone is the serial organization of two capillary systems, each typified by specific morphological and physiological features. Especially the arterial capillaries mediate the growth of the bone vascular system, serve as a niche for skeletal and hematopoietic progenitors and couple angiogenesis to osteogenesis. Endothelial cells and osteoprogenitor cells interact not only physically, but also communicate to each other by secretion of growth factors. A vital angiogenic growth factor is vascular endothelial growth factor and its expression in skeletal cells is controlled by osteogenic transcription factors and hypoxia signaling, whereas the secretion of angiocrine factors by endothelial cells is regulated by Notch signaling, blood flow and possibly hypoxia. Bone loss and impaired fracture repair are often associated with reduced and disorganized blood vessel network and therapeutic targeting of the angiogenic response may contribute to enhanced bone regeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

The relation of digital vascular function to cardiovascular risk factors in African-Americans using digital tonometry: the Jackson Heart Study.

PubMed

McClendon, Eric E; Musani, Solomon K; Samdarshi, Tandaw E; Khaire, Sushant; Stokes, Donny; Hamburg, Naomi M; Sheffy, Koby; Mitchell, Gary F; Taylor, Herman R; Benjamin, Emelia J; Fox, Ervin R

2017-06-01

Digital vascular tone and function, as measured by peripheral arterial tonometry (PAT), are associated with cardiovascular risk and events in non-Hispanic whites. There are limited data on relations between PAT and cardiovascular risk in African-Americans. PAT was performed on a subset of Jackson Heart Study participants using a fingertip tonometry device. Resting digital vascular tone was assessed as baseline pulse amplitude. Hyperemic vascular response to 5 minutes of ischemia was expressed as the PAT ratio (hyperemic/baseline amplitude ratio). Peripheral augmentation index (AI), a measure of relative wave reflection, also was estimated. The association of baseline pulse amplitude (PA), PAT ratio, and AI to risk factors was assessed using stepwise multivariable models. The study sample consisted of 837 participants from the Jackson Heart Study (mean age, 54 ± 11 years; 61% women). In stepwise multivariable regression models, baseline pulse amplitude was related to male sex, body mass index, and diastolic blood pressure (BP), accounting for 16% of the total variability of the baseline pulse amplitude. Age, male sex, systolic BP, diastolic BP, antihypertensive medication, and prevalent cardiovascular disease contributed to 11% of the total variability of the PAT ratio. Risk factors (primarily age, sex, and heart rate) explained 47% of the total variability of the AI. We confirmed in our cohort of African-Americans, a significant relation between digital vascular tone and function measured by PAT and multiple traditional cardiovascular risk factors. Further studies are warranted to investigate the utility of these measurements in predicting clinical outcomes in African-Americans. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Double-filter identification of vascular-expressed genes using Arabidopsis plants with vascular hypertrophy and hypotrophy.

PubMed

Ckurshumova, Wenzislava; Scarpella, Enrico; Goldstein, Rochelle S; Berleth, Thomas

2011-08-01

Genes expressed in vascular tissues have been identified by several strategies, usually with a focus on mature vascular cells. In this study, we explored the possibility of using two opposite types of altered tissue compositions in combination with a double-filter selection to identify genes with a high probability of vascular expression in early organ primordia. Specifically, we generated full-transcriptome microarray profiles of plants with (a) genetically strongly reduced and (b) pharmacologically vastly increased vascular tissues and identified a reproducible cohort of 158 transcripts that fulfilled the dual requirement of being underrepresented in (a) and overrepresented in (b). In order to assess the predictive value of our identification scheme for vascular gene expression, we determined the expression patterns of genes in two unbiased subsamples. First, we assessed the expression patterns of all twenty annotated transcription factor genes from the cohort of 158 genes and found that seventeen of the twenty genes were preferentially expressed in leaf vascular cells. Remarkably, fifteen of these seventeen vascular genes were clearly expressed already very early in leaf vein development. Twelve genes with published leaf expression patterns served as a second subsample to monitor the representation of vascular genes in our cohort. Of those twelve genes, eleven were preferentially expressed in leaf vascular tissues. Based on these results we propose that our compendium of 158 genes represents a sample that is highly enriched for genes expressed in vascular tissues and that our approach is particularly suited to detect genes expressed in vascular cell lineages at early stages of their inception. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

FGF-dependent metabolic control of vascular development

PubMed Central

Yu, Pengchun; Alves, Tiago C.; Fang, Jennifer S.; Xie, Yi; Zhu, Jie; Chen, Zehua; De Smet, Frederik; Zhang, Jiasheng; Jin, Suk-Won; Sun, Lele; Sun, Hongye; Kibbey, Richard G.; Hirschi, Karen K.; Hay, Nissim; Carmeliet, Peter; Chittenden, Thomas W.; Eichmann, Anne; Potente, Michael; Simons, Michael

2017-01-01

Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are of importance to these processes1. While much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism2,3, little is understood about the role of fibroblast growth factors (FGFs) in this context4. Here we identify FGF receptor (FGFR) signaling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signaling inputs results in decreased glycolysis leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/r3 double mutant mice while HK2 overexpression partially rescues the defects caused by suppression of FGF signaling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development. PMID:28467822

Oxidative stress and vascular inflammation in aging.

PubMed

El Assar, Mariam; Angulo, Javier; Rodríguez-Mañas, Leocadio

2013-12-01

Vascular aging, a determinant factor for cardiovascular disease and health status in the elderly, is now viewed as a modifiable risk factor. Impaired endothelial vasodilation is a early hallmark of arterial aging that precedes the clinical manifestations of vascular dysfunction, the first step to cardiovascular disease and influencing vascular outcomes in the elderly. Accordingly, the preservation of endothelial function is thought to be an essential determinant of healthy aging. With special attention on the effects of aging on the endothelial function, this review is focused on the two main mechanisms of aging-related endothelial dysfunction: oxidative stress and inflammation. Aging vasculature generates an excess of the reactive oxygen species (ROS), superoxide and hydrogen peroxide, that compromise the vasodilatory activity of nitric oxide (NO) and facilitate the formation of the deleterious radical, peroxynitrite. Main sources of ROS are mitochondrial respiratory chain and NADPH oxidases, although NOS uncoupling could also account for ROS generation. In addition, reduced antioxidant response mediated by erythroid-2-related factor-2 (Nrf2) and downregulation of mitochondrial manganese superoxide dismutase (SOD2) contributes to the establishment of chronic oxidative stress in aged vessels. This is accompanied by a chronic low-grade inflammatory phenotype that participates in defective endothelial vasodilation. The redox-sensitive transcription factor, nuclear factor-κB (NF-κB), is upregulated in vascular cells from old subjects and drives a proinflammatory shift that feedbacks oxidative stress. This chronic NF-κB activation is contributed by increased angiotensin-II signaling and downregulated sirtuins and precludes adequate cellular response to acute ROS generation. Interventions targeted to recover endogenous antioxidant capacity and cellular stress response rather than exogenous antioxidants could reverse oxidative stress-inflammation vicious cycle in

Modified model of VX2 tumor overexpressing vascular endothelial growth factor.

PubMed

Pascale, Florentina; Ghegediban, Saida-Homayra; Bonneau, Michel; Bedouet, Laurent; Namur, Julien; Verret, Valentin; Schwartz-Cornil, Isabelle; Wassef, Michel; Laurent, Alexandre

2012-06-01

To determine whether upregulated expression of vascular endothelial growth factor (VEGF) in VX2 cells can increase vessel density (VD) and reduce tumor necrosis. The VX2 cell line was transfected with expression vectors containing cDNA for rabbit VEGF. Stable clones producing rabbit VEGF (VEGF-VX2) were selected. VEGF-VX2 cells (n = 5 rabbits) or nontransfected VX2 cells (controls; n = 5 rabbits) were implanted into leg muscle of 10 rabbits. The animals were sacrificed at day 21. Tumor volume, percentage of necrosis, VD, and VEGF concentration in tumor protein extract were quantified. Overexpression of VEGF by VX2 cells augmented tumor implantation efficiency 100% and favored cyst formation. The tumor volume was significantly larger for VEGF-VX2 transfected tumors versus controls (P = .0143). Overexpression of VEGF in VX2 cells significantly increased the VD of the tumors (P = .0138). The percentage of necrosis was reduced in VEGF-VX2 tumors versus controls (19.5% vs 38.5 %; P = .002). VEGF concentration in VEGF-VX2 tumors was significantly higher than in control tumors (P = .041) and was correlated with tumor volume (ρ = .883, P = .012). The overexpression of VEGF increased tumor growth and vascularization, favored cyst formation, and reduced tumor necrosis. This new phenotype of the VX2 tumor may offer some advantages over classic models of VX2 tumor for evaluating anticancer therapies. Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.

Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease.

PubMed

Li, J; Wang, Y J; Zhang, M; Xu, Z Q; Gao, C Y; Fang, C Q; Yan, J C; Zhou, H D

2011-04-26

Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia. A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion. At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion. VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.

Vascular Cambium Development

PubMed Central

Nieminen, Kaisa; Blomster, Tiina; Helariutta, Ykä; Mähönen, Ari Pekka

2015-01-01

Secondary phloem and xylem tissues are produced through the activity of vascular cambium, the cylindrical secondary meristem which arises among the primary plant tissues. Most dicotyledonous species undergo secondary development, among them Arabidopsis. Despite its small size and herbaceous nature, Arabidopsis displays prominent secondary growth in several organs, including the root, hypocotyl and shoot. Together with the vast genetic resources and molecular research methods available for it, this has made Arabidopsis a versatile and accessible model organism for studying cambial development and wood formation. In this review, we discuss and compare the development and function of the vascular cambium in the Arabidopsis root, hypocotyl, and shoot. We describe the current understanding of the molecular regulation of vascular cambium and compare it to the function of primary meristems. We conclude with a look at the future prospects of cambium research, including opportunities provided by phenotyping and modelling approaches, complemented by studies of natural variation and comparative genetic studies in perennial and woody plant species. PMID:26078728

Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study

PubMed Central

2013-01-01

Introduction Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). An early manifestation of CVD is endothelial dysfunction which can lead to functional and morphological vascular abnormalities. Classical CVD risk factors and inflammation are both implicated in causing endothelial dysfunction in RA. The objective of the present study was to examine the effect of baseline inflammation, cumulative inflammation, and classical CVD risk factors on the vasculature following a six-year follow-up period. Methods A total of 201 RA patients (155 females, median age (25th to 75th percentile): 61 years (53 to 67)) were examined at baseline (2006) for presence of classical CVD risk factors and determination of inflammation using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. The CRP and ESR were recorded from the baseline study visit to the follow-up visit for each patient to calculate cumulative inflammatory burden. Results Classical CVD risk factors, but not RA disease-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function and carotid atherosclerosis. These findings were similar in a sub-group of patients free from CVD, and not receiving non-steroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors or biologics. Cumulative inflammation was not associated with microvascular and macrovascular endothelial function, but a weak association was apparent between area under the curve for CRP and carotid atherosclerosis. Conclusions Classical CVD risk factors may be better long-term predictors of vascular function and morphology than systemic disease-related inflammation in patients with RA. Further studies are needed to

Joint scientific statement of the European Association for the Study of Obesity and the European Society of Hypertension: Obesity and early vascular ageing.

PubMed

Jordan, Jens; Nilsson, Peter M; Kotsis, Vasilios; Olsen, Michael H; Grassi, Guido; Yumuk, Volkan; Hauner, Hans; Zahorska-Markiewicz, Barbara; Toplak, Hermann; Engeli, Stefan; Finer, Nick

2015-03-01

Current cardiovascular risk scores do not include obesity or fat distribution as independent factors, and may underestimate risk in obese individuals. Assessment of early vascular ageing (EVA) biomarkers including arterial stiffness, central blood pressure, carotid intima-media thickness and flow-mediated vasodilation may help to refine risk assessment in obese individuals in whom traditional cardiovascular risk scores and factors suggest no need for specific medical attention. A number of issues need to be addressed before this approach is ready for translation into routine clinical practice. Methodologies for measurements of vascular markers need to be further standardized and less operator-dependent. The utility of these nontraditional risk factors will also need to be proven in sufficiently large and properly designed interventional studies. Indeed, published studies on vascular markers in obesity and weight loss vary in quality and study design, are sometimes conducted in small populations, use a variety of differing methodologies and study differing vascular beds. Finally, current vascular measurements are still crude and may not be sufficient to cover the different aspects of EVA in obesity.

Sox17 drives functional engraftment of endothelium converted from non-vascular cells

PubMed Central

Schachterle, William; Badwe, Chaitanya R.; Palikuqi, Brisa; Kunar, Balvir; Ginsberg, Michael; Lis, Raphael; Yokoyama, Masataka; Elemento, Olivier; Scandura, Joseph M.; Rafii, Shahin

2017-01-01

Transplanting vascular endothelial cells (ECs) to support metabolism and express regenerative paracrine factors is a strategy to treat vasculopathies and to promote tissue regeneration. However, transplantation strategies have been challenging to develop, because ECs are difficult to culture and little is known about how to direct them to stably integrate into vasculature. Here we show that only amniotic cells could convert to cells that maintain EC gene expression. Even so, these converted cells perform sub-optimally in transplantation studies. Constitutive Akt signalling increases expression of EC morphogenesis genes, including Sox17, shifts the genomic targeting of Fli1 to favour nearby Sox consensus sites and enhances the vascular function of converted cells. Enforced expression of Sox17 increases expression of morphogenesis genes and promotes integration of transplanted converted cells into injured vessels. Thus, Ets transcription factors specify non-vascular, amniotic cells to EC-like cells, whereas Sox17 expression is required to confer EC function. PMID:28091527

Sox17 drives functional engraftment of endothelium converted from non-vascular cells.

PubMed

Schachterle, William; Badwe, Chaitanya R; Palikuqi, Brisa; Kunar, Balvir; Ginsberg, Michael; Lis, Raphael; Yokoyama, Masataka; Elemento, Olivier; Scandura, Joseph M; Rafii, Shahin

2017-01-16

Transplanting vascular endothelial cells (ECs) to support metabolism and express regenerative paracrine factors is a strategy to treat vasculopathies and to promote tissue regeneration. However, transplantation strategies have been challenging to develop, because ECs are difficult to culture and little is known about how to direct them to stably integrate into vasculature. Here we show that only amniotic cells could convert to cells that maintain EC gene expression. Even so, these converted cells perform sub-optimally in transplantation studies. Constitutive Akt signalling increases expression of EC morphogenesis genes, including Sox17, shifts the genomic targeting of Fli1 to favour nearby Sox consensus sites and enhances the vascular function of converted cells. Enforced expression of Sox17 increases expression of morphogenesis genes and promotes integration of transplanted converted cells into injured vessels. Thus, Ets transcription factors specify non-vascular, amniotic cells to EC-like cells, whereas Sox17 expression is required to confer EC function.

[Descriptive epidemiology of the vascular risk factors in Bañeres. Study group 'Bañeres Project'].

PubMed

Mulet, M J; Sánchez-Pérez, R M; Moltó, J M; Adam, A; Blanquer, J; López-Arlandis, J

Epidemiological studies of the risk factors of cerebrovascular disease are of great interest, particularly the identification of factors which may be modified. Previous studies carried out in the Alcoi region of Alicante province, showed a high prevalence of cerebrovascular disease. The town of Bañeres was therefore chosen for confirmation of this data and identification of the frequency of vascular risk factors. To compare the group of patients with cerebrovascular disease with the remainder of the population interviewed. In a door-to-door study in Bañeres 1,832 people were interviewed as part of the Bañeres Project. The population aged over 45 years was interviewed and filled in a questionnaire for diagnosis of transient ischemic accidents. Arterial hypertension: estimated prevalence 500/1,000 inhabitants, relative risk 3.24; diabetes mellitus: estimated prevalence 195/1,000, relative risk 2.18; coronary artery disease: estimated prevalence 58/1,000, relative risk 1.88; peptic ulcer: estimated prevalence 75/1,000, relative risk 1.23; smoking: estimated prevalence 110/1,000, relative risk 0.46; complete arrhythmia: prevalence 73/1,000, relative risk 5.23. Family histories of cerebrovascular accident, arterial hypertension, diabetes and coronary artery disease were not significant. Arterial hypertension, diabetes mellitus and arrhythmia were significantly more prevalent amongst patients with vascular disease in our setting. We found no association with the other risk factors analyzed.

Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation on Tumor-Associated Endothelial Cells Leads to Treatment of Orthotopic Human Colon Cancer in Nude Mice1

PubMed Central

Sasaki, Takamitsu; Kitadai, Yasuhiko; Nakamura, Toru; Kim, Jang-Seong; Tsan, Rachel Z; Kuwai, Toshio; Langley, Robert R; Fan, Dominic; Kim, Sun-Jin; Fidler, Isaiah J

2007-01-01

The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-α) and vascular endothelial growth factor (VEGF) but were negative for EGFR, human epidermal growth factor receptor 2 (HER2), and VEGFR. Double immunofluorescence staining revealed that tumor-associated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR), and phosphorylated VEGFR (pVEGFR). Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase) or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01); this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001). AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, and increased the level of apoptosis in both tumor-associated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer. PMID:18084614

Vascular Effects of Estrogenic Menopausal Hormone Therapy

PubMed Central

Reslan, Ossama M.; Khalil, Raouf A.

2011-01-01

Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the ‘timing hypothesis’, which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of

Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis

PubMed Central

Weidemann, Anja K; Crawshaw, Ania A; Byrne, Emily; Young, Helen S

2013-01-01

Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF)-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation) and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased cardiovascular risk. PMID:24101875

Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis.

PubMed

Weidemann, Anja K; Crawshaw, Ania A; Byrne, Emily; Young, Helen S

2013-09-26

Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF)-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation) and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased cardiovascular risk.

Vascular anomalies of the head and neck.

PubMed

Donald, P J

2001-02-01

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

Vascular tissue engineering: towards the next generation vascular grafts.

PubMed

Naito, Yuji; Shinoka, Toshiharu; Duncan, Daniel; Hibino, Narutoshi; Solomon, Daniel; Cleary, Muriel; Rathore, Animesh; Fein, Corey; Church, Spencer; Breuer, Christopher

2011-04-30

The application of tissue engineering technology to cardiovascular surgery holds great promise for improving outcomes in patients with cardiovascular diseases. Currently used synthetic vascular grafts have several limitations including thrombogenicity, increased risk of infection, and lack of growth potential. We have completed the first clinical trial evaluating the feasibility of using tissue engineered vascular grafts (TEVG) created by seeding autologous bone marrow-derived mononuclear cells (BM-MNC) onto biodegradable tubular scaffolds. Despite an excellent safety profile, data from the clinical trial suggest that the primary graft related complication of the TEVG is stenosis, affecting approximately 16% of grafts within the first seven years after implantation. Continued investigation into the cellular and molecular mechanisms underlying vascular neotissue formation will improve our basic understanding and provide insights that will enable the rationale design of second generation TEVG. Published by Elsevier B.V.

Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor.

PubMed Central

Cheng, S Y; Huang, H J; Nagane, M; Ji, X D; Wang, D; Shih, C C; Arap, W; Huang, C M; Cavenee, W K

1996-01-01

The development of new capillary networks from the normal microvasculature of the host appears to be required for growth of solid tumors. Tumor cells influence this process by producing both inhibitors and positive effectors of angiogenesis. Among the latter, the vascular endothelial growth factor (VEGF) has assumed prime candidacy as a major positive physiological effector. Here, we have directly tested this hypothesis in the brain tumor, glioblastoma multiforme, one of the most highly vascularized human cancers. We introduced an antisense VEGF expression construct into glioblastoma cells and found that (i) VEGF mRNA and protein levels were markedly reduced, (ii) the modified cells did not secrete sufficient factors so as to be chemoattractive for primary human microvascular endothelial cells, (iii) the modified cells were not able to sustain tumor growth in immunodeficient animals, and (iv) the density of in vivo blood vessel formation was reduced in direct relation to the reduction of VEGF secretion and tumor formation. Moreover, revertant cells that recovered the ability to secrete VEGF regained each of these tumorigenic properties. These results suggest that VEGF plays a major angiogenic role in glioblastoma. Images Fig. 1 Fig. 4 PMID:8710899

Patients with metabolic syndrome exhibit higher platelet activity than those with conventional risk factors for vascular disease.

PubMed

Serebruany, Victor L; Malinin, Alex; Ong, Stephen; Atar, Dan

2008-04-01

The metabolic syndrome is a matter of ongoing debate with regard to its existence, classification, clinical meaningfulness, and associated risks for vessel occlusion. Considering that persistent platelet activation is a cornerstone for the development of acute vascular events, and that patients with type 2 diabetes consistently exhibit high platelet activity, these characteristics may be critical for distinguishing and triageing specific features of metabolic syndrome among established risk factors for vascular disease. We assessed the platelet activity by conventional aggregation, expression of major surface receptors by flow cytometry, and quantitatively by rapid bedside analyzers in 20 aspirin-naïve patients with documented metabolic syndrome, and compared these with 20 untreated subjects with multiple cardiovascular risk factors. Closure time by the PFA-100 analyzer was significantly (P = 0.002) shorter in patients with metabolic syndrome indicating platelet inhibition under high shear conditions. Ultegra analyzer readings revealed increased fibrinogen binding (P = 0.0003) what in combination with the increased expression of PAC-1 (P = 0.32) strongly suggest activation of platelet glycoprotein IIb/IIIa receptor. Surface expression of CD107a (P = 0.014), and SPAN-12 (P = 0.003) were also higher in patients with metabolic syndrome. In contrast, platelet aggregation induced by collagen or ADP, CD31, CD41, CD42b, CD51/61, CD62p, CD63, CD154, CD165, so as formation of platelet-monocyte aggregates, PAR-1 thrombin receptor, and thrombospondin did not differ between groups. Patients with metabolic syndrome exhibited a higher degree of platelet activation than subjects with conventional risk factors for vascular disease. Conceptually, applying adequate antiplatelet strategies may reduce the risk of acute thrombotic events in these patients. Further prospective studies exploring this notion are encouraged.

Resveratrol prevents angiotensin II-induced hypertrophy of vascular smooth muscle cells through the transactivation of growth factor receptors.

PubMed

Hossain, Ekhtear; Anand-Srivastava, Madhu B

2017-08-01

We previously showed that augmented levels of endogenous angiotensin II (AngII) contribute to vascular smooth muscle cell (VSMC) hypertrophy through the transactivation of growth factor receptors in spontaneously hypertensive rats. Resveratrol (RV), a polyphenolic component of red wine, has also been shown to attenuate AngII-evoked VSMC hypertrophy; however, the molecular mechanism mediating this response is obscure. The present study was therefore undertaken to examine whether RV could prevent AngII-induced VSMC hypertrophy through the transactivation of growth factor receptor and associated signaling pathways. AngII treatment of VSMC enhanced the protein synthesis that was attenuated towards control levels by RV pretreatment as well as by the inhibitors of NADPH oxidase, c-Src, and growth factor receptors. Furthermore, RV pretreatment also inhibited enhanced levels of superoxide anion, NADPH oxidase activity, increased expression of NADPH oxidase subunits, and phosphorylation of c-Src, EGF-R, PDGE-R, ERK1/2, and AKT1/2. In conclusion, these results indicate that RV attenuates AngII-induced VSMC hypertrophy through the inhibition of enhanced oxidative stress and activation of c-Src, growth factor receptors, and MAPK/AKT signaling. We suggest that RV could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension and hypertrophy.

Expression of vascular endothelial growth factor in Juvenile Angiofibroma.

PubMed

Hota, Ashutosh; Sarkar, Chitra; Gupta, Siddhartha Datta; Kumar, Rakesh; Bhalla, Ashu Seith; Thakar, Alok

2015-06-01

To examine Juvenile Angiofibroma (JA) tissue for expression of vascular endothelial growth factor (VEGF), and to explore its relationship with puberty status, stage, recurrence and the intraoperative blood loss. Retrospective cohort study of 36 histologically proven cases of JA. Minimum follow up period was 3 years. VEGF expression on tumor cells assessed by immunohistochemistry and graded on two criteria--percentage of cells expressing positivity and the intensity of positivity. These two parameters assessed for impact on puberty status, stage, recurrence, and blood loss. VEGF expression noted on the tumor endothelial cells in 36/36, and on the tumor stromal cells in 34/36. The percentage of cells expressing VEGF and the intensity of expression were not significantly related to puberty status, tumor stage, recurrence, or intra-operative blood loss (p values 0.3-1.0). VEGF expression is near universal in JA. Such expression is independent of puberty status and stage, and does not impact on intra operative blood loss and recurrence. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Orf virus interleukin-10 and vascular endothelial growth factor-E modulate gene expression in cultured equine dermal fibroblasts.

PubMed

Wise, Lyn M; Bodaan, Christa J; Mercer, Andrew A; Riley, Christopher B; Theoret, Christine L

2016-10-01

Wounds in horses often exhibit sustained inflammation and inefficient vascularization, leading to excessive fibrosis and clinical complications such as "proud flesh". Orf virus-derived proteins, vascular endothelial growth factor (VEGF)-E and interleukin (ovIL)-10, enhance angiogenesis and control inflammation and fibrosis in skin wounds of laboratory animals. The study aimed to determine if equine dermal cells respond to VEGF-E and ovIL-10. Equine dermal cells are expected to express VEGF and IL-10 receptors, so viral protein treatment is likely to alter cellular gene expression and behaviour in a manner conducive to healing. Skin samples were harvested from the lateral thoracic wall of two healthy thoroughbred horses. Equine dermal cells were isolated using a skin explant method and their phenotype assessed by immunofluorescence. Cells were treated with recombinant proteins, with or without inflammatory stimuli. Gene expression was examined using standard and quantitative reverse transcriptase PCR. Cell behaviour was evaluated in a scratch assay. Cultured cells were half vimentin(+ve) fibroblasts and half alpha smooth muscle actin(+ve) and vimentin(+ve) myofibroblasts. VEGF-E increased basal expression of IL-10 mRNA, whereas VEGF-A and collagenase-1 mRNA expression was increased by ovIL-10. In cells exposed to inflammatory stimulus, both treatments dampened tumour necrosis factor mRNA expression, and ovIL-10 exacerbated expression of monocyte chemoattractant protein. Neither viral protein influenced cell migration greatly. This study shows that VEGF-E and ovIL-10 are active on equine dermal cells and exert anti-inflammatory and anti-fibrotic effects that may enhance skin wound healing in horses. © 2016 ESVD and ACVD.

Angiogenic Type I Collagen Extracellular Matrix Integrated with Recombinant Bacteriophages Displaying Vascular Endothelial Growth Factors.

PubMed

Yoon, Junghyo; Korkmaz Zirpel, Nuriye; Park, Hyun-Ji; Han, Sewoon; Hwang, Kyung Hoon; Shin, Jisoo; Cho, Seung-Woo; Nam, Chang-Hoon; Chung, Seok

2016-01-21

Here, a growth-factor-integrated natural extracellular matrix of type I collagen is presented that induces angiogenesis. The developed matrix adapts type I collagen nanofibers integrated with synthetic colloidal particles of recombinant bacteriophages that display vascular endothelial growth factor (VEGF). The integration is achieved during or after gelation of the type I collagen and the matrix enables spatial delivery of VEGF into a desired region. Endothelial cells that contact the VEGF are found to invade into the matrix to form tube-like structures both in vitro and in vivo, proving the angiogenic potential of the matrix. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biomechanical factors as regulators of biological responses to vascular grafts.

PubMed

Fortunato, J E; Glagov, S; Bassiouny, H S

1999-03-01

Biomechanical forces have been implicated in the induction and progression of intimal hyperplastic thickening in vein, prosthetic, and endovascular bypass grafts. Graft implantation imposes significant alterations is shear and tensile forces. Such physical forces play an important role in modulating those cellular and molecular events that underlie regulation of vascular healing and adaptation. Characterization of such hemodynamic variables that induce perpetual medial vascular smooth muscle cell proliferation and migration will help in identification of those grafts at risk for occlusion and limited long-term patency and in design of therapeutic strategies that attenuate progressive intimal hyperplasia.

[Molecular mechanisms in vascular osteocartilaginous metaplasia: systematic review].

PubMed

Rosero Salazar, Doris Haydee

2016-01-01

The cartilage and bone metaplasia occurring in both the heart and blood vessels, are the result of risk factors or chronic diseases that gradually adversely affect the performance of a person in society; however, clinical signs are reversible in early and intermediate stages of alterations. To establish how the molecular mechanisms underlying the increased vascular metaplastic changes and possible aspects of treatment and prevention. A systematic review was performed by searching for articles indexed in PubMed, Scopus and Science Direct data from 1995 to 2015. The MeSH descriptors used were metaplasia and vascular calcification, which terms associated were molecular mechanisms, condrogenic and osteogenic. Multiple factors influence the metaplastic change, especially the pro-inflammatory associated with vascular oxidation and the presence of free radicals; this development is reversible by treatment with antioxidants and changes in lifestyle and secondary prevention as there is a diagnosis of chronic degenerative disease. The literature evidences that factors that reduce the tissue oxidative stress and promote the maintenance of vascular phenotype are protective and / or reducing the osteochondral metaplastic formations.

Predictive model of thrombospondin-1 and vascular endothelial growth factor in breast tumor tissue.

PubMed

Rohrs, Jennifer A; Sulistio, Christopher D; Finley, Stacey D

2016-01-01

Angiogenesis, the formation of new blood capillaries from pre-existing vessels, is a hallmark of cancer. Thus far, strategies for reducing tumor angiogenesis have focused on inhibiting pro-angiogenic factors, while less is known about the therapeutic effects of mimicking the actions of angiogenesis inhibitors. Thrombospondin-1 (TSP1) is an important endogenous inhibitor of angiogenesis that has been investigated as an anti-angiogenic agent. TSP1 impedes the growth of new blood vessels in many ways, including crosstalk with pro-angiogenic factors. Due to the complexity of TSP1 signaling, a predictive systems biology model would provide quantitative understanding of the angiogenic balance in tumor tissue. Therefore, we have developed a molecular-detailed, mechanistic model of TSP1 and vascular endothelial growth factor (VEGF), a promoter of angiogenesis, in breast tumor tissue. The model predicts the distribution of the angiogenic factors in tumor tissue, revealing that TSP1 is primarily in an inactive, cleaved form due to the action of proteases, rather than bound to its cellular receptors or to VEGF. The model also predicts the effects of enhancing TSP1's interactions with its receptors and with VEGF. To provide additional predictions that can guide the development of new anti-angiogenic drugs, we simulate administration of exogenous TSP1 mimetics that bind specific targets. The model predicts that the CD47-binding TSP1 mimetic dramatically decreases the ratio of receptor-bound VEGF to receptor-bound TSP1, in favor of anti-angiogenesis. Thus, we have established a model that provides a quantitative framework to study the response to TSP1 mimetics.

[Analysis of vascular complications of IABP therapy in open-heart surgery patients 1999-2004].

PubMed

Kovács, Endre; Becker, Dávid; Daróczi, László; Gálfy, Ildikó; Hüttl, Tivadar; Laczkó, Agnes; Paukovits, Tamas; Vargha, Péter; Szabolcs, Zoltán

2006-04-01

Intraaortic balloon pump (IABP) is being used in cardiac surgery in an increased ratio. IABP therapy involves considerable risk, mainly vascular complications, postoperative bleeding and infection can represent danger. Between 1999 and 2004 out of 4443 open heart surgery operations we have performed intraaortic balloon pump treatment in case of 75 patients. The mean age was 64 years, 23 patients had diabetes mellitus, 47 patients had hypertension, 20 patients had peripheral vascular disease as well. We performed IABP therapy most frequently during isolated coronary bypass operations (42 cases), but also combined operations (implantation of valve prosthesis + coronary bypass) represent a significant part (implantation of aortic valve prosthesis + CABG: 5 cases, implantation of mitral valve prosthesis + CABG: 8 cases). Vascular complications occurred in 10 cases--13.3%--out of 75 patients, including 7 fatal ones. Three cases are due to the IABP treatment itself: Crush syndrome was developed leading to the loss of the patient. Applying the multiple logistic regression model we have examined the effect of the following factors on the occurrence of vascular complications: gender, age, body surface, accompanying diseases (hypertension, diabetes, peripheral vascular disease), the method and timing of insertion. Peripheral vascular disease (p < 0.005) and hypertension (p = 0.01) represent independent risk factors regarding the occurrence of complications. Having performed chi-square test we have not identified significant correlations between mortality and vascular complications. In case of prevailing peripheral vascular disease, the application of alternative insertion techniques--via the ascending aorta, the axillary artery--are recommended.

Methodology for the evaluation of vascular surgery manpower in France.

PubMed

Berger, L; Mace, J M; Ricco, J B; Saporta, G

2013-01-01

The French population is growing and ageing. It is expected to increase by 2.7% by 2020, and the number of individuals over 65 years of age is expected to increase by 3.3 million, a 33% increase, between 2005 and 2020. As the number of vascular surgery procedures is closely associated with the age of a population, it is anticipated that there will be a significant increase in the workload of vascular surgeons. A model is presented to predict changes in vascular surgery activity according to population ageing, including other parameters that could affect workload evolution. Three types of arterial procedures were studied: infrarenal abdominal aortic aneurysm (AAA) surgery, peripheral arterial occlusive disease (PAOD) procedures and carotid artery (CEA) procedures. Data were selected and extracted from the national PMSI (Medical Information System Program) database. Data obtained from 2000 were used to predict data based on an ageing population for 2008. From this model, a weighted index was defined for each group by comparing expected and observed workloads. According to the model, over this 8-year period, there was an overall increase in vascular procedures of 52.2%, with an increase of 89% in PAOD procedures. Between 2000 and 2009, the total increase was 58.0%, with 3.9% for AAA procedures, 101.7% for PAOD procedures and 13.2% for CEA procedures. The weighted model based on an ageing population and corrected by a weighted factor predicted this increase. This weighted model is able to predict the workload of vascular surgeons over the coming years. An ageing population and other factors could result in a significant increase in demand for vascular surgical services. Copyright © 2012 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Vascular complications in diabetes: Microparticles and microparticle associated microRNAs as active players.

PubMed

Alexandru, Nicoleta; Badila, Elisabeta; Weiss, Emma; Cochior, Daniel; Stępień, Ewa; Georgescu, Adriana

2016-03-25

The recognition of the importance of diabetes in vascular disease has greatly increased lately. Common risk factors for diabetes-related vascular disease include hyperglycemia, insulin resistance, dyslipidemia, inflammation, hypercoagulability, hypertension, and atherosclerosis. All of these factors contribute to the endothelial dysfunction which generates the diabetic complications, both macro and microvascular. Knowledge of diabetes-related vascular complications and of associated mechanisms it is becoming increasingly important for therapists. The discovery of microparticles (MPs) and their associated microRNAs (miRNAs) have opened new perspectives capturing the attention of basic and clinical scientists for their potential to become new therapeutic targets and clinical biomarkers. MPs known as submicron vesicles generated from membranes of apoptotic or activated cells into circulation have the ability to act as autocrine and paracrine effectors in cell-to-cell communication. They operate as biological vectors modulating the endothelial dysfunction, inflammation, coagulation, angiogenesis, thrombosis, subsequently contributing to the progression of macro and microvascular complications in diabetes. More recently, miRNAs have started to be actively investigated, leading to first exciting reports, which suggest their significant role in vascular physiology and disease. The contribution of MPs and also of their associated miRNAs to the development of vascular complications in diabetes was largely unexplored and undiscussed. In essence, with this review we bring light upon the understanding of impact diabetes has on vascular biology, and the significant role of MPs and MPs associated miRNAs as novel mediators, potential biomarkers and therapeutic targets in vascular complications in diabetes. Copyright © 2016 Elsevier Inc. All rights reserved.

Rac regulates vascular endothelial growth factor stimulated motility.

PubMed

Soga, N; Connolly, J O; Chellaiah, M; Kawamura, J; Hruska, K A

2001-01-01

During angiogenesis endothelial cells migrate towards a chemotactic stimulus. Understanding the mechanism of endothelial cell migration is critical to the therapeutic manipulation of angiogenesis and ultimately cancer prevention. Vascular endothelial growth factor (VEGF) is a potent chemotactic stimulus of endothelial cells during angiogenesis. The endothelial cell signal transduction pathway of VEGF represents a potential target for cancer therapy, but the mechanisms of post-receptor signal transduction including the roles of rho family GTPases in regulating the cytoskeletal effects of VEGF in endothelial cells are not understood. Here we analyze the mechanisms of cell migration in the mouse brain endothelial cell line (bEND3). Stable transfectants containing a tetracycline repressible expression vector were used to induce expression of Rac mutants. Endothelial cell haptotaxis was stimulated by constitutively active V12Rac on collagen and vitronectin coated supports, and chemotaxis was further stimulated by VEGF. Osteopontin coated supports were the most stimulatory to bEND3 haptotaxis, but VEGF was not effective in further increasing migration on osteopontin coated supports. Haptotaxis on support coated with collagen, vitronectin, and to a lesser degree osteopontin was inhibited by N17 Rac. N17 Rac expression blocked stimulation of endothelial cell chemotaxis by VEGF. As part of the chemotactic stimulation, VEGF caused a loss of actin organization at areas of cell-cell contact and increased stress fiber expression in endothelial cells which were directed towards pores in the transwell membrane. N17 Rac prevented the stimulation of cell-cell contact disruption and the stress fiber stimulation by VEGF. These data demonstrate two pathways of regulating endothelial cell motility, one in which Rac is activated by matrix/integrin stimulation and is a crucial modulator of endothelial cell haptotaxis. The other pathway, in the presence of osteopontin, is Rac independent

Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.

PubMed

Ollivier, V; Bentolila, S; Chabbat, J; Hakim, J; de Prost, D

1998-04-15

The transmembrane protein tissue factor (TF) is the cell surface receptor for coagulation factor VII (FVII) and activated factor VII (FVIIa). Recently, TF has been identified as a regulator of angiogenesis, tumor growth, and metastasis. This study was designed to link the binding of FVII(a) to its receptor, TF, with the subsequent triggering of angiogenesis through vascular endothelial growth factor (VEGF) production by human lung fibroblasts. We report that incubation of fibroblasts, which express constitutive surface TF, with FVII(a) induces VEGF synthesis. FVII(a)-induced VEGF secretion, assessed by a specific enzyme-linked immunosorbent assay, was time- and concentration-dependent. VEGF secretion was maximal after 24 hours of incubation of the cells with 100 nmol/L FVII(a) and represented a threefold induction of the basal VEGF level. Reverse transcriptase-polymerase chain reaction analysis of VEGF detected three mRNA species of 180, 312, and 384 bp corresponding, respectively, to VEGF121, VEGF165, and VEGF189. A 2.5- to 3.5-fold increase was observed for the 180- and 312-bp transcripts at 12 and 24 hours, respectively. FVII(a)-dependent VEGF production was inhibited by a pool of antibodies against TF, pointing to the involvement of this receptor. On specific active-site inhibition with dansyl-glutamyl-glycinyl-arginyl chloromethyl ketone, FVIIa lost 70% of its capacity to elicit VEGF production. Consistent with this, the native form (zymogen) of FVII only had a 1.8-fold stimulating effect. Protein tyrosine kinase and protein kinase C are involved in signal transduction leading to VEGF production, as shown by the inhibitory effects of genistein and GF 109203X. The results of this study indicate that TF is essential for VIIa-induced VEGF production by human fibroblasts and that its role is mainly linked to the proteolytic activity of the TF-VIIa complex.

Photonic Monitoring in Real-time of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Gene Expression Under Relaxin-induced Conditions in a Novel Murine Wound Model

USDA-ARS?s Scientific Manuscript database

Relaxin is known to promote vascular endotheilial growth factor (VEGF) expression in reproductive tissue and successful wound-healing is dependent upon good vascularization of wound sites, a process that relaxin may facilitate. Thus, the objective of this study was to evaluate the efficacy of relaxi...

Endothelial cell markers in vascular neoplasms: an immunohistochemical study comparing factor VIII-related antigen, blood group specific antigens, 6-keto-PGF1 alpha, and Ulex europaeus 1 lectin.

PubMed

Little, D; Said, J W; Siegel, R J; Fealy, M; Fishbein, M C

1986-06-01

Markers for endothelial cells including Ulex europaeus 1 lectin, blood group A, B, and H, and the prostaglandin metabolite 6-keto-PGF1 alpha were evaluated in paraffin secretions from formalin-fixed benign and malignant vascular neoplasms using a variety of immunohistochemical techniques, and results compared with staining for factor VIII-related antigen. Staining for Ulex appeared more sensitive than factor VIII-related antigen in identifying poorly differentiated neoplasms including haemangiosarcomas and spindle cell proliferations in Kaposi's sarcoma. Staining for blood group related antigens correlated with blood group in all cases. Ulex europaeus 1 lectin was the only marker for endothelial cells in lymphangiomas.

Biology of vascular malformations of the brain.

PubMed

Leblanc, Gabrielle G; Golanov, Eugene; Awad, Issam A; Young, William L

2009-12-01

This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia. Summary of Review- The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene. Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further

Vascular targets for cannabinoids: animal and human studies

PubMed Central

Stanley, Christopher; O'Sullivan, Saoirse E

2014-01-01

Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the result is vasorelaxation, although vasoconstrictor responses are also observed. Cannabinoids also modulate the actions of vasoactive compounds including acetylcholine, methoxamine, angiotensin II and U46619 (thromboxane mimetic). Numerous mechanisms of action have been proposed including receptor activation, potassium channel activation, calcium channel inhibition and the production of vasoactive mediators such as calcitonin gene-related peptide, prostanoids, NO, endothelial-derived hyperpolarizing factor and hydrogen peroxide. The purpose of this review is to examine the evidence for the range of receptors now known to be activated by cannabinoids. Direct activation by cannabinoids of CB1, CBe, TRPV1 (and potentially other TRP channels) and PPARs in the vasculature has been observed. A potential role for CB2, GPR55 and 5-HT1A has also been identified in some studies. Indirectly, activation of prostanoid receptors (TP, IP, EP1 and EP4) and the CGRP receptor is involved in the vascular responses to cannabinoids. The majority of this evidence has been obtained through animal research, but recent work has confirmed some of these targets in human arteries. Vascular responses to cannabinoids are enhanced in hypertension and cirrhosis, but are reduced in obesity and diabetes, both due to changes in the target sites of action. Much further work is required to establish the extent of vascular actions of cannabinoids and the application of this research in physiological and pathophysiological situations. Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6 PMID:24329566

Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity.

PubMed

Palmer, Kirsten R; Kaitu'u-Lino, Tu'uhevaha J; Hastie, Roxanne; Hannan, Natalie J; Ye, Louie; Binder, Natalie; Cannon, Ping; Tuohey, Laura; Johns, Terrance G; Shub, Alexis; Tong, Stephen

2015-12-01

In preeclampsia, the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) is released from placenta into the maternal circulation, causing endothelial dysfunction and organ injury. A recently described splice variant, sFLT-1 e15a, is primate specific and the most abundant placentally derived sFLT-1. Therefore, it may be the major sFLT-1 isoform contributing to the pathophysiology of preeclampsia. sFLT-1 e15a protein remains poorly characterized: its bioactivity has not been comprehensively examined, and serum levels in normal and preeclamptic pregnancy have not been reported. We generated and validated an sFLT-1 e15a-specific ELISA to further characterize serum levels during pregnancy, and in the presence of preeclampsia. Furthermore, we performed assays to examine the bioactivity and antiangiogenic properties of sFLT-1 e15a protein. sFLT-1 e15a was expressed in the syncytiotrophoblast, and serum levels rose across pregnancy. Strikingly, serum levels were increased 10-fold in preterm preeclampsia compared with normotensive controls. We confirmed sFLT-1 e15a is bioactive and is able to inhibit vascular endothelial growth factor signaling of vascular endothelial growth factor receptor 2 and block downstream Akt phosphorylation. Furthermore, sFLT-1 e15a has antiangiogenic properties. sFLT-1 e15a decreased endothelial cell migration, invasion, and inhibited endothelial cell tube formation. Administering sFLT-1 e15a blocked vascular endothelial growth factor induced sprouts from mouse aortic rings ex vivo. We have demonstrated that sFLT-1 e15a is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Future development of diagnostics and therapeutics for preeclampsia should consider targeting placentally derived sFLT-1 e15a. © 2015 American Heart Association, Inc.

Cocoa, Blood Pressure, and Vascular Function

PubMed Central

Ludovici, Valeria; Barthelmes, Jens; Nägele, Matthias P.; Enseleit, Frank; Ferri, Claudio; Flammer, Andreas J.; Ruschitzka, Frank; Sudano, Isabella

2017-01-01

Cardiovascular disease (CVD) represents the most common cause of death worldwide. The consumption of natural polyphenol-rich foods, and cocoa in particular, has been related to a reduced risk of CVD, including coronary heart disease and stroke. Intervention studies strongly suggest that cocoa exerts a beneficial impact on cardiovascular health, through the reduction of blood pressure (BP), improvement of vascular function, modulation of lipid and glucose metabolism, and reduction of platelet aggregation. These potentially beneficial effects have been shown in healthy subjects as well as in patients with risk factors (arterial hypertension, diabetes, and smoking) or established CVD (coronary heart disease or heart failure). Several potential mechanisms are supposed to be responsible for the positive effect of cocoa; among them activation of nitric oxide (NO) synthase, increased bioavailability of NO as well as antioxidant, and anti-inflammatory properties. It is the aim of this review to summarize the findings of cocoa and chocolate on BP and vascular function. PMID:28824916

Vascular oxidative stress: a key factor in the development of hypertension associated with ethanol consumption.

PubMed

Ceron, Carla S; Marchi, Katia C; Muniz, Jaqueline J; Tirapelli, Carlos R

2014-01-01

The observation that the excessive consumption of ethyl alcohol (ethanol) is associated with high blood pressure is nearing its centennial mark. Mechanisms linking ethanol consumption and hypertension are complex and not fully understood. It is established that chronic ethanol consumption leads to hypertension and that this process is a multimediated event involving increased sympathetic activity, stimulation of the renin-angiotensin-aldosterone system with a subsequent increase in vascular oxidative stress and endothelial dysfunction. Under physiological conditions, reactive oxygen species (ROS) play an important role as a signaling molecule in the control of vascular tone and endothelial function. Increased ROS bioavailability is associated with important processes underlying vascular injury in cardiovascular disease such as endothelial dysfunction, vascular remodeling, and inflammation. Studies focusing on molecular mechanisms showed a link between overproduction of ROS in the vasculature and ethanol-induced hypertension. Of the ROS generated in vascular cells, superoxide anion (O2(-)) and hydrogen peroxide (H2O2) appear to be especially important. Ethanol-mediated generation of O2(-) and H2O2 in vascular tissues is associated with elevations in intracellular calcium ([Ca(2+)]i), reduced nitric oxide (NO) bioavailability, endothelial dysfunction and vasoconstriction. O2(-) can also act as a vascular signaling molecule regulating signaling pathways that lead to vascular contraction. Thus, through increased generation of ROS and activation of redox-sensitive pathways, ethanol induces vascular dysfunction, a response that might contribute to the hypertension associated with ethanol consumption. The present article reviews the role of ROS in vascular (patho)biology of ethanol.

The role of vascular endothelial growth factor-B in metabolic homoeostasis: current evidence.

PubMed

Zafar, Mohammad Ishraq; Zheng, Juan; Kong, Wen; Ye, Xiaofeng; Gou, Luoning; Regmi, Anita; Chen, Lu-Lu

2017-08-31

It has been shown that adipose tissue and skeletal muscles in lean individuals respond to meal-induced hyperinsulinemia by increase in perfusion, the effect not observed in patients with metabolic syndrome. In conditions of hyperglycaemia and hypertriglyceridemia, this insufficient vascularization leads to the liberation of reactive oxygen species (ROS), and disruption of nitric oxide (NO) synthesis and endothelial signalling responsible for the uptake of circulating fatty acids (FAs), whose accumulation in skeletal muscles and adipose tissue is widely associated with the impairment of insulin signalling. While the angiogenic role of VEGF-A and its increased circulating concentrations in obesity have been widely confirmed, the data related to the metabolic role of VEGF-B are diverse. However, recent discoveries indicate that this growth factor may be a promising therapeutic agent in patients with metabolic syndrome. Preclinical studies agree over two crucial metabolic effects of VEGF-B: (i) regulation of FAs uptake and (ii) regulation of tissue perfusion via activation of VEGF-A/vascular endothelial growth factor receptor (VEGFR) 2 (VEGFR2) pathway. While in some preclinical high-fat diet studies, VEGF-B overexpression reverted glucose intolerance and stimulated fat burning, in others it further promoted accumulation of lipids and lipotoxicity. Data from clinical studies point out the changes in circulating or tissue expression levels of VEGF-B in obese compared with lean patients. Potentially beneficial effects of VEGF-B, achieved through enhanced blood flow (increased availability of insulin and glucose uptake in target organs) and decreased FAs uptake (prevention of lipotoxicity and improved insulin signalling), and its safety for clinical use, remain to be clarified through future translational research. © 2017 The Author(s).

The effects of a lupin-enriched diet on oxidative stress and factors influencing vascular function in overweight subjects.

PubMed

Yang, Xingbin; Croft, Kevin D; Lee, Ya P; Mori, Trevor A; Puddey, Ian B; Sipsas, Sofia; Barden, Anne; Swinny, Ewald; Hodgson, Jonathan M

2010-11-15

A diet enriched in lupin kernel flour can lower blood pressure, but mechanisms responsible are unclear. Lupin is a source of polyphenols, protein, and L-arginine, factors that may influence blood pressure via effects on oxidative stress and vascular function. Therefore, we aimed to determine the effects of a lupin-enriched diet on oxidative stress and factors influencing vascular function as potential mechanisms for demonstrated benefits on blood pressure. Overweight men and women (n = 88) were recruited to a 16-week parallel-design study. Participants were randomly assigned to replace 15%-20% of their usual daily energy intake with white bread (control) or lupin kernel flour-enriched bread (lupin). All measurements were taken at baseline and 16 weeks. At baseline, plasma F₂-isoprostanes and 20-hydroxyeicosatetraenoic acid (20-HETE) were positively associated with blood pressure, and plasma nitrite was negatively associated with blood pressure (p < 0.05). For lupin relative to control, the estimated differences in plasma F₂-isoprostanes (45 pmol/L; 95%CI: -68, 158), urinary F₂-isoprostanes (17 pmol/mmol creatinine; 95%CI: -43, 76), plasma 20-HETE (75 pmol/L; 95%CI: -91, 241), and plasma nitrite (-0.3 μmol/L; 95%CI: -1.1, 0.4) were not significant. Although regular consumption of lupin-enriched bread can lower blood pressure, these results do not support for the hypothesis that this is via effects on oxidative stress or vascular function.

Cell sheet engineering using the stromal vascular fraction of adipose tissue as a vascularization strategy.

PubMed

Costa, Marina; Cerqueira, Mariana T; Santos, Tírcia C; Sampaio-Marques, Belém; Ludovico, Paula; Marques, Alexandra P; Pirraco, Rogério P; Reis, Rui L

2017-06-01

Current vascularization strategies for Tissue Engineering constructs, in particular cell sheet-based, are limited by time-consuming and expensive endothelial cell isolation and/or by the complexity of using extrinsic growth factors. Herein, we propose an alternative strategy using angiogenic cell sheets (CS) obtained from the stromal vascular fraction (SVF) of adipose tissue that can be incorporated into more complex constructs. Cells from the SVF were cultured in normoxic and hypoxic conditions for up to 8days in the absence of extrinsic growth factors. Immunocytochemistry against CD31 and CD146 revealed spontaneous organization in capillary-like structures, more complex after hypoxic conditioning. Inhibition of HIF-1α pathway hindered capillary-like structure formation in SVF cells cultured in hypoxia, suggesting a role of HIF-1α. Moreover, hypoxic SVF cells showed a trend for increased secretion of angiogenic factors, which was reflected in increased network formation by endothelial cells cultured on matrigel using that conditioned medium. In vivo implantation of SVF CS in a mouse hind limb ischemia model revealed that hypoxia-conditioned CS led to improved restoration of blood flow. Both in vitro and in vivo data suggest that SVF CS can be used as simple and cost-efficient tools to promote functional vascularization of TE constructs. Neovascularization after implantation is a major obstacle for producing clinically viable cell sheet-based tissue engineered constructs. Strategies using endothelial cells and extrinsic angiogenic growth factors are expensive and time consuming and may raise concerns of tumorigenicity. In this manuscript, we describe a simplified approach using angiogenic cell sheets fabricated from the stromal vascular fraction of adipose tissue. The strong angiogenic behavior of these cell sheets, achieved without the use of external growth factors, was further stimulated by low oxygen culture. When implanted in an in vivo model of hind limb

Regulation of thrombosis and vascular function by protein methionine oxidation

PubMed Central

Gu, Sean X.; Stevens, Jeff W.

2015-01-01

Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis. PMID:25900980

Regulation of thrombosis and vascular function by protein methionine oxidation.

PubMed

Gu, Sean X; Stevens, Jeff W; Lentz, Steven R

2015-06-18

Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis. © 2015 by The American Society of Hematology.

Urticarial Reactions: Vascular Erythema, Urticaria, Vasculitis

PubMed Central

Sibbald, R. Gary

1987-01-01

Vascular erythemas, including urticaria and vasculitis, represent diagnostic and therapeutic challenges. A careful systemic approach to history and physical examination should be followed by appropriate investigations to rule out systemic disease. Chronic urticaria patients should be physically tested to identify cholinergic, dermagraphic, and cold-induced responses. Food diaries and careful drug history may be important to identify exacerbating factors in chronic urticaria. A skin biopsy is necessary to diagnose vasculitis. Therapy of any underlying cause is supplemented with H1 antihistamines in urticaria patients, while vasculitis requires a different anti-inflammatory approach. PMID:21263956

CD13 as target for tissue factor induced tumor vascular infarction in small cell lung cancer.

PubMed

Schmidt, Lars Henning; Stucke-Ring, Janine; Brand, Caroline; Schliemann, Christoph; Harrach, Saliha; Muley, Thomas; Herpel, Esther; Kessler, Torsten; Mohr, Michael; Görlich, Dennis; Kreuter, Michael; Lenz, Georg; Wardelmann, Eva; Thomas, Michael; Berdel, Wolfgang E; Schwöppe, Christian; Hartmann, Wolfgang

2017-11-01

Zinc-binding protease aminopeptidase N (CD13) is expressed on tumor vascular cells and tumor cells. It represents a potential candidate for molecular targeted therapy, e.g. employing truncated tissue factor (tTF)-NGR, which can bind CD13 and thereby induce tumor vascular infarction. We performed a comprehensive analysis of CD13 expression in a clinically well characterized cohort of patients with small cell lung cancer (SCLC) to evaluate its potential use for targeted therapies in this disease. CD13 expression was analyzed immunohistochemically in 27 SCLC patients and correlated with clinical course and outcome. In CD-1 nude mice bearing human HTB119 SCLC xenotransplants, the systemic effects of the CD13-targeting fusion protein tTF-NGR on tumor growth were tested. In 52% of the investigated SCLC tissue samples, CD13 was expressed in tumor stroma cells, while the tumor cells were negative for CD13. No prognostic effect was found in the investigated SCLC study collective with regard to overall survival (p>0.05). In CD-1 nude mice, xenografts of CD13 negative HTB119 SCLC cells showed CD13 expression in the intratumoral vascular and perivascular cells, and the systemic application of CD13-targeted tissue factor tTF-NGR led to a significant reduction of tumor growth. We here present first data on the expression of CD13 in SCLC tumor samples. Our results strongly recommend the further investigation of tTF-NGR and other molecules targeted by NGR-peptides in SCLC patients. Considering the differential expression of CD13 in SCLC samples pre-therapeutic CD13 analysis is proposed for testing as investigational predictive biomarker for patient selection. Copyright © 2017 Elsevier B.V. All rights reserved.

Vascular endothelial growth factor-C enhances radiosensitivity of lymphatic endothelial cells

PubMed Central

Kesler, Cristina T.; Kuo, Angera; Wong, Hon-Kit; Masuck, David J.; Shah, Jennifer L.; Kozak, Kevin; Held, Kathryn D.; Padera, Timothy P.

2013-01-01

Radiation therapy after lymph node dissection increases the risk of developing painful and incurable lymphedema in breast cancer patients. Lymphedema occurs when lymphatic vessels become unable to maintain proper fluid balance. The sensitivity of lymphatic endothelial cells (LECs) to ionizing radiation has not been reported to date. Here, the radiosensitivity of LECs in vitro has been determined using clonogenic survival assays. The ability of various growth factors to alter LEC radiosensitivity was also examined. Vascular endothelial growth factor (VEGF)-C enhanced radiosensitivity when LECs were treated prior to radiation. VEGF-C-treated LECs exhibited higher levels of entry into the cell cycle at the time of radiation, with a greater number of cells in the S and G2/M phases. These LECs showed higher levels of H2A.X—an indicator of DNA damage—after radiation. VEGF-C did not increase cell death as a result of radiation. Instead, it increased the relative number of quiescent LECs. These data suggest that abundant VEGF-C or lymphangiogenesis may predispose patients to radiation-induced lymphedema by impairing lymphatic vessel repair through induction of LEC quiescence. PMID:24201897

Effect of Intravitreal Bevacizumab on Vascular Endothelial Growth Factor Expression in Patients with Proliferative Diabetic Retinopathy

PubMed Central

Chung, Eun Jee; Kang, Shin Jeong; Koo, Ja Seung; Choi, Yoon Jung; Grossniklaus, Hans E.

2011-01-01

Purpose To investigate the effect of bevacizumab (Avastin; Genentech, San Francisco, CA, USA) on vascular endothelial growth factor (VEGF) expression and inflammation in fibrovascular membranes in patients with proliferative diabetic retinopathy (PDR). Materials and Methods Fibrovascular membranes from 19 eyes of 18 patients with PDR were studied using immunohistochemistry and analyzed in the following 3 groups; group 1: 4 inactive PDR eyes, group 2: 10 active PDR eyes treated preoperatively with adjunctive intravitreal bevacizumab, group 3: five active PDR eyes not treated preoperatively with bevacizumab. Immunohistochemical staining for VEGF, CD31 and CD68 were done. Results The immunoreactivity to VEGF and CD 31-positive blood vessels was significantly higher in membranes from group 3 than group 1 (p = 0.007 for VEGF, 0.013 for CD 31-positive vessels). Intravitreal bevacizumab caused a reduction in VEGF expression and vascular densities in 4 out of 10 (40%) excised membranes from eyes with PDR. However, six membranes (60%) in group 2 still demonstrated relatively strong VEGF expression and high vascular density. Infiltration of macrophages was observed in 16 out of the 19 membranes, and the density of macrophages was increased in group 2 compared with group 1 (p = 0.043). Conclusion Intravitreal bevacizumab injections caused some reduction in VEGF expression and vascular densities in a limited number of active PDR patients. A single intravitreal bevacizumab injection may not be enough to induce complete blockage of VEGF and pathologic neovascularization in active PDR patients. Repeated injections, panretinal photocoagulation and/or PPV may be necessary following intravitreal bevacizumab to reinforce the anti-VEGF effect of the drug. PMID:21155048

Continuous exposure to low amplitude extremely low frequency electrical fields characterizing the vascular streaming potential alters elastin accumulation in vascular smooth muscle cells.

PubMed

Bergethon, Peter R; Kindler, Dean D; Hallock, Kevin; Blease, Susan; Toselli, Paul

2013-07-01

In normal development and pathology, the vascular system depends on complex interactions between cellular elements, biochemical molecules, and physical forces. The electrokinetic vascular streaming potential (EVSP) is an endogenous extremely low frequency (ELF) electrical field resulting from blood flowing past the vessel wall. While generally unrecognized, it is a ubiquitous electrical biophysical force to which the vascular tree is exposed. Extracellular matrix elastin plays a central role in normal blood vessel function and in the development of atherosclerosis. It was hypothesized that ELF fields of low amplitude would alter elastin accumulation, supporting a link between the EVSP and the biology of vascular smooth muscle cells. Neonatal rat aortic smooth muscle cell cultures were exposed chronically to electrical fields characteristic of the EVSP. Extracellular protein accumulation, DNA content, and electron microscopic (EM) evaluation were performed after 2 weeks of exposure. Stimulated cultures showed no significant change in cellular proliferation as measured by the DNA concentration. The per-DNA normalized protein in the extracellular matrix was unchanged while extracellular elastin accumulation decreased 38% on average. EM analysis showed that the stimulated cells had a 2.85-fold increase in mitochondrial number. These results support the formulation that ELF fields are a potential factor in both normal vessel biology and in the pathogenesis of atherosclerotic diseases including heart disease, stroke, and peripheral vascular disease. Copyright © 2013 Wiley Periodicals, Inc.

NADPH Oxidases in Vascular Pathology

PubMed Central

Konior, Anna; Schramm, Agata; Czesnikiewicz-Guzik, Marta

2014-01-01

Abstract Significance: Reactive oxygen species (ROS) play a critical role in vascular disease. While there are many possible sources of ROS, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases play a central role. They are a source of “kindling radicals,” which affect other enzymes, such as nitric oxide synthase endothelial nitric oxide synthase or xanthine oxidase. This is important, as risk factors for atherosclerosis (hypertension, diabetes, hypercholesterolemia, and smoking) regulate the expression and activity of NADPH oxidases in the vessel wall. Recent Advances: There are seven isoforms in mammals: Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2. Nox1, Nox2, Nox4, and Nox5 are expressed in endothelium, vascular smooth muscle cells, fibroblasts, or perivascular adipocytes. Other homologues have not been found or are expressed at very low levels; their roles have not been established. Nox1/Nox2 promote the development of endothelial dysfunction, hypertension, and inflammation. Nox4 may have a role in protecting the vasculature during stress; however, when its activity is increased, it may be detrimental. Calcium-dependent Nox5 has been implicated in oxidative damage in human atherosclerosis. Critical Issues: NADPH oxidase-derived ROS play a role in vascular pathology as well as in the maintenance of normal physiological vascular function. We also discuss recently elucidated mechanisms such as the role of NADPH oxidases in vascular protection, vascular inflammation, pulmonary hypertension, tumor angiogenesis, and central nervous system regulation of vascular function and hypertension. Future Directions: Understanding the role of individual oxidases and interactions between homologues in vascular disease is critical for efficient pharmacological regulation of vascular NADPH oxidases in both the laboratory and clinical practice. Antioxid. Redox Signal. 20, 2794–2814. PMID:24180474

Computational analysis of integrated biosensing and shear flow in a microfluidic vascular model

NASA Astrophysics Data System (ADS)

Wong, Jeremy F.; Young, Edmond W. K.; Simmons, Craig A.

2017-11-01

Fluid flow and flow-induced shear stress are critical components of the vascular microenvironment commonly studied using microfluidic cell culture models. Microfluidic vascular models mimicking the physiological microenvironment also offer great potential for incorporating on-chip biomolecular detection. In spite of this potential, however, there are few examples of such functionality. Detection of biomolecules released by cells under flow-induced shear stress is a significant challenge due to severe sample dilution caused by the fluid flow used to generate the shear stress, frequently to the extent where the analyte is no longer detectable. In this work, we developed a computational model of a vascular microfluidic cell culture model that integrates physiological shear flow and on-chip monitoring of cell-secreted factors. Applicable to multilayer device configurations, the computational model was applied to a bilayer configuration, which has been used in numerous cell culture applications including vascular models. Guidelines were established that allow cells to be subjected to a wide range of physiological shear stress while ensuring optimal rapid transport of analyte to the biosensor surface and minimized biosensor response times. These guidelines therefore enable the development of microfluidic vascular models that integrate cell-secreted factor detection while addressing flow constraints imposed by physiological shear stress. Ultimately, this work will result in the addition of valuable functionality to microfluidic cell culture models that further fulfill their potential as labs-on-chips.

Age differences in arterial and venous extra-cerebral blood flow in healthy adults: contributions of vascular risk factors and genetic variants.

PubMed

Raz, Naftali; Daugherty, Ana M; Sethi, Sean K; Arshad, Muzamil; Haacke, E Mark

2017-08-01

Sufficient cerebral blood flow (CBF) and venous drainage are critical for normal brain function, and their alterations can affect brain aging. However, to date, most studies focused on arterial CBF (inflow) with little attention paid to the age differences in venous outflow. We measured extra-cerebral arterial and venous blood flow rates with phase-contrast MRI and assessed the influence of vascular risk factors and genetic polymorphisms (ACE insertion/deletion, COMT val158met, and APOEε4) in 73 adults (age 18-74 years). Advanced age, elevated vascular risk, ACE Deletion, and COMT met alleles were linked to lower in- and outflow, with no effects of APOE ε4 noted. Lower age-related CBF rate was unrelated to brain volume and was observed only in val homozygotes of COMTval158met. Thus, in a disease-free population, age differences in CBF may be notable only in persons with high vascular risk and carriers of genetic variants associated with vasoconstriction and lower dopamine availability. It remains to be established if treatments targeting alleviation of the mutable factors can improve the course of cerebrovascular aging in spite of the immutable genetic influence.

UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes.

PubMed

Adler, Amanda I; Stevens, Richard J; Neil, Andrew; Stratton, Irene M; Boulton, Andrew J M; Holman, Rury R

2002-05-01

To determine the role of hyperglycemia in prospective analyses of peripheral vascular disease (PVD) in type 2 diabetes, taking into account other potential risk factors. Potential risk factors for the development of PVD were examined in 3,834 of 5,102 individuals enrolled in the U.K. Prospective Diabetes Study (UKPDS) without PVD at diagnosis of diabetes, followed for 6 years, and for whom relevant data were available. PVD was defined as two of the following: ankle-arm blood pressure index < 0.8, absence of both dorsalis pedis and posterior tibial pulses to palpation in one or both legs, and intermittent claudication. Logistic regression was used to estimate the association between potential risk factors measured 3-4 months after diagnosis of diabetes and incident PVD. The prevalence of PVD at 3-year intervals to 18 years was determined. Hyperglycemia, assessed as HbA(1c), was associated with an increased risk for incident PVD, independent of other risk factors including age, increased systolic blood pressure, reduced HDL cholesterol, smoking, prior cardiovascular disease, peripheral sensory neuropathy, and retinopathy. Each 1% increase in HbA(1c) was associated with a 28% increased risk of PVD (95% CI 12-46), and each 10-mmHg increase in systolic blood pressure with a 25% increase in risk (95% CI 10-43). Hyperglycemia, as well as smoking, dyslipidemia, and blood pressure are potentially modifiable risk factors for the development of PVD.

Engineering the mechanical and biological properties of nanofibrous vascular grafts for in situ vascular tissue engineering.

PubMed

Henry, Jeffrey J D; Yu, Jian; Wang, Aijun; Lee, Randall; Fang, Jun; Li, Song

2017-08-17

Synthetic small diameter vascular grafts have a high failure rate, and endothelialization is critical for preventing thrombosis and graft occlusion. A promising approach is in situ tissue engineering, whereby an acellular scaffold is implanted and provides stimulatory cues to guide the in situ remodeling into a functional blood vessel. An ideal scaffold should have sufficient binding sites for biomolecule immobilization and a mechanical property similar to native tissue. Here we developed a novel method to blend low molecular weight (LMW) elastic polymer during electrospinning process to increase conjugation sites and to improve the mechanical property of vascular grafts. LMW elastic polymer improved the elasticity of the scaffolds, and significantly increased the amount of heparin conjugated to the micro/nanofibrous scaffolds, which in turn increased the loading capacity of vascular endothelial growth factor (VEGF) and prolonged the release of VEGF. Vascular grafts were implanted into the carotid artery of rats to evaluate the in vivo performance. VEGF treatment significantly enhanced endothelium formation and the overall patency of vascular grafts. Heparin coating also increased cell infiltration into the electrospun grafts, thus increasing the production of collagen and elastin within the graft wall. This work demonstrates that LMW elastic polymer blending is an approach to engineer the mechanical and biological property of micro/nanofibrous vascular grafts for in situ vascular tissue engineering.

Increased expression of high mobility group box protein 1 and vascular endothelial growth factor in placenta previa.

PubMed

Xie, Han; Qiao, Ping; Lu, Yi; Li, Ying; Tang, Yuping; Huang, Yiying; Bao, Yirong; Ying, Hao

2017-12-01

Placenta previa is often associated with preterm delivery, reduced birth weight, a higher frequency of placental accreta and postpartum haemorrhage, and increased likelihood of blood transfusion. The present study aimed to examine the expression of high mobility group box protein 1 (HMGB1) in the placenta of women with or without placenta previa. The study group consisted of placental tissues obtained from women with or without placenta previa. The expression levels of HMGB1 and vascular endothelial growth factor (VEGF) were evaluated in the placental tissues using reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry. The mRNA expression levels of HMGB1 and VEGF were significantly increased in the placenta previa group compared with in the normal group. In addition, the placenta previa group exhibited increased HMGB1 and VEGF staining in vascular endothelial cells and trophoblasts. There were no significant differences in the expression of HMGB1 or VEGF between groups with or without placenta accreta or postpartum haemorrhage. The present study hypothesised that the increased expression of HMGB1 in the placenta may be associated with the pathogenesis of placenta previa by regulating the expression of the proangiogenic factor VEGF.

Association of vascular risk factors with cervical artery dissection and ischemic stroke in young adults.

PubMed

Debette, Stéphanie; Metso, Tiina; Pezzini, Alessandro; Abboud, Shérine; Metso, Antti; Leys, Didier; Bersano, Anna; Louillet, Fabien; Caso, Valeria; Lamy, Chantal; Medeiros, Elisabeth; Samson, Yves; Grond-Ginsbach, Caspar; Engelter, Stefan T; Thijs, Vincent; Beretta, Simone; Béjot, Yannick; Sessa, Maria; Lorenza Muiesan, Maria; Amouyel, Philippe; Castellano, Maurizio; Arveiler, Dominique; Tatlisumak, Turgut; Dallongeville, Jean

2011-04-12

Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. The study sample comprised 690 CEAD patients (mean age, 44.2 ± 9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7 ± 10.5 years; 39.9% women), and 1170 referents (45.9 ± 8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index ≥ 30 kg/m²) or overweightness (body mass index ≥ 25 kg/m² and <30 kg/m²) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; P<0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; P<0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; P=0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; P<0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents. These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD.

Collagen-binding vascular endothelial growth factor attenuates CCl4-induced liver fibrosis in mice

PubMed Central

Wu, Kangkang; Huang, Rui; Wu, Hongyan; Liu, Yong; Yang, Chenchen; Cao, Shufeng; Hou, Xianglin; Chen, Bing; Dai, Jianwu; Wu, Chao

2016-01-01

Vascular endothelial growth factor (VEGF) serves an important role in promoting angiogenesis and tissue regeneration. However, the lack of an effective delivery system that can target this growth factor to the injured site reduces its therapeutic efficacy. Therefore, in the current study, collagen-binding VEGF was constructed by fusing a collagen-binding domain (CBD) to the N-terminal of native VEGF. The CBD-VEGF can specifically bind to collagen which is the major component of the extracellular matrix in fibrotic liver. The anti-fibrotic effects of this novel material were investigated by the carbon tetrachloride (CCl4)-induced liver fibrotic mouse model. Mice were injected with CCl4 intraperitoneally to induce liver fibrosis. CBD-VEGF was injected directly into the liver tissue of mice. The liver tissues were stained with hematoxylin and eosin for general observation or with Masson's trichrome staining for detection of collagen deposition. The hepatic stellate cell activation, blood vessel formation and hepatocyte proliferation were measured by immunohistochemical staining for α-smooth muscle actin, CD31 and Ki67 in the liver tissue. The fluorescent TUNEL assay was performed to evaluate the hepatocyte apoptosis. The present study identified that the CBD-VEGF injection could significantly promote vascularization of the liver tissue of fibrotic mice and attenuate liver fibrosis. Furthermore, hepatocyte apoptosis and hepatic stellate cell activation were attenuated by CBD-VEGF treatment. CBD-VEGF treatment could additionally promote hepatocyte regeneration in the liver tissue of fibrotic mice. Thus, it was suggested that CBD-VEGF may be used as a novel therapeutic intervention for liver fibrosis. PMID:27748931

Mechanical stretch augments insulin-induced vascular smooth muscle cell proliferation by insulin-like growth factor-1 receptor

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

Liu, Gang; Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang; Hitomi, Hirofumi, E-mail: hitomi@kms.ac.jp

Insulin resistance and hypertension have been implicated in the pathogenesis of cardiovascular disease; however, little is known about the roles of insulin and mechanical force in vascular smooth muscle cell (VSMC) remodeling. We investigated the contribution of mechanical stretch to insulin-induced VSMC proliferation. Thymidine incorporation was stimulated by insulin in stretched VSMCs, but not in un-stretched VSMCs. Insulin increased 2-deoxy-glucose incorporation in both stretched and un-stretched VSMCs. Mechanical stretch augmented insulin-induced extracellular signal-regulated kinase (ERK) and Akt phosphorylation. Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinase and Src attenuated insulin-induced ERK and Akt phosphorylation, as well as thymidine incorporation,more » whereas 2-deoxy-glucose incorporation was not affected by these inhibitors. Moreover, stretch augmented insulin-like growth factor (IGF)-1 receptor expression, although it did not alter the expression of insulin receptor and insulin receptor substrate-1. Insulin-induced ERK and Akt activation, and thymidine incorporation were inhibited by siRNA for the IGF-1 receptor. Mechanical stretch augments insulin-induced VSMC proliferation via upregulation of IGF-1 receptor, and downstream Src/EGF receptor-mediated ERK and Akt activation. Similar to in vitro experiment, IGF-1 receptor expression was also augmented in hypertensive rats. These results provide a basis for clarifying the molecular mechanisms of vascular remodeling in hypertensive patients with hyperinsulinemia. -- Highlights: {yields} Mechanical stretch augments insulin-induced VSMC proliferation via IGF-1 receptor. {yields} Src/EGFR-mediated ERK and Akt phosphorylation are augmented in stretched VSMCs. {yields} Similar to in vitro experiment, IGF-1 receptor is increased in hypertensive rats. {yields} Results provide possible mechanisms of vascular remodeling in hypertension with DM.« less

Vascular delay and administration of basic fibroblast growth factor augment latissimus dorsi muscle flap perfusion and function.

PubMed

Carroll, S M; Carroll, C M; Stremel, R W; Heilman, S J; Steffen, J M; Tobin, G R; Barker, J H

2000-03-01

Ischemia of the distal latissimus dorsi muscle flap occurs when the entire muscle is acutely elevated. Although this level of ischemia may not be critical if the muscle is to be used as a conventional muscle flap, the ischemia causes decreased distal muscle function if it is used for dynamic muscle flap transfer. This experiment was designed to determine whether or not the administration of exogenous basic fibroblast growth factor (bFGF), combined with a sublethal ischemic insult (i.e., vascular delay), would further augment muscle perfusion and function. Both latissimus dorsi muscles of nine canines were subjected to a bipedicle vascular delay procedure immediately followed by thoracodorsal intraarterial injection of 100 microg of bFGF on one side and by intraarterial injection of vehicle on the other. Ten days later, both latissimus dorsi muscles were raised as thoracodorsally based island flaps, with perfusion determined by laser-Doppler fluximetry. The muscles were wrapped around silicone chambers, simulating cardiomyoplasty, and stimulating electrodes were placed around each thoracodorsal nerve. The muscles were then subjected to an experimental protocol to determine muscle contractile function. At the end of the experiment, latissimus dorsi muscle biopsies were obtained for measurement of bFGF expression. The results demonstrated that the administration of 100 microg of bFGF immediately after the vascular delay procedure increases expression of native bFGF. In the distal and middle muscle segments, it also significantly increased muscle perfusion by approximately 20 percent and fatigue resistance by approximately 300 percent. The administration of growth factors may serve as an important adjuvant to surgical procedures using dynamic muscle flap transfers.

Vascular anomalies: classification, imaging characteristics and implications for interventional radiology treatment approaches

PubMed Central

Prajapati, H J S; Martin, L G; Patel, T H

2014-01-01

The term vascular anomaly represents a broad spectrum of vascular pathology, including proliferating vascular tumours and vascular malformations. While the treatment of most vascular anomalies is multifactorial, interventional radiology procedures, including embolic therapy, sclerotherapy and laser coagulation among others, are playing an increasingly important role in vascular anomaly management. This review discusses the diagnosis and treatment of common vascular malformations, with emphasis on the technique, efficacy and complications of different interventional radiology procedures. PMID:24588666

Vascular endothelial growth factor modified macrophages transdifferentiate into endothelial-like cells and decrease foam cell formation.

PubMed

Yan, Dan; He, Yujuan; Dai, Jun; Yang, Lili; Wang, Xiaoyan; Ruan, Qiurong

2017-06-30

Macrophages are largely involved in the whole process of atherosclerosis from an initiation lesion to an advanced lesion. Endothelial disruption is the initial step and macrophage-derived foam cells are the hallmark of atherosclerosis. Promotion of vascular integrity and inhibition of foam cell formation are two important strategies for preventing atherosclerosis. How can we inhibit even the reverse negative role of macrophages in atherosclerosis? The present study was performed to investigate if overexpressing endogenous human vascular endothelial growth factor (VEGF) could facilitate transdifferentiation of macrophages into endothelial-like cells (ELCs) and inhibit foam cell formation. We demonstrated that VEGF-modified macrophages which stably overexpressed human VEGF (hVEGF 165 ) displayed a high capability to alter their phenotype and function into ELCs in vitro Exogenous VEGF could not replace endogenous VEGF to induce the transdifferentiation of macrophages into ELCs in vitro We further showed that VEGF-modified macrophages significantly decreased cytoplasmic lipid accumulation after treatment with oxidized LDL (ox-LDL). Moreover, down-regulation of CD36 expression in these cells was probably one of the mechanisms of reduction in foam cell formation. Our results provided the in vitro proof of VEGF-modified macrophages as atheroprotective therapeutic cells by both promotion of vascular repair and inhibition of foam cell formation. © 2017 The Author(s).

Tissue Engineering Strategies for Promoting Vascularized Bone Regeneration

PubMed Central

Almubarak, Sarah; Nethercott, Hubert; Freeberg, Marie; Beaudon, Caroline; Jha, Amit; Jackson, Wesley; Marcucio, Ralph; Miclau, Theodore; Healy, Kevin; Bahney, Chelsea

2016-01-01

This review focuses on current tissue engineering strategies for promoting vascularized bone regeneration. We review the role of angiogenic growth factors in promoting vascularized bone regeneration and discuss the different therapeutic strategies for controlled/sustained growth factor delivery. Next, we address the therapeutic uses of stem cells in vascularized bone regeneration. Specifically, this review addresses the concept of co-culture using osteogenic and vasculogenic stem cells, and how adipose derived stem cells compare to bone marrow derived mesenchymal stem cells in the promotion of angiogenesis. We conclude this review with a discussion of a novel approach to bone regeneration through a cartilage intermediate, and discuss why it has the potential to be more effective than traditional bone grafting methods. PMID:26608518

Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo.

PubMed

Proulx, Steven T; Luciani, Paola; Alitalo, Annamari; Mumprecht, Viviane; Christiansen, Ailsa J; Huggenberger, Reto; Leroux, Jean-Christophe; Detmar, Michael

2013-07-01

Preclinical vascular research has been hindered by a lack of methods that can sensitively image and quantify vascular perfusion and leakage in vivo. In this study, we have developed dynamic near-infrared imaging methods to repeatedly visualize and quantify vascular leakage in mouse skin in vivo, and we have applied these methods to transgenic mice with overexpression of vascular endothelial growth factors VEGF-A or -C. Near-infrared dye conjugates were developed to identify a suitable vascular tracer that had a prolonged circulation lifetime and slow leakage into normal tissue after intravenous injection. Dynamic simultaneous imaging of ear skin and a large blood vessel in the leg enabled determination of the intravascular signal (blood volume fraction) from the tissue signal shortly after injection and quantifications of vascular leakage into the extravascular tissue over time. This method allowed for the sensitive detection of increased blood vascularity and leakage rates in K14-VEGF-A transgenic mice and also reliably measured inflammation-induced changes of vascularity and leakage over time in the same mice. Measurements after injection of recombinant VEGF-A surprisingly revealed increased blood vascular leakage and lymphatic clearance in K14-VEGF-C transgenic mice which have an expanded cutaneous lymphatic vessel network, potentially indicating unanticipated effects of lymphatic drainage on vascular leakage. Increased vascular leakage was also detected in subcutaneous tumors, confirming that the method can also be applied to deeper tissues. This new imaging method might facilitate longitudinal investigations of the in vivo effects of drug candidates, including angiogenesis inhibitors, in preclinical disease models.

Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo

PubMed Central

Proulx, Steven T.; Luciani, Paola; Alitalo, Annamari; Mumprecht, Viviane; Christiansen, Ailsa J.; Huggenberger, Reto

2013-01-01

Preclinical vascular research has been hindered by a lack of methods that can sensitively image and quantify vascular perfusion and leakage in vivo. In this study, we have developed dynamic near-infrared imaging methods to repeatedly visualize and quantify vascular leakage in mouse skin in vivo, and we have applied these methods to transgenic mice with overexpression of vascular endothelial growth factors VEGF-A or -C. Near-infrared dye conjugates were developed to identify a suitable vascular tracer that had a prolonged circulation lifetime and slow leakage into normal tissue after intravenous injection. Dynamic simultaneous imaging of ear skin and a large blood vessel in the leg enabled determination of the intravascular signal (blood volume fraction) from the tissue signal shortly after injection and quantifications of vascular leakage into the extravascular tissue over time. This method allowed for the sensitive detection of increased blood vascularity and leakage rates in K14-VEGF-A transgenic mice and also reliably measured inflammation-induced changes of vascularity and leakage over time in the same mice. Measurements after injection of recombinant VEGF-A surprisingly revealed increased blood vascular leakage and lymphatic clearance in K14-VEGF-C transgenic mice which have an expanded cutaneous lymphatic vessel network, potentially indicating unanticipated effects of lymphatic drainage on vascular leakage. Increased vascular leakage was also detected in subcutaneous tumors, confirming that the method can also be applied to deeper tissues. This new imaging method might facilitate longitudinal investigations of the in vivo effects of drug candidates, including angiogenesis inhibitors, in preclinical disease models. PMID:23325334

Serum vascular endothelial growth factor A levels reflect itch severity in mycosis fungoides and Sézary syndrome.

PubMed

Sakamoto, Minami; Miyagaki, Tomomitsu; Kamijo, Hiroaki; Oka, Tomonori; Takahashi, Naomi; Suga, Hiraku; Yoshizaki, Ayumi; Asano, Yoshihide; Sugaya, Makoto; Sato, Shinichi

2018-01-01

Angiogenesis is an important step to support progression of malignancies, including mycosis fungoides (MF) and Sézary syndrome (SS). Vascular endothelial growth factor (VEGF)-A, a key player in angiogenesis, is secreted by tumor cells of MF/SS and its expression levels in lesional skin correlated with disease severity. In this study, we examined serum VEGF-A levels in MF/SS patients. Serum VEGF-A levels were elevated in patients with erythrodermic MF/SS and the levels decreased after treatment. Importantly, serum VEGF-A levels positively correlated with markers for pruritus. We also found that VEGF-A upregulated mRNA expression of thymic stromal lymphopoietin by keratinocytes. Taken together, our study suggests that VEGF-A can promote progression and pruritus in MF/SS. Inhibition of VEGF-A signaling can be a therapeutic strategy for patients with erythrodermic MF/SS. © 2017 Japanese Dermatological Association.

Vascular complications following intra-aortic balloon pump implantation: an updated review

PubMed Central

de Jong, Monique M; Lorusso, Roberto; Al Awami, Fatima; Matteuci, Francesco; Parise, Orlando; Lozekoot, Pieter; Bonacchi, Massimo; Maessen, Jos G; Johnson, Daniel M; Gelsomino, Sandro

2017-01-01

Background: The use of the intra-aortic balloon pump (IABP) as a support device remains controversial due to the fact that a number of studies have shown no benefit in end mortality whilst using this device. One of the reasons for this could be the increase in vascular complications when using the pump. Therefore, the aim of the present review was to assess the current literature available with regards to IABP vascular complications during the clinical situation. Methods: A literature search was performed, searching for IABP complications in adult human studies between 1990 and 2016. Results: A total of 20 reports were identified as fitting the criteria of this study. The majority of vascular complications were limb ischemia, bleeding or mesenteric ischemia. The overall incidence of vascular complications ranged from 0.94% to 31.1%. Diabetes, peripheral vascular disease and hypertension, as well as smoking were all identified as risk factors for complications following IABP. Furthermore, studies supported the use of sheathless balloon insertion to reduce the risk of complications. Conclusion: Major vascular complications, including limb and mesenteric ischemia as well as bleeding and hemorrhage, have been associated with IABP. However, the incidence of these complications was generally low. Further studies are still required to truly understand the risk/benefit associated with the use of IABP. PMID:28816093

VESGEN Software for Mapping and Quantification of Vascular Regulators

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, Patricia A.; Vickerman, Mary B.; Keith, Patricia A.

2012-01-01

VESsel GENeration (VESGEN) Analysis is an automated software that maps and quantifies effects of vascular regulators on vascular morphology by analyzing important vessel parameters. Quantification parameters include vessel diameter, length, branch points, density, and fractal dimension. For vascular trees, measurements are reported as dependent functions of vessel branching generation. VESGEN maps and quantifies vascular morphological events according to fractal-based vascular branching generation. It also relies on careful imaging of branching and networked vascular form. It was developed as a plug-in for ImageJ (National Institutes of Health, USA). VESGEN uses image-processing concepts of 8-neighbor pixel connectivity, skeleton, and distance map to analyze 2D, black-and-white (binary) images of vascular trees, networks, and tree-network composites. VESGEN maps typically 5 to 12 (or more) generations of vascular branching, starting from a single parent vessel. These generations are tracked and measured for critical vascular parameters that include vessel diameter, length, density and number, and tortuosity per branching generation. The effects of vascular therapeutics and regulators on vascular morphology and branching tested in human clinical or laboratory animal experimental studies are quantified by comparing vascular parameters with control groups. VESGEN provides a user interface to both guide and allow control over the users vascular analysis process. An option is provided to select a morphological tissue type of vascular trees, network or tree-network composites, which determines the general collections of algorithms, intermediate images, and output images and measurements that will be produced.

Progranulin protects vascular endothelium against atherosclerotic inflammatory reaction via Akt/eNOS and nuclear factor-κB pathways.

PubMed

Hwang, Hwan-Jin; Jung, Tae Woo; Hong, Ho Cheol; Choi, Hae Yoon; Seo, Ji-A; Kim, Sin Gon; Kim, Nan Hee; Choi, Kyung Mook; Choi, Dong Seop; Baik, Sei Hyun; Yoo, Hye Jin

2013-01-01

Atherosclerosis is considered a chronic inflammatory disease, initiated by activation and dysfunction of the endothelium. Recently, progranulin has been regarded as an important modulator of inflammatory processes; however, the role for prgranulin in regulating inflammation in vascular endothelial cells has not been described. Signaling pathways mediated by progranulin were analyzed in human umbilical vein endothelial cells (HUVECs) treated with progranulin. Progranulin significantly induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs, an effect that was blocked with Akt inhibitor. Furthermore, nitric oxide (NO) level, the end product of Akt/eNOS pathway, was significantly upregulated after progranulin treatment. Next, we showed that progranulin efficiently inhibited lipopolysaccharide (LPS)-mediated pro-inflammatory signaling. LPS-induced phosphorylation of IκB and nuclear factor-κB (NF-κB) levels decreased after progranulin treatment. Also, progranulin blocked translocation of NF-κB from the cytosol to the nucleus. In addition, progranulin significantly reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by inhibiting binding of NF- κB to their promoter regions and blocked attachment of monocytes to HUVECs. Progranulin also significantly reduced the expression of tumor necrosis factor receptor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1), the crucial inflammatory molecules known to aggravate atherosclerosis. Progranulin efficiently inhibited LPS-mediated pro-inflammatory signaling in endothelial cells through activation of the Akt/eNOS pathway and attenuation of the NF-κB pathway, suggesting its protective roles in vascular endothelium against inflammatory reaction underlying atherosclerosis.

Progranulin Protects Vascular Endothelium against Atherosclerotic Inflammatory Reaction via Akt/eNOS and Nuclear Factor-κB Pathways

PubMed Central

Hwang, Hwan-Jin; Jung, Tae Woo; Hong, Ho Cheol; Choi, Hae Yoon; Seo, Ji-A; Kim, Sin Gon; Kim, Nan Hee; Choi, Kyung Mook; Choi, Dong Seop; Baik, Sei Hyun; Yoo, Hye Jin

2013-01-01

Objective Atherosclerosis is considered a chronic inflammatory disease, initiated by activation and dysfunction of the endothelium. Recently, progranulin has been regarded as an important modulator of inflammatory processes; however, the role for prgranulin in regulating inflammation in vascular endothelial cells has not been described. Method and Results Signaling pathways mediated by progranulin were analyzed in human umbilical vein endothelial cells (HUVECs) treated with progranulin. Progranulin significantly induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs, an effect that was blocked with Akt inhibitor. Furthermore, nitric oxide (NO) level, the end product of Akt/eNOS pathway, was significantly upregulated after progranulin treatment. Next, we showed that progranulin efficiently inhibited lipopolysaccharide (LPS)-mediated pro-inflammatory signaling. LPS-induced phosphorylation of IκB and nuclear factor-κB (NF-κB) levels decreased after progranulin treatment. Also, progranulin blocked translocation of NF-κB from the cytosol to the nucleus. In addition, progranulin significantly reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by inhibiting binding of NF- κB to their promoter regions and blocked attachment of monocytes to HUVECs. Progranulin also significantly reduced the expression of tumor necrosis factor receptor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1), the crucial inflammatory molecules known to aggravate atherosclerosis. Conclusion Progranulin efficiently inhibited LPS-mediated pro-inflammatory signaling in endothelial cells through activation of the Akt/eNOS pathway and attenuation of the NF-κB pathway, suggesting its protective roles in vascular endothelium against inflammatory reaction underlying atherosclerosis. PMID:24098801

Vascular effects of wine polyphenols.

PubMed

Dell'Agli, Mario; Buscialà, Alessandra; Bosisio, Enrica

2004-09-01

Moderate consumption of red wine has been putatively associated with lowering the risk of developing coronary heart disease. This beneficial effect is mainly attributed to the occurrence of polyphenol compounds such as anthocyanosides (ACs), catechins, proanthocyanidins (PAs), stilbenes and other phenolics in red wine. This review focuses on the vascular effects of red wine polyphenols (RWPs), with emphasis on anthocyanosides and proanthocyanidins. From in vitro studies, the effect of red wine polyphenols on the vascular tone is thought to be due to short- and long-term mechanisms. NO-mediated vasorelaxation represents the short-term response to wine polyphenols, which exert the effect by increasing the influx of extracellular Ca(2+), and the mobilization of intracellular Ca(2+) in endothelial cells. Polyphenolic compounds may also have long-term properties, as they increase endothelial NO synthase expression acting on the promoter activity. In addition, they decrease the expression of adhesion molecules and growth factors, involved in migration and proliferation of vascular smooth muscle cells. Moreover, they inhibit platelet aggregation. However, a paucity of data as regards the bioavailability and metabolism of these compounds in human studies is a limiting factor to proving their efficacy in vivo.

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

PubMed Central

Hu, Xiaoming; De Silva, T. Michael; Chen, Jun; Faraci, Frank M.

2017-01-01

The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury following ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier (BBB) is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in BBB integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events. PMID:28154097

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke.

PubMed

Hu, Xiaoming; De Silva, T Michael; Chen, Jun; Faraci, Frank M

2017-02-03

The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury after ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in blood-brain barrier integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events. © 2017 American Heart Association, Inc.

Relationship between tumour necrosis factor-related apoptosis inducing ligand (TRAIL) and vascular endothelial growth factor in human multiple myeloma patients.

PubMed

Bolkun, Lukasz; Lemancewicz, Dorota; Piszcz, Jaroslaw; Moniuszko, Marcin; Bolkun-Skornicka, Urszula; Szkiladz, Malgorzata; Jablonska, Ewa; Kloczko, Janusz; Dzieciol, Janusz

2015-12-01

Tumour necrosis factor-alfa (TNF-α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL), which belongs to the TNF family of proteins, plays a role in the regulation of vascular responses, but its effect on the formation of new blood vessels (angiogenesis) is unclear. We analysed TRAIL concentrations in parallel with pro-angiogenic cytokines in serum and their expression in trephine biopsy (TB) in 56 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of TRAIL and TNF-α, as well as of VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. Furthermore, we observed a significant decrease in all studied pro-angiogenic cytokines and significant increase of TRAIL concentration after anti-angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with progression during the induction treatment. It was also established that TRAIL correlated statistically and negatively with pro-angiogenic cytokines such as VEGF with its receptor and expression of VEGF and syndecan-1 in TB. In summary, our data indicate that in MM patients, both clinical course and treatment responsiveness are associated with dynamic yet corresponding changes of levels of TRAIL parallel pro-angiogenic mediators such as VEGF with its receptor and expression of VEGF and syndecan-1 in TB. Copyright © 2014 John Wiley & Sons, Ltd.

Vascular Endothelial Growth Factor-A Is Associated with Chronic Mountain Sickness in the Andean Population

PubMed Central

Espinoza, Jose R.; Alvarez, Giancarlo; León-Velarde, Fabiola; Ju Preciado, Hugo F.; Macarlupu, Jose-Luis; Rivera-Ch, Maria; Rodriguez, Jorge; Favier, Judith; Gimenez-Roqueplo, Anne-Paule

2014-01-01

Abstract Espinoza, Jose R., Giancarlo Alvarez, Fabiola León-Velarde, Hugo F. Ju Preciado, Jose-Luis Macarlupu, Maria Rivera-Ch, Jorge Rodriguez, Judith Favier, Anne-Paule Gimenez-Roqueplo, and Jean-Paul Richalet. Vascular endothelial growth factor-A is associated with chronic mountain sickness in Andean population. High Alt Med Biol. 15:146–154, 2014.—A study of chronic mountain sickness (CMS) with a candidate gene—vascular endothelial growth factor A (VEGFA)—was carried out in a Peruvian population living at high altitude in Cerro de Pasco (4380 m). The study was performed by genotyping of 11 tag SNPs encompassing 2.2 kb of region of VEGFA gene in patients with a diagnosis of CMS (n=131; 49.1±12.7 years old) and unrelated healthy controls (n=84; 47.2±13.4 years old). The VEGFA tag SNP rs3025033 was found associated with CMS (p<0.05), individuals with AG genotype have 2.5 more risk of CMS compared to those with GG genotype (p<0.02; OR, 2.54; 95% CI: 1.10–5.88). Pairwise Fst and Nei's distance indicate genetic differentiation between Cerro de Pasco population and HapMap3 population (Fst>0.36, p<0.01), suggesting selection is operating on the VEGF gene. Our results suggest that VEGFA is associated with CMS in long-term residents at high altitude in the Peruvian Andes. PMID:24971768

Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets

PubMed Central

Möhle, Robert; Green, David; Moore, Malcolm A. S.; Nachman, Ralph L.; Rafii, Shahin

1997-01-01

We have shown that coculture of bone marrow microvascular endothelial cells with hematopoietic progenitor cells results in proliferation and differentiation of megakaryocytes. In these long-term cultures, bone marrow microvascular endothelial cell monolayers maintain their cellular integrity in the absence of exogenous endothelial growth factors. Because this interaction may involve paracrine secretion of cytokines, we evaluated megakaryocytic cells for secretion of vascular endothelial growth factor (VEGF). Megakaryocytes (CD41a+) were generated by ex vivo expansion of hematopoietic progenitor cells with kit-ligand and thrombopoietin for 10 days and further purified with immunomagnetic microbeads. Using reverse transcription–PCR, we showed that megakaryocytic cell lines (Dami, HEL) and purified megakaryocytes expressed mRNA of the three VEGF isoforms (121, 165, and 189 amino acids). Large quantities of VEGF (>1 ng/106 cells/3 days) were detected in the supernatant of Dami cells, ex vivo-generated megakaryocytes, and CD41a+ cells isolated from bone marrow. The constitutive secretion of VEGF by CD41a+ cells was stimulated by growth factors of the megakaryocytic lineage (interleukin 3, thrombopoietin). Western blotting of heparin–Sepharose-enriched supernatant mainly detected the isoform VEGF165. In addition, immunohistochemistry showed intracytoplasmic VEGF in polyploid megakaryocytes. Thrombin stimulation of megakaryocytes and platelets resulted in rapid release of VEGF within 30 min. We conclude that human megakaryocytes produce and secrete VEGF in an inducible manner. Within the bone marrow microenvironment, VEGF secreted by megakaryocytes may contribute to the proliferation of endothelial cells. VEGF delivered to sites of vascular injury by activated platelets may initiate angiogenesis. PMID:9012841

S1P1 inhibits sprouting angiogenesis during vascular development.

PubMed

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

2012-10-01

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

γ-Oryzanol reduces adhesion molecule expression in vascular endothelial cells via suppression of nuclear factor-κB activation.

PubMed

Sakai, Satoshi; Murata, Takahisa; Tsubosaka, Yoshiki; Ushio, Hideki; Hori, Masatoshi; Ozaki, Hiroshi

2012-04-04

γ-Oryzanol (γ-ORZ) is a mixture of phytosteryl ferulates purified from rice bran oil. In this study, we examined whether γ-ORZ represents a suppressive effect on the lipopolysaccharide (LPS)-induced adhesion molecule expression on vascular endothelium. Treatment with LPS elevated the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in bovine aortic endothelial cells (BAECs). Pretreatment with γ-ORZ dose-dependently decreased the LPS-mediated expression of these genes. Western blotting also revealed that pretreatment with γ-ORZ dose-dependently inhibited LPS-induced VCAM-1 expression in human umbilical vein endothelial cells. Consistently, pretreatment with γ-ORZ dose-dependently reduced LPS-induced U937 monocyte adhesion to BAECs. In immunofluorescence, LPS caused nuclear factor-κB (NF-κB) nuclear translocation in 40% of BAECs, which indicates NF-κB activation. Pretreatment with γ-ORZ, as well as its components (cycloartenyl ferulate, ferulic acid, or cycloartenol), dose-dependently inhibited LPS-mediated NF-κB activation. Collectively, our results suggested that γ-ORZ reduced LPS-mediated adhesion molecule expression through NF-κB inhibition in vascular endothelium.

A Systematic Review and Meta-Analysis on the Safety of Vascular Endothelial Growth Factor (VEGF) Inhibitors for the Treatment of Retinopathy of Prematurity

PubMed Central

Pertl, Laura; Steinwender, Gernot; Mayer, Christoph; Hausberger, Silke; Pöschl, Eva-Maria; Wackernagel, Werner; Wedrich, Andreas; El-Shabrawi, Yosuf; Haas, Anton

2015-01-01

Introduction Laser photocoagulation is the current gold standard treatment for proliferative retinopathy of prematurity (ROP). However, it permanently reduces the visual field and might induce myopia. Vascular endothelial growth factor (VEGF) inhibitors for the treatment of ROP may enable continuing vascularization of the retina, potentially allowing the preservation of the visual field. However, for their use in infants concern remains. This meta-analysis explores the safety of VEGF inhibitors. Methods The Ovid Interface was used to perform a systematic review of the literature in the databases PubMed, EMBASE and the Cochrane Library. Results This meta-analysis included 24 original reports (including 1.457 eyes) on VEGF inhibitor treatment for ROP. The trials were solely observational except for one randomized and two case-control studies. We estimated a 6-month risk of retreatment per eye of 2.8%, and a 6-month risk of ocular complication without the need of retreatment of 1.6% per eye. Systemic complications were only reported as isolated incidents. Discussion VEGF inhibitors seem to be associated with low recurrence rates and ocular complication rates. They may have the benefit of potentially allowing the preservation of visual field and lower rates of myopia. Due to the lack of data, the risk of systemic side effects cannot be assessed. PMID:26083024

Risk Stratification for the Development of Respiratory Adverse Events Following Vascular Surgery Using the Society of Vascular Surgery’s Vascular Quality Initiative

PubMed Central

Genovese, Elizabeth A; Fish, Larry; Chaer, Rabih A; Makaroun, Michel S; Baril, Donald T

2017-01-01

Objective Post-operative respiratory adverse events (RAEs) are associated with high rates of morbidity and mortality in general surgery, however little is known about these complications in the vascular surgery population, a frail subset with multiple comorbidities. The objective of this study was to describe the contemporary incidence of RAEs in vascular surgery patients, the risk factors for this complication and the overall impact of RAEs on patient outcomes. Methods The Vascular Quality Initiative was queried (2003–2014) for patients who underwent endovascular abdominal aortic repair, open abdominal aortic aneurysm (AAA) repair, thoracic endovascular aortic repair (TEVAR), suprainguinal bypass or infrainguinal bypass. A mixed-effects logistic regression model determined the independent risk factors for RAEs. Using a random 85% of the cohort, a risk prediction score for RAEs was created and the score was validated using the remaining 15% of the cohort, comparing the predicted to the actual incidence of RAE and determining the area under the receiver operating characteristic curve. The independent risk of in-hospital mortality and discharge to a nursing facility associated with RAEs was determined using a mixed-effects logistic regression to control for baseline patient characteristics, operative variables and other post-operative adverse events. Results The cohort consisted of 52,562 patients, with a 5.4% incidence of RAEs. The highest rates of RAEs were seen in current smokers (6.1%), recent acute myocardial infarction (10.1%), symptomatic congestive heart failure (CHF) (9.9%), chronic obstructive pulmonary disease (COPD) requiring oxygen therapy (11.0%), urgent and emergent procedures (6.4% and 25.9%, respectively), open AAA repairs (17.6%), in-situ suprainguinal bypasses (9.68%) and TEVARs (9.6%). The variables included in the risk prediction score were age, body mass index, smoking status, CHF severity, COPD severity, degree of renal insufficiency

Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions

PubMed Central

Li, Bo; Wang, Hai; Qiu, Guixing; Su, Xinlin

2016-01-01

Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), as key mediators in angiogenesis and osteogenesis, are used in a combined delivery manner as a novel strategy in bone tissue engineering. VEGF has the potential to enhance BMPs induced bone formation. Both gene delivery and material-based delivery systems were incorporated in previous studies to investigate the synergistic effects of VEGF and BMPs. However, their results were controversial due to variation of methods incorporated in different studies. Factors influencing the synergistic effects of VEGF on BMPs induced bone formation were identified and analyzed in this review to reduce confusion on this issue. The potential mechanisms and directions of future studies were also proposed here. Further investigating mechanisms of the synergistic effects and optimizing these influencing factors will help to generate more effective bone regeneration. PMID:28070506

Diffusion tensor imaging, intracranial vascular resistance and cognition in middle-aged asymptomatic subjects.

PubMed

López-Olóriz, Jorge; López-Cancio, Elena; Arenillas, Juan F; Hernández, María; Dorado, Laura; Dacosta-Aguayo, Rosalía; Barrios, Maite; Soriano-Raya, Juan José; Miralbell, Júlia; Bargalló, Núria; Cáceres, Cynthia; Torán, Pere; Alzamora, Maite; Dávalos, Antonio; Mataró, Maria

2014-01-01

The contribution of traditional vascular risk factors to cognitive impairment and dementia is well known. However, in order to obtain possible targets for prevention of vascular cognitive impairment (VCI), it may be important to identify other early and noninvasive markers in asymptomatic middle-aged adults. The calculation of middle cerebral artery-pulsatility index (MCA-PI) is an ultrasonologic, noninvasive, validated and easily reproducible technique to assess increased distal resistance to blood flow. This study aims to assess the relationship between MCA-PI, microstructural white matter (WM) integrity and cognition in a middle-aged asymptomatic population. Ninety-five participants from the Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) neuropsychology study were included. Subjects were 50-65 years old, free from dementia and without history of vascular disease. Transcranial color-coded duplex ultrasound examination was performed to assess MCA-PI as a measure of vascular resistance. WM integrity was evaluated by fractional anisotropy (FA) measurements of diffusion tensor images (DTI) acquired on a 3T-MRI. The neuropsychological battery was specifically selected to be sensitive to VCI, and included tests that were grouped into six cognitive domains: executive functioning, attention, verbal fluency, memory, visuospatial skills and psychomotor speed. A multivariate linear regression model adjusted for age, gender, years of education, diabetes and hypertension was performed. MCA-PI was significantly associated with WM disintegration in different tracts (fornix, corticospinal and anterior thalamic), all p < 0.05 uncorrected. Both mean MCA-PI and mean FA of those significant tracts were independently associated with poor performance in attention, psychomotor speed, and visuospatial skills after adjustment for age, gender, years of education, and vascular risk factors (all p < 0.05). MCA-PI was independently associated with lower scores in all cognitive

Vascular Anomalies (Part I): Classification and Diagnostics of Vascular Anomalies.

PubMed

Sadick, Maliha; Müller-Wille, René; Wildgruber, Moritz; Wohlgemuth, Walter A

2018-06-06

 Vascular anomalies are a diagnostic and therapeutic challenge. They require dedicated interdisciplinary management. Optimal patient care relies on integral medical evaluation and a classification system established by experts in the field, to provide a better understanding of these complex vascular entities.  A dedicated classification system according to the International Society for the Study of Vascular Anomalies (ISSVA) and the German Interdisciplinary Society of Vascular Anomalies (DiGGefA) is presented. The vast spectrum of diagnostic modalities, ranging from ultrasound with color Doppler, conventional X-ray, CT with 4 D imaging and MRI as well as catheter angiography for appropriate assessment is discussed.  Congenital vascular anomalies are comprised of vascular tumors, based on endothelial cell proliferation and vascular malformations with underlying mesenchymal and angiogenetic disorder. Vascular tumors tend to regress with patient's age, vascular malformations increase in size and are subdivided into capillary, venous, lymphatic, arterio-venous and combined malformations, depending on their dominant vasculature. According to their appearance, venous malformations are the most common representative of vascular anomalies (70 %), followed by lymphatic malformations (12 %), arterio-venous malformations (8 %), combined malformation syndromes (6 %) and capillary malformations (4 %).  The aim is to provide an overview of the current classification system and diagnostic characterization of vascular anomalies in order to facilitate interdisciplinary management of vascular anomalies.   · Vascular anomalies are comprised of vascular tumors and vascular malformations, both considered to be rare diseases.. · Appropriate treatment depends on correct classification and diagnosis of vascular anomalies, which is based on established national and international classification systems, recommendations and guidelines.. · In the classification

The Arabidopsis gene MONOPTEROS encodes a transcription factor mediating embryo axis formation and vascular development.

PubMed Central

Hardtke, C S; Berleth, T

1998-01-01

The vascular tissues of flowering plants form networks of interconnected cells throughout the plant body. The molecular mechanisms directing the routes of vascular strands and ensuring tissue continuity within the vascular system are not known, but are likely to depend on general cues directing plant cell orientation along the apical-basal axis. Mutations in the Arabidopsis gene MONOPTEROS (MP) interfere with the formation of vascular strands at all stages and also with the initiation of the body axis in the early embryo. Here we report the isolation of the MP gene by positional cloning. The predicted protein product contains functional nuclear localization sequences and a DNA binding domain highly similar to a domain shown to bind to control elements of auxin inducible promoters. During embryogenesis, as well as organ development, MP is initially expressed in broad domains that become gradually confined towards the vascular tissues. These observations suggest that the MP gene has an early function in the establishment of vascular and body patterns in embryonic and post-embryonic development. PMID:9482737

Thrombomodulin as a marker for vascular tumors. Comparative study with factor VIII and Ulex europaeus I lectin.

PubMed

Yonezawa, S; Maruyama, I; Sakae, K; Igata, A; Majerus, P W; Sato, E

1987-10-01

Thrombomodulin (TM) is a newly described endothelial cell-associated protein that functions as a potent natural anticoagulant by converting thrombin from a procoagulant protease to an anticoagulant. Various vascular tumors were characterized with immunoperoxidase staining with the use of a polyclonal anti-TM serum. The staining patterns of TM were compared with those of Factor VIII-related antigen (FVIII-RAG) and Ulex europaeus agglutinin-I (UEA-I), which have been used as markers for endothelial cells. The results showed that TM is a specific and a highly sensitive marker for angiosarcomas in comparison with FVIII-RAG or UEA-I. In contrast, UEA-I is more sensitive for benign vascular tumors than TM or FVIII-RAG. The other mesenchymal tumors of nonvascular origin showed negative staining for three endothelial markers. These results indicate that TM is a new specific and sensitive tool for the diagnosis of angiosarcomas.

Vascular calcification: When should we interfere in chronic kidney disease patients and how?

PubMed Central

Sharaf El Din, Usama Abdel Azim; Salem, Mona Mansour; Abdulazim, Dina Ossama

2016-01-01

Chronic kidney disease (CKD) patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifications affect most of the CKD patients. Most of this calcification is related to disturbed renal phosphate handling. Fibroblast growth factor 23 and klotho deficiency were incriminated in the pathogenesis of vascular calcification through different mechanisms including their effects on endothelium and arterial wall smooth muscle cells. In addition, deficient klotho gene expression, a constant feature of CKD, promotes vascular pathology and shares in progression of the CKD. The role of gut in the etio-pathogenesis of systemic inflammation and vascular calcification is a newly discovered mechanism. This review will cover the medical history, prevalence, pathogenesis, clinical relevance, different tools used to diagnose, the ideal timing to prevent or to withhold the progression of vascular calcification and the different medications and medical procedures that can help to prolong the survival of CKD patients. PMID:27648404

Lipoprotein(a) levels predict adverse vascular events after acute myocardial infarction.

PubMed

Mitsuda, Takayuki; Uemura, Yusuke; Ishii, Hideki; Takemoto, Kenji; Uchikawa, Tomohiro; Koyasu, Masayoshi; Ishikawa, Shinji; Miura, Ayako; Imai, Ryo; Iwamiya, Satoshi; Ozaki, Yuta; Kato, Tomohiro; Shibata, Rei; Watarai, Masato; Murohara, Toyoaki

2016-12-01

Lipoprotein(a) [Lp(a)], which is genetically determined, has been reported as an independent risk factor for atherosclerotic vascular disease. However, the prognostic value of Lp(a) for secondary vascular events in patients after coronary artery disease has not been fully elucidated. This 3-year observational study included a total of 176 patients with ST-elevated myocardial infarction (STEMI), whose Lp(a) levels were measured within 24 h after primary percutaneous coronary intervention. We divided enrolled patients into two groups according to Lp(a) level and investigated the association between Lp(a) and the incidence of major adverse cardiac and cerebrovascular events (MACCE). A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of MACCE than those with lower Lp(a) levels (log-rank P = 0.034). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the occurrence of MACCE after adjusting for other classical risk factors of atherosclerotic vascular diseases (hazard ratio 1.030, 95 % confidence interval: 1.011-1.048, P = 0.002). In receiver-operating curve analysis, the cutoff value to maximize the predictive power of Lp(a) was 19.0 mg/dl (area under the curve = 0.674, sensitivity 69.2 %, specificity 62.0 %). Evaluation of Lp(a) in addition to the established coronary risk factors improved their predictive value for the occurrence of MACCE. In conclusion, Lp(a) levels at admission independently predict secondary vascular events in patients with STEMI. Lp(a) might provide useful information for the development of secondary prevention strategies in patients with myocardial infarction.

Juvenile nasopharyngeal angiofibroma: vascular determinates for operative complications and tumor recurrence.

PubMed

Chan, Kenny H; Gao, Dexiang; Fernandez, Patrick G; Kingdom, Todd T; Kumpe, David A

2014-03-01

Operative complications and tumor recurrence in juvenile nasopharyngeal angiofibroma (JNA) are measurable and meaningful outcomes. This study aimed to assess the association of these two outcomes to various clinical indices and in particular, vascular determinates. Retrospective cohort study. An 18-year retrospective chart review of an academic tertiary center was undertaken. Data from clinical notes, imaging studies, and arteriograms were analyzed. Thirty-seven male (mean age, 14.4 years) patients were included in the study. Tumor stages included: IA (three), IB (three), IIA (14), IIB (three), IIC (five), IIIA (five), and IIIB (four). Four complications (cerebrospinal fluid leak, cerebral vascular accident, and two transient ocular defects) occurred. Eight recurrences occurred within 24 months following surgery. Complications were associated with estimated intraoperative blood loss (EBL) (P = .045). Tumor recurrence was associated with feeding vessels from the contralateral internal carotid artery (ICA) (P = .017). EBL was significantly associated with surgical technique used. EBL, tumor stage, and tumor vascular supply were significantly associated with each other. Vascular factors were associated with JNA complication and tumor recurrence. EBL might affect complications, and contralateral ICA as a feeding vessel might affect recurrence. EBL was influenced by procedure choice and was interrelated to size and vascular supply of the tumor. This study bolsters the need to decrease intraoperative blood loss by preoperative embolization and use of endoscopic removal techniques. Furthermore, when branches of the ICA are found to be feeding vessels, greater surgical attention for a dry surgical field is encouraged. © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Protecting against vascular disease in brain

PubMed Central

2011-01-01

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

Coexistence of pheochromocytoma with uncommon vascular lesions

PubMed Central

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

2012-01-01

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

Running multiple marathons is not a risk factor for premature subclinical vascular impairment.

PubMed

Pressler, Axel; Suchy, Christiane; Friedrichs, Tasja; Dallinger, Sophia; Grabs, Viola; Haller, Bernhard; Halle, Martin; Scherr, Johannes

2017-08-01

Background In contrast to the well-accepted benefits of moderate exercise, recent research has suggested potential deleterious effects of repeated marathon running on the cardiovascular system. We thus performed a comprehensive analysis of markers of subclinical vascular damage in a cohort of runners having finished multiple marathon races successfully. Design This was a prospective, observational study. Methods A total of 97 healthy male Munich marathon participants (mean age 44 ± 10 years) underwent detailed training history, cardiopulmonary exercise testing for assessment of peak oxygen uptake, ultrasound for assessment of intima-media-thickness as well as non-invasive assessments of ankle-brachial index, augmentation index, pulse wave velocity and reactive hyperaemia index. Results Runners had previously completed a median of eight (range 1-500) half marathons, six (1-100) full marathons and three (1-40) ultramarathons; mean weekly and annual training volumes were 59 ± 23 and 1639 ± 979 km. Mean peak oxygen uptake was 50 ± 8 ml/min/kg, and the Munich marathon was finished in 3:45 ± 0:32 h. Runners showed normal mean values for intima-media-thickness (0.60 ± 0.14 mm), ankle-brachial index (1.2 ± 0.1), augmentation index (17 ± 13%), pulse wave velocity (8.7 ± 1.4 cm/s) and reactive hyperaemia index (1.96 ± 0.50). Age was significantly and independently associated with intima-media-thickness ( r = 0.531; p < 0.001), augmentation index ( r = 0.593; p < 0.001) and pulse wave velocity ( r = 0.357; p < 0.001). However, no independent associations of peak oxygen uptake, marathon finishing time, number of completed races or weekly and annual training km with any of the vascular parameters were observed. Conclusions In this cohort of healthy male runners, running multiple marathon races did not pose an additional risk factor for premature subclinical vascular impairment beyond age.

Activation of RelA homodimers by tumour necrosis factor α: a possible transcriptional activator in human vascular endothelial cells

PubMed Central

2005-01-01

In vascular endothelial cells, cytokines induce genes that are expressed in inflammatory lesions partly through the activation of transcription factor NF-κB (nuclear factor-κB). Among the members of the NF-κB/rel protein family, homodimers of the RelA subunit of NF-κB can also function as strong transactivators when expressed in cells. However, the functional role of endogenous RelA homodimers has not been clearly elucidated. We investigated whether RelA homodimers are induced in cytokine-treated vascular endothelial cells. Gel mobility-shift and supershift assays revealed that a cytokine TNFα (tumour necrosis factor α) activated both NF-κB1/RelA heterodimers and RelA homodimers that bound to a canonical κB sequence, IgκB (immunoglobulin κB), in SV40 (simian virus 40) immortalized HMEC-1 (human dermal microvascular endothelial cell line 1). In HMEC-1 and HUVEC (human umbilical-vein endothelial cells), TNFα also induced RelA homodimers that bound to the sequence 65-2κB, which specifically binds to RelA homodimers but not to NF-κB1/RelA heterodimers in vitro. Deoxycholic acid, a detergent that can dissociate the NF-κB–IκB complex (where IκB stands for inhibitory κB), induced the binding of the RelA homodimers to 65-2κB from the cytosolic fraction of resting HMEC-1. Furthermore, TNFα induced the transcriptional activity of a reporter gene that was driven by 65-2κB in HMEC-1. These results suggest that in addition to NF-κB1/RelA heterodimers, TNFα also induces RelA homodimers that are functionally active. Thus RelA homodimers may actively participate in cytokine regulation of gene expression in human vascular endothelial cells. PMID:15876188

The impact of high-intensity interval training versus moderate-intensity continuous training on vascular function: a systematic review and meta-analysis.

PubMed

Ramos, Joyce S; Dalleck, Lance C; Tjonna, Arnt Erik; Beetham, Kassia S; Coombes, Jeff S

2015-05-01

Vascular dysfunction is a precursor to the atherosclerotic cascade, significantly increasing susceptibility to cardiovascular events such as myocardial infarction or stroke. Previous studies have revealed a strong relationship between vascular function and cardiorespiratory fitness (CRF). Thus, since high-intensity interval training (HIIT) is a potent method of improving CRF, several small randomized trials have investigated the impact on vascular function of HIIT relative to moderate-intensity continuous training (MICT). The aim of this study was to systematically review the evidence and quantify the impact on vascular function of HIIT compared with MICT. Three electronic databases (PubMed, Embase, and MEDLINE) were searched (until May 2014) for randomized trials comparing the effect of at least 2 weeks of HIIT and MICT on vascular function. HIIT protocols involved predominantly aerobic exercise at a high intensity, interspersed with active or passive recovery periods. We performed a meta-analysis to compare the mean difference in the change in vascular function assessed via brachial artery flow-mediated dilation (FMD) from baseline to post-intervention between HIIT and MICT. The impact of HIIT versus MICT on CRF, traditional cardiovascular disease (CVD) risk factors, and biomarkers associated with vascular function (oxidative stress, inflammation, and insulin resistance) was also reviewed across included studies. Seven randomized trials, including 182 patients, met the eligibility criteria and were included in the meta-analysis. A commonly used HIIT prescription was four intervals of 4 min (4 × 4 HIIT) at 85-95% of maximum or peak heart rate (HRmax/peak), interspersed with 3 min of active recovery at 60-70% HRmax/peak, three times per week for 12-16 weeks. Brachial artery FMD improved by 4.31 and 2.15% following HIIT and MICT, respectively. This resulted in a significant (p < 0.05) mean difference of 2.26%. HIIT also had a greater tendency than MICT to induce

Vacuum-assisted closure therapy increases local interleukin-8 and vascular endothelial growth factor levels in traumatic wounds.

PubMed

Labler, Ludwig; Rancan, Mario; Mica, Ladislav; Härter, Luc; Mihic-Probst, Daniela; Keel, Marius

2009-03-01

Clinical observations are suggesting accelerated granulation tissue formation in traumatic wounds treated with vacuum-assisted closure (VAC). Aim of this study was to determine the impact of VAC therapy versus alternative Epigard application on local inflammation and neovascularization in traumatic soft tissue wounds. Thirty-two patients with traumatic wounds requiring temporary coverage (VAC n = 16; Epigard n = 16) were included. At each change of dressing, samples of wound fluid and serum were collected (n = 80). The cytokines interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), and fibroblast growth factor-2 were measured by ELISA. Wound biopsies were examined histologically for inflammatory cells and degree of neovascularization present. All cytokines were found to be elevated in wound fluids during both VAC and Epigard treatment, whereas serum concentrations were negligible or not detectable. In wound fluids, significantly higher IL-8 (p < 0.001) and VEGF (p < 0.05) levels were detected during VAC therapy. Furthermore, histologic examination revealed increased neovascularization (p < 0.05) illustrated by CD31 and von Willebrand factor immunohistochemistry in wound biopsies of VAC treatment. In addition, there was an accumulation of neutrophils as well as an augmented expression of VEGF (p < 0.005) in VAC wound biopsies. This study suggests that VAC therapy of traumatic wounds leads to increased local IL-8 and VEGF concentrations, which may trigger accumulation of neutrophils and angiogenesis and thus, accelerate neovascularization.

Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of white matter lesions on MRI: the evaluation of vascular care in Alzheimer's disease (EVA) study.

PubMed

Richard, Edo; Gouw, Alida A; Scheltens, Philip; van Gool, Willem A

2010-03-01

White matter lesions (WMLs) and cerebral infarcts are common findings in Alzheimer disease and may contribute to dementia severity. WMLs and lacunar infarcts may provide a potential target for intervention strategies. This study assessed whether multicomponent vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs and prevents occurrence of new infarcts. A randomized controlled clinical trial, including 123 subjects, compared vascular care with standard care in patients with Alzheimer disease with cerebrovascular lesions on MRI. Progression of WMLs, lacunes, medial temporal lobe atrophy, and global cortical atrophy were semiquantitatively scored after 2-year follow-up. Sixty-five subjects (36 vascular care, 29 standard care) had a baseline and a follow-up MRI and in 58 subjects, a follow-up scan could not be obtained due to advanced dementia or death. Subjects in the vascular care group had less progression of WMLs as measured with the WML change score (1.4 versus 2.3, P=0.03). There was no difference in the number of new lacunes or change in global cortical atrophy or medial temporal lobe atrophy between the 2 groups. Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs. Treatment aimed at vascular risk factors in patients with early Alzheimer disease may be beneficial, possibly in an even earlier stage of the disease.

STATs MEDIATE FIBROBLAST GROWTH FACTOR INDUCED VASCULAR ENDOTHELIAL MORPHOGENESIS

PubMed Central

Yang, Xinhai; Qiao, Dianhua; Meyer, Kristy; Friedl, Andreas

2009-01-01

The fibroblast growth factors (FGFs) play diverse roles in development, wound healing and angiogenesis. The intracellular signal transduction pathways which mediate these pleiotropic activities remain incompletely understood. We show here that the proangiogenic factors FGF2 and FGF8b can activate signal transducers and activators of transcription (STATs) in mouse microvascular endothelial cells. Both FGF2 and FGF8b activate STAT5 and to a lesser extent STAT1, but not STAT3. The FGF2-dependent activation of endothelial STAT5 was confirmed in vivo with the matrigel plug angiogenesis assay. In tissue samples of human gliomas, a tumor type where FGF-induced angiogenesis is important, STAT5 is detected in tumor vessel endothelial cell nuclei, consistent with STAT5 activation. By forced expression of constitutively active or dominant-negative mutant STAT5A in mouse brain endothelial cells, we further show that STAT5 activation is both necessary and sufficient for FGF-induced cell migration, invasion and tube formation, which are key events in vascular endothelial morphogenesis and angiogenesis. In contrast, STAT5 is not required for brain endothelial cell mitogenesis. The cytoplasmic tyrosine kinases Src and Janus kinase 2 (Jak2) both appear to be involved in the activation of STAT5, as their inhibition reduces FGF2 and FGF8b induced STAT5 phosphorylation and endothelial cell tube formation. Constitutively active STAT5A partially restores tube formation in the presence of Src or Jak2 inhibitors. These observations demonstrate that FGFs utilize distinct signaling pathways to induce angiogenic phenotypes. Together, our findings implicate the FGF-Jak2/Src-STAT5 cascade as a critical angiogenic FGF signaling pathway. PMID:19176400

Preliminary investigations on the effects of a Strongylus vulgaris larval extract, mononuclear factors and platelet factors on equine smooth muscle cells in vitro.

PubMed

Morgan, S J; Storts, R W; Stromberg, P C; Sowa, B A; Lay, J C

1989-01-01

Factors involved in the proliferation of equine vascular smooth muscle cells were studied in vitro. The most prominent proliferative responses in cultured vascular smooth muscle cells were induced by Strongylus vulgaris larval antigen extract (LAE) and platelet-derived factors. Less significant proliferative responses were obtained with conditioned media from S. vulgaris LAE stimulated and from unstimulated equine mononuclear leukocytes. Additionally, vascular smooth muscle cells exposed to S. vulgaris LAE developed numerous perinuclear vacuoles and were more spindle-shaped than control or smooth muscle cells exposed to other factors. Equine mononuclear leukocytes exposed to LAE developed prominent morphological changes, including enlargement, clumping and increased numbers of mitotic figures.

Serum vascular endothelial growth factor in dogs with soft tissue sarcomas.

PubMed

de Queiroz, G Fernandes; Dagli, M Lúcia Zaidan; Meira, S Aparecida; Matera, J Maria

2013-09-01

This work aimed to evaluate serum vascular endothelial growth factor (VEGF) in 25 dogs with soft tissue sarcoma, and in 30 healthy dogs. Blood was collected once time from the control animals and three times, in the same way, from animals with sarcoma. Blood count was performed in the blood collected, and serum VEGF was measured by enzyme-linked immunosorbent assay quantitative method. Serum VEGF in control animals was similar to patients with soft tissue sarcoma. There was a reduction in serum VEGF after the sarcoma resection. There was positive correlation between serum VEGF and neutrophil counts, and negative between VEGF and hemoglobin content in animals with sarcoma. Animals with hemangiopericytoma showed higher serum VEGF levels compared to the patients with malignant peripheral nerve sheath. Circulating blood cells can contribute to elevate VEGF serum concentrations in dogs with soft tissue sarcomas and a possible role of VEGF in the angiogenesis of these tumors. © 2012 John Wiley & Sons Ltd.

Atherosclerotic vascular disease in systemic lupus erythematosus.

PubMed

Liang, Matthew H; Mandl, Lisa A; Costenbader, Karen; Fox, Ervin; Karlson, Elizabeth

2002-09-01

In the United States, systemic lupus erythematosus (SLE) disproportionately affects African Americans. It has become a chronic disease with long-term morbidity including chronic renal disease, osteoporosis, cataracts, psychosocial impairment, and importantly, atherosclerotic vascular disease (ASVD). The latter (myocardial infarction, angina, peripheral vascular disease and stroke) are strikingly accelerated, occurring in subjects who are predominantly premenopausal women at an age when ASVD is rare or unusual. Although much is known about the biology, risk factors, and the prevention of atherosclerosis in normal individuals, little work has been done in SLE. In fact, ASVD in people with SLE may be a different disease. Approximately 1.5% of SLE patients per year will have a myocardial infarction or equivalent; about 0.5% of SLE patients per year will have a stroke. The risk factors for ASVD in SLE are based on small, retrospective, single center studies. These suggest that the risk factors known for the general population (i.e., smoking, obesity, sedentary lifestyle, high LDL cholesterol, etc.) are also observed in SLE. The best study of risk factors shows that even accounting for the known factors, SLE and/or its treatment (glucocorticoids) is by far the most important. Our current management of cardiovascular risk factors in SLE patients with ASVD is substandard and our adherence to national guidelines for prevention is substandard. It is not known whether improving either will prevent these disastrous outcomes. Very little is known about the risk factors in African Americans with SLE, although there is data to suggest that they may not be identical to those seen in Caucasian populations. The study of the best and most effective means to prevent ASVD in SLE and in African Americans with SLE and in African Americans with SLE should be a major priority.

Engineering Pre-vascularized Scaffolds for Bone Regeneration.

PubMed

Barabaschi, Giada D G; Manoharan, Vijayan; Li, Qing; Bertassoni, Luiz E

2015-01-01

Survival of functional tissue constructs of clinically relevant size depends on the formation of an organized and uniformly distributed network of blood vessels and capillaries. The lack of such vasculature leads to spatio-temporal gradients in oxygen, nutrients and accumulation of waste products inside engineered tissue constructs resulting in negative biological events at the core of the scaffold. Unavailability of a well-defined vasculature also results in ineffective integration of scaffolds to the host vasculature upon implantation. Arguably, one of the greatest challenges in engineering clinically relevant bone substitutes, therefore, has been the development of vascularized bone scaffolds. Various approaches ranging from peptide and growth factor functionalized biomaterials to hyper-porous scaffolds have been proposed to address this problem with reasonable success. An emerging alternative to address this challenge has been the fabrication of pre-vascularized scaffolds by taking advantage of biomanufacturing techniques, such as soft- and photo-lithography or 3D bioprinting, and cell-based approaches, where functional capillaries are engineered in cell-laden scaffolds prior to implantation. These strategies seek to engineer pre-vascularized tissues in vitro, allowing for improved anastomosis with the host vasculature upon implantation, while also improving cell viability and tissue development in vitro. This book chapter provides an overview of recent methods to engineer pre-vascularized scaffolds for bone regeneration. We first review the development of functional blood capillaries in bony structures and discuss controlled delivery of growth factors, co-culture systems, and on-chip studies to engineer vascularized cell-laden biomaterials. Lastly, we review recent studies using microfabrication techniques and 3D printing to engineer pre-vascularized scaffolds for bone tissue engineering.

Vascular dysfunctions following spinal cord injury

PubMed Central

Popa, F; Grigorean, VT; Onose, G; Sandu, AM; Popescu, M; Burnei, G; Strambu, V; Sinescu, C

2010-01-01

The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1–L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin–angiotensin–aldosterone activity, peripheral alpha–adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as

Essential roles of angiotensin II in vascular endothelial growth factor expression in sleep apnea syndrome.

PubMed

Takahashi, Susumu; Nakamura, Yutaka; Nishijima, Tsuguo; Sakurai, Shigeru; Inoue, Hiroshi

2005-09-01

Hypoxia-induced endothelial cell dysfunction has been implicated in increased cardiovascular disease associated with obstructive sleep apnea syndrome (OSAS). OSAS mediates hypertension by stimulating angiotensin II (Ang II) production. Hypoxia and Ang II are the major stimuli of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine and also contributes to the atherogenic process itself. We observed serum Ang II and VEGF levels and peripheral blood mononuclear cell (PBMC) and neutrophil VEGF expression. Compared to controls, subjects with OSAS had significantly increased levels of serum Ang II and VEGF and VEGF mRNA expression in their leukocytes. To examine whether Ang II stimulates VEGF expression in OSAS, we treated PBMCs obtained from control subjects with Ang II and with an Ang II receptor type 1 (AT(1)) blocker, olmesartan. We observed an increased expression of VEGF in the Ang II-stimulated PBMCs and decreased in VEGF mRNA and protein expression in the PBMCs treated with olmesartan. These findings suggest that the Ang II-AT(1) receptors pathway potentially are involved in OSAS and VEGF-induced vascularity and that endothelial dysfunction might be linked to this change in Ang II activity within leukocytes of OSAS patients.

Extended Duration Vascular Endothelial Growth Factor Inhibition in the Eye: Failures, Successes, and Future Possibilities.

PubMed

Stewart, Michael W

2018-01-27

Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of neovascularization and edema from several common chorioretinal vascular conditions. The intravitreally injected drugs (aflibercept, bevacizumab, conbercept, pegaptanib, and ranibizumab) used to treat these conditions improve the visual acuity and macular morphology in most patients. Monthly or bimonthly injections were administered in the phase III pivotal trials but physicians usually individualize therapy with pro re nata (PRN) or treat and extend regimens. Despite these lower frequency treatment regimens, frequent injections and clinic visits are still needed to produce satisfactory outcomes. Newly developed drugs and refillable reservoirs with favorable pharmacokinetic profiles may extend durations of action and require fewer office visits. However, we have learned from previous experiences that the longer durations of action seen in strategically designed phase III trials often do not translate to less frequent injections in real-life clinical practice. Unfortunately, long-acting therapies that produce soluble VEGF receptors (encapsulated cell technology and adenovirus injected DNA) have failed in phase II trials. The development of longer duration therapies remains a difficult and frustrating process, and frequent drug injections are likely to remain the standard-of-care for years to come.

[Orbito-palpebral vascular pathology].

PubMed

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

2016-11-01

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

[Aspects of vascular physiology in clinical and vascular surgical practice: basic principles of vascular mechanics].

PubMed

Nocke, H; Meyer, F; Lessmann, V

2014-10-01

To be able to evaluate properly a vascular problem, basic concepts of vascular physiology need to be considered, as they have been taught in physiology for a long time. This article deals with selected definitions and laws of passive vascular mechanics, subdivided into parameters of vascular filling and parameters of vascular flow. PARAMETERS OF VASCULAR FILLING: During vascular filling the transmural pressure distends the vascular wall until it is balanced by the wall tension. The extent of this distension up to the point of balance depends on the elasticity of the wall. Transmural pressure, wall tension and elasticity are defined, and their respective importance is described by clinical examples, e.g. aneurysm and varix. PARAMETERS OF VASCULAR FLOW: The vascular flow can be divided into stationary and pulsating components. Both components are relevant for the bloodstream. Since the blood flow is directed in the circuit, it can be understood in first approximation as stationary ("direct current").The direct current model uses only the average values of the pulsating variables. The great advantage of the direct current model is that it can be described with simple laws, which are not valid without reservation, but often allow a first theoretical approach to a vascular problem: Ohm's law, driving pressure, flow resistance, Hagen-Poiseuille law, wall shear stress, law of continuity, Bernoulli's equation and Reynold's number are described and associated with clinical examples.The heart is a pressure-suction pump and produces a pulsating flow, the pulse. The pulse runs with pulse wave velocity, which is much larger than the blood flow velocity, through the arterial vascular system. During propagation, the pulse has to overcome the wave resistance (impedance). Wherever the wave resistance changes, e.g., at vascular bifurcations and in the periphery, it comes to reflections. The incident (forward) and reflected (backward) waves are superimposed to yield the resulting

Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling.

PubMed

Marsano, Anna; Medeiros da Cunha, Carolina M; Ghanaati, Shahram; Gueven, Sinan; Centola, Matteo; Tsaryk, Roman; Barbeck, Mike; Stuedle, Chiara; Barbero, Andrea; Helmrich, Uta; Schaeren, Stefan; Kirkpatrick, James C; Banfi, Andrea; Martin, Ivan

2016-12-01

: Chondrogenic differentiation of bone marrow-derived mesenchymal stromal/stem cells (MSCs) can be induced by presenting morphogenetic factors or soluble signals but typically suffers from limited efficiency, reproducibility across primary batches, and maintenance of phenotypic stability. Considering the avascular and hypoxic milieu of articular cartilage, we hypothesized that sole inhibition of angiogenesis can provide physiological cues to direct in vivo differentiation of uncommitted MSCs to stable cartilage formation. Human MSCs were retrovirally transduced to express a decoy soluble vascular endothelial growth factor (VEGF) receptor-2 (sFlk1), which efficiently sequesters endogenous VEGF in vivo, seeded on collagen sponges and immediately implanted ectopically in nude mice. Although naïve cells formed vascularized fibrous tissue, sFlk1-MSCs abolished vascular ingrowth into engineered constructs, which efficiently and reproducibly developed into hyaline cartilage. The generated cartilage was phenotypically stable and showed no sign of hypertrophic evolution up to 12 weeks. In vitro analyses indicated that spontaneous chondrogenic differentiation by blockade of angiogenesis was related to the generation of a hypoxic environment, in turn activating the transforming growth factor-β pathway. These findings suggest that VEGF blockade is a robust strategy to enhance cartilage repair by endogenous or grafted mesenchymal progenitors. This article outlines the general paradigm of controlling the fate of implanted stem/progenitor cells by engineering their ability to establish specific microenvironmental conditions rather than directly providing individual morphogenic cues. Chondrogenic differentiation of mesenchymal stromal/stem cells (MSCs) is typically targeted by morphogen delivery, which is often associated with limited efficiency, stability, and robustness. This article proposes a strategy to engineer MSCs with the capacity to establish specific

[The age-related macular degeneration as a vascular disease/part of systemic vasculopathy: contributions to its pathogenesis].

PubMed

Fischer, Tamás

2015-03-01

The wall of blood vessels including those in choroids may be harmed by several repeated and/or prolonged mechanical, physical, chemical, microbiological, immunologic, and genetic impacts (risk factors), which may trigger a protracted response, the so-called host defense response. As a consequence, pathological changes resulting in vascular injury (e. g. atherosclerosis, age-related macular degeneration) may be evolved. Risk factors can also act directly on the endothelium through an increased production of reactive oxygen species promoting an endothelial activation, which leads to endothelial dysfunction, the onset of vascular disease. Thus, endothelial dysfunction is a link between the harmful stimulus and vascular injury; any kind of harmful stimuli may trigger the defensive chain that results in inflammation that may lead to vascular injury. It has been shown that even early age-related macular degeneration is associated with the presence of diffuse arterial disease and patients with early age-related macular degeneration demonstrate signs of systemic and retinal vascular alterations. Chronic inflammation, a feature of AMD, is tightly linked to diseases associated with ED: AMD is accompanied by a general inflammatory response, in the form of complement system activation, similar to that observed in degenerative vascular diseases such as atherosclerosis. All these facts indicate that age-related macular degeneration may be a vascular disease (or part of a systemic vasculopathy). This recognition could have therapeutic implications because restoration of endothelial dysfunction may prevent the development or improve vascular disease resulting in prevention or improvement of age-related macular degeneration as well.

Bevacizumab, an anti-vascular endothelial growth factor antibody, inhibits osteoarthritis.

PubMed

Nagai, Toshihiro; Sato, Masato; Kobayashi, Miyuki; Yokoyama, Munetaka; Tani, Yoshiki; Mochida, Joji

2014-09-18

Angiogenesis is an important factor in the development of osteoarthritis (OA). We investigated the efficacy of bevacizumab, an antibody against vascular endothelial growth factor and an inhibitor of angiogenesis, in the treatment of OA using a rabbit model of anterior cruciate ligament transection. First, we evaluated the response of gene expression and histology of the normal joint to bevacizumab treatment. Next, in a rabbit model of OA induced by anterior cruciate ligament transection, we used macroscopic and histological evaluations and real-time polymerase chain reaction (PCR) to examine the responses to intravenous (systemic) administration of bevacizumab (OAB IV group). We also investigated the efficacy of intra-articular (local) administration of bevacizumab in OA-induced rabbits (OAB IA group). Histologically, bevacizumab had no negative effect in normal joints. Bevacizumab did not increase the expression of genes for catabolic factors in the synovium, subchondral bone, or articular cartilage, but it increased the expression of collagen type 2 in the articular cartilage. Macroscopically and histologically, the OAB IV group exhibited a reduction in articular cartilage degeneration and less osteophyte formation and synovitis compared with the control group (no bevacizumab; OA group). Real-time PCR showed significantly lower expression of catabolic factors in the synovium in the OAB IV group compared with the OA group. In articular cartilage, expression levels of aggrecan, collagen type 2, and chondromodulin-1 were higher in the OAB IV group than in the OA group. Histological evaluation and assessment of pain behaviour showed a superior effect in the OAB IA group compared with the OAB IV group 12 weeks after administration of bevacizumab, even though the total dosage given to the OAB IA group was half that received by the OAB IV group. Considering the dosage and potential adverse effects of bevacizumab, the local administration of bevacizumab is a more

Adenoviral mediated interferon-alpha 2b gene therapy suppresses the pro-angiogenic effect of vascular endothelial growth factor in superficial bladder cancer.

PubMed

Adam, Liana; Black, Peter C; Kassouf, Wassim; Eve, Beryl; McConkey, David; Munsell, Mark F; Benedict, William F; Dinney, Colin P N

2007-05-01

Intravesical adenovirus mediated interferon-alpha gene transfer has a potent therapeutic effect against superficial human bladder carcinoma xenografts growing in the bladder of athymic nude mice. We determined whether the inhibition of angiogenesis might contribute to the antitumor effect. We treated several human urothelial carcinoma cells with adenovirus mediated interferon-alpha 2b and monitored its effects on the production of angiogenic factors using real-time reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemical analysis and a gel shift based transcription factor array. To assess the role of adenovirus mediated interferon 2b in angiogenic activity we used in vitro invasion assays and evaluated the anti-angiogenic effects of adenovirus mediated interferon gene therapy in an orthotopic murine model of human superficial bladder cancer. In adenovirus mediated interferon-alpha infected 253J B-V cells vascular endothelial growth factor was decreased and anti-angiogenic interferon-gamma inducible protein 10 was up-regulated. In contrast, the addition of as much as 100,000 IU recombinant interferon had no apparent effect on vascular endothelial growth factor production. Conditioned medium derived from adenovirus mediated interferon 2b infected 253J B-V cells greatly decreased the invasive potential of human endothelial cells and down-regulated their matrix metalloproteinase 2 expression compared to controls. Furthermore, adenovirus mediated interferon 2b blocked pro-angiogenic nuclear signals, such as the transcription factors activating protein-1 and 2, stimulating protein-1, nuclear factor kappaB and c-myb. In vivo experiments revealed significant vascular endothelial growth factor down-regulation and decreased tumor vessel density in the adenovirus mediated interferon 2b treated group compared to controls. Treatment with adenovirus mediated interferon 2b increases the angiostatic activity of the bladder cancer microenvironment

Modeling Vascularized Bone Regeneration Within a Porous Biodegradable CaP Scaffold Loaded with Growth Factors

PubMed Central

Sun, X; Kang, Y; Bao, J; Zhang, Y; Yang, Y; Zhou, X

2013-01-01

Osteogenetic microenvironment is a complex constitution in which extracellular matrix (ECM) molecules, stem cells and growth factors each interact to direct the coordinate regulation of bone tissue development. Importantly, angiogenesis improvement and revascularization are critical for osteogenesis during bone tissue regeneration processes. In this study, we developed a three-dimensional (3D) multi-scale system model to study cell response to growth factors released from a 3D biodegradable porous calcium phosphate (CaP) scaffold. Our model reconstructed the 3D bone regeneration system and examined the effects of pore size and porosity on bone formation and angiogenesis. The results suggested that scaffold porosity played a more dominant role in affecting bone formation and angiogenesis compared with pore size, while the pore size could be controlled to tailor the growth factor release rate and release fraction. Furthermore, a combination of gradient VEGF with BMP2 and Wnt released from the multi-layer scaffold promoted angiogenesis and bone formation more readily than single growth factors. These results demonstrated that the developed model can be potentially applied to predict vascularized bone regeneration with specific scaffold and growth factors. PMID:23566802

Multinucleate cell angiohistiocytoma: a fibrohistiocytic proliferation with increased mast cell numbers and vascular hyperplasia.

PubMed

Puig, Lluís; Fernández-Figueras, María-Teresa; Bielsa, Isabel; Lloveras, Betlem; Alomar, Agustín

2002-04-01

Multinucleate cell angiohistiocytoma (MCAH) is an uncommon lesion clinically characterized by multiple papules usually located on the face and acral regions of elderly women. Histopathologically, MCAH is characterized by dermal vascular hyperplasia associated with increased number of factor XIIIa-positive fibrohistiocytic cells and multinucleate cells with scalloped borders. We report the clinical, histopathological and immunohistochemical features of three cases of MCAH, with ulstrastructural study in one of them. The patients were a woman and two men of 56, 40 and 70 years of age, respectively. They all had multiple dull-red papules, which had appeared over several years and were located on the face, the trunk and the dorsa of the hands, respectively. The reticular dermis presented a fibrohistiocytic proliferation of factor XIIIa-positive cells, with abundant bizarre multinucleate cells and vascular hyperplasia. Increased mast cell numbers were seen in all cases, often in apposition to multinucleate cells. Histopathological differential diagnosis of MCAH includes mainly angiofibromas and dermatofibromas, even though vascular hyperplasia can be prominent and has led to many authors to classify MCAH among vascular tumors. Bizarre multinucleate cells can be found in reactive, neoplastic and inflammatory lesions in many sites of the body, and mast cells can play a role in their morphogenesis.

Low vascularity predicts favourable outcomes in leiomyoma patients treated with uterine artery embolization.

PubMed

Tang, Yixin; Chen, Chunlin; Duan, Hui; Ma, Ben; Liu, Ping

2016-10-01

To investigate the clinical factors predicting outcomes of leiomyoma treated with uterine artery embolization (UAE). A total of 183 uterine leiomyoma patients undergoing UAE were retrospectively analyzed. Patient age, characteristics of vascular supply in magnetic resonance imaging (MRI)/digital subtraction angiography (DSA), number, size and location of leiomyoma were recorded. Leiomyoma regrowth, new leiomyoma appearance and recurrence of any previously reported symptoms were carefully monitored over a mean follow-up of 30 months (median 32 months, range 12-80). Potential recurrence risk factors were analyzed by univariate and multivariate cox regression analysis. Twenty-three recurrences were recorded. The difference in the vascularity classification systems between MRI and DSA was not statistically significant (P = 0.059). High vascularity in MRI, high vascularity in DSA and multiple leiomyoma showed a significant risk of recurrence using univariate and multivariate analysis (P = 0.004, P < 0.001 and P = 0.023, respectively). The other factors were not significantly associated with leiomyoma recurrence (P > 0.05). Low vascularity and solitary leiomyoma indicated favourable outcomes in patients treated with UAE. • Low vascularity and solitary mass predicted favourable outcomes in UAE-treated patients. • MRI might provide information on vascularity in leiomyoma before UAE. • Variations in vascular supply, age, size, location were not associated with recurrence.

Magnesium Counteracts Vascular Calcification: Passive Interference or Active Modulation?

PubMed

Ter Braake, Anique D; Shanahan, Catherine M; de Baaij, Jeroen H F

2017-08-01

Over the last decade, an increasing number of studies report a close relationship between serum magnesium concentration and cardiovascular disease risk in the general population. In end-stage renal disease, an association was found between serum magnesium and survival. Hypomagnesemia was identified as a strong predictor for cardiovascular disease in these patients. A substantial body of in vitro and in vivo studies has identified a protective role for magnesium in vascular calcification. However, the precise mechanisms and its contribution to cardiovascular protection remain unclear. There are currently 2 leading hypotheses: first, magnesium may bind phosphate and delay calcium phosphate crystal growth in the circulation, thereby passively interfering with calcium phosphate deposition in the vessel wall. Second, magnesium may regulate vascular smooth muscle cell transdifferentiation toward an osteogenic phenotype by active cellular modulation of factors associated with calcification. Here, the data supporting these major hypotheses are reviewed. The literature supports both a passive inorganic phosphate-buffering role reducing hydroxyapatite formation and an active cell-mediated role, directly targeting vascular smooth muscle transdifferentiation. However, current evidence relies on basic experimental designs that are often insufficient to delineate the underlying mechanisms. The field requires more advanced experimental design, including determination of intracellular magnesium concentrations and the identification of the molecular players that regulate magnesium concentrations in vascular smooth muscle cells. © 2017 American Heart Association, Inc.

Role of Staphylococcus aureus Virulence Factors in Inducing Inflammation and Vascular Permeability in a Mouse Model of Bacterial Endophthalmitis

PubMed Central

Kumar, Ajay; Kumar, Ashok

2015-01-01

Staphylococcus (S.) aureus is a common causative agent of bacterial endophthalmitis, a vision threatening complication of eye surgeries. The relative contribution of S. aureus virulence factors in the pathogenesis of endophthalmitis remains unclear. Here, we comprehensively analyzed the development of intraocular inflammation, vascular permeability, and the loss of retinal function in C57BL/6 mouse eyes, challenged with live S. aureus, heat-killed S. aureus (HKSA), peptidoglycan (PGN), lipoteichoic acid (LTA), staphylococcal protein A (SPA), α-toxin, and Toxic-shock syndrome toxin 1 (TSST1). Our data showed a dose-dependent (range 0.01 μg/eye to 1.0 μg/eye) increase in the levels of inflammatory mediators by all virulence factors. The cell wall components, particularly PGN and LTA, seem to induce higher levels of TNF-α, IL-6, KC, and MIP2, whereas the toxins induced IL-1β. Similarly, among the virulence factors, PGN induced higher PMN infiltration. The vascular permeability assay revealed significant leakage in eyes challenged with live SA (12-fold) and HKSA (7.3-fold), in comparison to other virulence factors (~2-fold) and controls. These changes coincided with retinal tissue damage, as evidenced by histological analysis. The electroretinogram (ERG) analysis revealed a significant decline in retinal function in eyes inoculated with live SA, followed by HKSA, SPA, and α-toxin. Together, these findings demonstrate the differential innate responses of the retina to S. aureus virulence factors, which contribute to intraocular inflammation and retinal function loss in endophthalmitis. PMID:26053426

Clopidogrel inhibits angiogenesis of gastric ulcer healing via downregulation of vascular endothelial growth factor receptor 2.

PubMed

Luo, Jiing-Chyuan; Peng, Yen-Ling; Chen, Tseng-Shing; Huo, Teh-Ia; Hou, Ming-Chih; Huang, Hui-Chun; Lin, Han-Chieh; Lee, Fa-Yauh

2016-09-01

Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogrel delays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms. Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation. The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK. Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway. Copyright © 2015. Published by Elsevier B.V.

Nestin upregulation characterizes vascular remodeling secondary to hypertension in the rat.

PubMed

Tardif, Kim; Hertig, Vanessa; Duquette, Natacha; Villeneuve, Louis; El-Hamamsy, Ismail; Tanguay, Jean-François; Calderone, Angelino

2015-05-15

Proliferation and hypertrophy of vascular smooth muscle cells represent hallmark features of vessel remodeling secondary to hypertension. The intermediate filament protein nestin was recently identified in vascular smooth muscle cells and in other cell types directly participated in proliferation. The present study tested the hypothesis that vessel remodeling secondary to hypertension was characterized by nestin upregulation in vascular smooth muscle cells. Two weeks after suprarenal abdominal aorta constriction of adult male Sprague-Dawley rats, elevated mean arterial pressure increased the media area and thickness of the carotid artery and aorta and concomitantly upregulated nestin protein levels. In the normal adult rat carotid artery, nestin immunoreactivity was observed in a subpopulation of vascular smooth muscle cells, and the density significantly increased following suprarenal abdominal aorta constriction. Filamentous nestin was detected in cultured rat carotid artery- and aorta-derived vascular smooth muscle cells and an analogous paradigm observed in human aorta-derived vascular smooth muscle cells. ANG II and EGF treatment of vascular smooth muscle cells stimulated DNA and protein synthesis and increased nestin protein levels. Lentiviral short-hairpin RNA-mediated nestin depletion of carotid artery-derived vascular smooth muscle cells inhibited peptide growth factor-stimulated DNA synthesis, whereas protein synthesis remained intact. These data have demonstrated that vessel remodeling secondary to hypertension was characterized in part by nestin upregulation in vascular smooth muscle cells. The selective role of nestin in peptide growth factor-stimulated DNA synthesis has revealed that the proliferative and hypertrophic responses of vascular smooth muscle cells were mediated by divergent signaling events. Copyright © 2015 the American Physiological Society.

Stem cell function during plant vascular development

PubMed Central

Miyashima, Shunsuke; Sebastian, Jose; Lee, Ji-Young; Helariutta, Yka

2013-01-01

The plant vascular system, composed of xylem and phloem, evolved to connect plant organs and transport various molecules between them. During the post-embryonic growth, these conductive tissues constitutively form from cells that are derived from a lateral meristem, commonly called procambium and cambium. Procambium/cambium contains pluripotent stem cells and provides a microenvironment that maintains the stem cell population. Because vascular plants continue to form new tissues and organs throughout their life cycle, the formation and maintenance of stem cells are crucial for plant growth and development. In this decade, there has been considerable progress in understanding the molecular control of the organization and maintenance of stem cells in vascular plants. Noticeable advance has been made in elucidating the role of transcription factors and major plant hormones in stem cell maintenance and vascular tissue differentiation. These studies suggest the shared regulatory mechanisms among various types of plant stem cell pools. In this review, we focus on two aspects of stem cell function in the vascular cambium, cell proliferation and cell differentiation. PMID:23169537

Correlation of serum intercellular adhesion molecule 1 and vascular endothelial growth factor with tumor grading and staging in breast cancer patients.

PubMed

Haghi, Alireza Rastgoo; Vahedi, Amir; Shekarchi, Ali Akbar; Kamran, Aziz

2017-01-01

Breast cancer is the most common cancer among women. There are several prognostic factors for this disease. The aim of this article is to explore the correlation of serum level of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule 1 (ICAM1) with tumor, node, metastasis staging and grading of breast cancer. Serum samples of 51 patients with breast cancer were assessed with enzyme-linked immunosorbent assay for the level of VEGF and ICAM1 preoperatively. After the operation, histopathologic specimens stained with hematoxylin and eosin were evaluated for tumor size, histopathologic subtype, grade, lymph node, vascular and lymphatic involvement. Then, the correlation of tumor stage and grade and serum level of markers was analyzed. There was no significant correlation between serum level of markers with vascular invasions, lymph node involvement, and menstruation. There was a weak correlation between tumor size and serum level of ICAM1 with Pearson score correlation, but there was no significant correlation with VEGF. There was no significant correlation between tumor grading and staging with the level of markers. There was a significant correlation between the level of VEGF and ICAM1 and histologic type of tumors in invasive through in situ tumors. Levels of VEGF and ICAM1 can be used as a predictor of tumor invasion and also for target therapy.

Beta-type transforming growth factor specifies organizational behavior in vascular smooth muscle cell cultures

PubMed Central

1987-01-01

In culture, vascular smooth muscle cells (SMC) grow in a "hill-and- valley" (multilayered) pattern of organization. We have studied the growth, behavioral organization, and biosynthetic phenotype of rat aortic SMC exposed to purified platelet-derived growth regulatory molecules. We show that multilayered growth is not a constitutive feature of cultured SMC, and that beta-type transforming growth factor (TGF-beta) is the primary determinant of multilayered growth and the hill-and-valley pattern of organization diagnostic for SMC in culture. TGF-beta inhibited, in a dose-dependent manner, the serum- or platelet- derived growth factor-mediated proliferation of these cells in two- dimensional culture, but only when cells were plated at subconfluent densities. The ability of TGF-beta to inhibit SMC growth was inversely correlated to plating cell density. When SMC were plated at monolayer density (5 X 10(4) cells/cm2) to allow maximal cell-to-cell contact, TGF-beta potentiated cell growth. This differential response of SMC to TGF-beta may contribute to the hill-and-valley pattern of organization. Unlike its effect on other cell types, TGF-beta did not enhance the synthesis of fibronectin or its incorporation into the extracellular matrix. However, the synthesis of a number of other secreted proteins was altered by TGF-beta treatment. SMC treated with TGF-beta for 4 or 8 h secreted markedly enhanced amounts of an Mr 38,000-D protein doublet whose synthesis is known to be increased by heparin (another inhibitor of SMC growth), suggesting metabolic similarities between heparin- and TGF-beta-mediated SMC growth inhibition. The data suggest that TGF-beta may play an important and complex regulatory role in SMC proliferation and organization during development and after vascular injury. PMID:3475277

Serum levels of vascular endothelial growth factor in preeclamptic and normotensive pregnancy.

PubMed

Hunter, A; Aitkenhead, M; Caldwell, C; McCracken, G; Wilson, D; McClure, N

2000-12-01

The purpose of these studies was first to determine if vascular endothelial growth factor (VEGF), a vascular permeability agent, is increased in the serum of women with preclinical and clinical preclampsia (PE), and second to determine how these levels change after delivery. Twenty preeclamptic and 25 normotensive women at term consented to have blood taken pre- and post-delivery. Ten preeclamptic, 10 gestational hypertensive, and 28 normotensive women had blood collected respectively at 12, 20, and 30 weeks gestation and predelivery. Serum was extracted from all samples, and VEGF concentrations were determined by radioimmunoassay. Predelivery, the median serum VEGF concentration in the preeclamptic group was 51.7 ng/mL, and in the control group the concentration was 13.9 ng/mL (P<0.0001). Serum VEGF concentrations fell within 24 hours of delivery in both groups, which resulted in median values of 3.8 ng/mL and 3.2 ng/mL respectively (P<0.3). At 12 and 20 weeks, there was no significant difference between the serum VEGF concentrations in the 3 groups (P<0.3, 0.052 respectively). At 30 weeks, prior to the onset of clinical PE, the serum VEGF levels in the eventual preeclamptic group were elevated significantly compared with the gestational hypertensive and normotensive groups (P<0.001). Predelivery serum VEGF concentrations were significantly elevated in the preeclamptic group and were similar to those in the first study (P<0.0001). These findings suggest that VEGF may be important in the pathophysiology of PE and has the potential to act as a preclinical marker for the condition.

Vascular endothelial growth factor increases fenestral permeability in hepatic sinusoidal endothelial cells.

PubMed

Yokomori, Hiroaki; Oda, Masaya; Yoshimura, Kazunori; Nagai, Toshihiro; Ogi, Mariko; Nomura, Masahiko; Ishii, Hiromasa

2003-12-01

Vascular endothelial growth factor (VEGF) is an important regulator of vasculogenesis and vascular permeability. Hepatic sinusoidal endothelial cells (SECs) possess sieve-like pores that form an anastomosing labyrinth structure by the deeply invaginated plasma membrane. Caveolin is the principal structural protein in caveolae. In this study, we examined the role of VEGF on the fenestration and permeability of SECs and the relation with caveolin-1. SECs isolated from rat livers by collagenase infusion method were cultured for 24 h with (10 or 100 ng/ml) or without VEGF. The cells were then examined by transmission and scanning electron microscopy (EM). The expression of caveolin was investigated by confocal immunofluorescence, immunogold EM, and Western blot. Endocytosis and intracellular traffic was studied using horseradish peroxidase (HRP) reaction as a marker of fluid phase transport in SECs. Both transmission and scanning EM showed an increased number of sinusoidal endothelial fenestrae (SEF) in SECs cultured with VEGF. By confocal immunofluorescence, SECs cultured with VEGF displayed prominent caveolin-l-positive aggregates in the cytoplasm, especially surrounding the nucleus region. Immunogold EM depicted increased caveolin-1 reactivity on vesicles and vacuoles of VEGF-treated SECs compared with VEGF-nontreated cells. However, there was no change in the level of caveolin-1 protein expression on Western blot. After HRP injection, an increase of electron-dense tracer filled the SEF in cells treated with VEGF. Our results suggested that VEGF induced fenestration in SECs, accompanied by an increased number of caveolae-like vesicles. Increased caveolin-1 might be associated with vesicle formation but not with fenestration. Increased fenestration may augment hepatic sinusoidal permeability and transendothelial transport.

Apatinib-loaded nanoparticles suppress vascular endothelial growth factor-induced angiogenesis and experimental corneal neovascularization.

PubMed

Lee, Jung Eun; Kim, Koung Li; Kim, Danbi; Yeo, Yeongju; Han, Hyounkoo; Kim, Myung Goo; Kim, Sun Hwa; Kim, Hyuncheol; Jeong, Ji Hoon; Suh, Wonhee

2017-01-01

Pathological angiogenesis is one of the major symptoms of severe ocular diseases, including corneal neovascularization. The blockade of vascular endothelial growth factor (VEGF) action has been recognized as an efficient strategy for treating corneal neovascularization. In this study, we aimed to investigate whether nanoparticle-based delivery of apatinib, a novel and selective inhibitor of VEGF receptor 2, inhibits VEGF-mediated angiogenesis and suppresses experimental corneal neovascularization. Water-insoluble apatinib was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro angiogenesis assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles potently inhibited VEGF-induced tube formation, scratch wounding migration, and proliferation of human endothelial cells. In a rat model of alkali burn injury-induced corneal neovascularization, a subconjunctival injection of Apa-HSA-PEG nanoparticles induced a significant decrease in neovascularization compared to that observed with an injection of free apatinib solution or phosphate-buffered saline. An in vivo distribution study using HSA-PEG nanoparticles loaded with fluorescent hydrophobic model drugs revealed the presence of a substantial number of nanoparticles in the corneal stroma within 24 h after injection. These in vitro and in vivo results demonstrate that apatinib-loaded nanoparticles may be promising for the prevention and treatment of corneal neovascularization-related ocular disorders.