Vascular dysfunction in cerebrovascular disease: mechanisms and therapeutic intervention

2010 ◽  
Vol 119 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Alyson A. Miller ◽  
Klaudia Budzyn ◽  
Christopher G. Sobey
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Cerebrovascular Disease ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Amyloid Β ◽  
Current Evidence ◽  
Underlying Causes ◽  
Strong Candidate ◽  
Vascular Oxidative Stress

The endothelium plays a crucial role in the control of vascular homoeostasis through maintaining the synthesis of the vasoprotective molecule NO• (nitric oxide). Endothelial dysfunction of cerebral blood vessels, manifested as diminished NO• bioavailability, is a common feature of several vascular-related diseases, including hypertension, hypercholesterolaemia, stroke, subarachnoid haemorrhage and Alzheimer's disease. Over the past several years an enormous amount of research has been devoted to understanding the mechanisms underlying endothelial dysfunction. As such, it has become apparent that, although the diseases associated with impaired NO• function are diverse, the underlying causes are similar. For example, compelling evidence indicates that oxidative stress might be an important mechanism of diminished NO• signalling in diverse models of cardiovascular ‘high-risk’ states and cerebrovascular disease. Although there are several sources of vascular ROS (reactive oxygen species), the enzyme NADPH oxidase is emerging as a strong candidate for the excessive ROS production that is thought to lead to vascular oxidative stress. The purpose of the present review is to outline some of the mechanisms thought to contribute to endothelial dysfunction in the cerebral vasculature during disease. More specifically, we will highlight current evidence for the involvement of ROS, inflammation, the RhoA/Rho-kinase pathway and amyloid β-peptides. In addition, we will discuss currently available therapies for improving endothelial function and highlight future therapeutic strategies.

scholarly journals Nanoparticles in Medicine: A Focus on Vascular Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-20 ◽  
Author(s):  
M. D. Mauricio ◽  
S. Guerra-Ojeda ◽  
P. Marchio ◽  
S. L. Valles ◽  
M. Aldasoro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Biomedical Applications ◽  
Vascular Tone ◽  
Vascular Dysfunction ◽  
Antioxidant Properties ◽  
Cell Toxicity ◽  
No Bioavailability ◽  
Vascular Alteration ◽  
Vascular Oxidative Stress

Nanotechnology has had a significant impact on medicine in recent years, its application being referred to as nanomedicine. Nanoparticles have certain properties with biomedical applications; however, in some situations, they have demonstrated cell toxicity, which has caused concern surrounding their clinical use. In this review, we focus on two aspects: first, we summarize the types of nanoparticles according to their chemical composition and the general characteristics of their use in medicine, and second, we review the applications of nanoparticles in vascular alteration, especially in endothelial dysfunction related to oxidative stress. This condition can lead to a reduction in nitric oxide (NO) bioavailability, consequently affecting vascular tone regulation and endothelial dysfunction, which is the first phase in the development of cardiovascular diseases. Therefore, nanoparticles with antioxidant properties may improve vascular dysfunction associated with hypertension, diabetes mellitus, or atherosclerosis.

Vascular and Endothelial Biology of Aging

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-5-SCI-5
Author(s):  
Frank M. Faraci
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Transgenic Mice ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Vascular Aging ◽  
Age Related ◽  
The Brain

Abstract Although aging is one of the greatest risk factors for vascular disease, very little is known regarding mechanisms that control the progression of vascular aging at the level of the endothelial cell. Endothelial dysfunction - a critical element of carotid artery and cerebrovascular disease - progresses with age, contributing to hypoperfusion, increased risk for ischemic stroke, and cognitive decline. Studies from several laboratories support the concept that age-induced endothelial dysfunction may occur earlier and be larger in magnitude in the cerebral circulation than in blood vessels outside of the brain. Thus, the circulationof the brain may be particularly sensitive to age-induced endothelial dysfunction. In relation to underlying mechanisms, angiotensin II type 1 receptors, NADPH oxidase, and oxidative stress appear to play a key role in age-related vascular dysfunction. The nuclear receptor peroxisome proliferator-activated receptor-g (PPARg) exerts protective effects in the vasculature when pharmacologically activated. We recently examined the hypothesis that endothelial PPARg protects against vascular aging. We studied carotid arteries from adult and old transgenic mice with endothelial specific expression of a human dominant negative mutation in PPARg driven by the vascular cadherin promoter (designated E-V290M), along with non-transgenic littermates. Endothelial function was similar in arteries from adult non-transgenic and E-V290M mice as well as old non-transgenic mice. In contrast, there was a marked reduction in endothelial function in old E-V290M mice. This augmented endothelial dysfunction was not altered by inhibition of cyclooxygenase, but was restored to normal by a superoxide scavenger, an inhibitor of NADPH oxidase, or inhibition of Rho kinase. Oxidant and inflammatory related mechanisms often interact. Vascular expression of interleukin-6, another mediator of vascular disease, was increased 1.6-fold in old non-transgenic mice, but almost 9-fold in old E-V290M mice. Expression of CDKN2A, a molecular marker of senescence, was ~two-fold greater in old E-V290M mice compared to controls. These findings provide the first evidence that senescence and age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARg through mechanisms that involve oxidative stress, inflammation, and Rho kinase. This critical role for endothelial PPARg has implications for vascular pathophysiology as well as therapeutic approaches for age-induced large and small vessel disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting mitochondrial fitness as a strategy for healthy vascular aging

2020 ◽  
Vol 134 (12) ◽  
pp. 1491-1519 ◽  
Author(s):  
Matthew J. Rossman ◽  
Rachel A. Gioscia-Ryan ◽  
Zachary S. Clayton ◽  
Michael P. Murphy ◽  
Douglas R. Seals
Keyword(s):  
Oxidative Stress ◽  
Carotid Arteries ◽  
Vascular Dysfunction ◽  
Current Evidence ◽  
Vascular Aging ◽  
Cvd Risk ◽  
Age Related ◽  
Vascular Oxidative Stress ◽  
Primary Risk Factor ◽  
Related Increase

Abstract Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations (‘research gaps’) for future investigation.

Abstract MP30: Circulating Sars-cov-2 Spike Protein 1 Causes Microarteriolar Oxidative Stress, Endothelial Dysfunction And Enhanced Thromboxane And Endothelin Contractility That Are Prevented By Spironolactone.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Dan Wang ◽  
Christopher S Wilcox
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Fluorescence Microscopy ◽  
Vascular Dysfunction ◽  
Microvascular Complications ◽  
Spike Protein ◽  
Ros Generation ◽  
Intravenous Injections ◽  
Novel Model

Introduction and hypothesis: Following bodily entry, the SARS-CoV-2 virus undergoes pulmonary replication with release of circulating viral spike protein 1 (SP1) into the bloodstream. Uptake of SP1 by endothelial cells might provoke vascular dysfunction and thrombosis. We hypothesized that spironolactone could prevent microvascular complications from circulating SP1 in COVID-19. Methods: male C57Bl/6 mice received spironolactone (100 mg · kg -1 · d -1 PO x 3d) or vehicle and intravenous injections of recombinant full-length human SP1 (10 μg per mouse) or vehicle. They were euthanized after 3 days. Mesenteric resistant arterioles (n=4 per group) were dissected and mounted on isometric myographs. Acetylcholine-induced EDRF responses and L-NAME-inhibitable NO generation (DAF-FM fluorescence) were studied in pre-constricted vessels and contraction to endothelin 1 (ET1) or thromboxane (U-46, 619) and ET1-induced ROS (PEG-SOD inhibitable ethidium: dihydroethidium fluorescence) were studied by fluorescence microscopy in other vessels. Results: SP1 reduced acetylcholine-induced EDRF (17 ± 3 vs 27 ± 5 % mean ± sem; P < 0.05) and NO generation (0.21 ± 0.03 vs 0.36 ± 0.04, F 1 /F 0 ; P < 0.05) while increasing contraction to ET1 (10 -7 mol·l -1 : 124 ± 13 vs 89 ± 4 %; P < 0.05) and U-46, 619 (10 -6 mol·l -1 :114± 5 vs 87± 6 %; P < 0.05) and ET1-induced ROS generation(0.30± 0.08 vs 0.09± 0.03; P < 0.05). Spironolactone did not modify any of these responses in vessels from normal mice but prevented all the effects of SP1. Conclusion: these preliminary studies provide a novel model to study COVID-19 vasculopathy. They indicate that spironolactone can provide protection from microvascular oxidative stress, endothelial dysfunction and enhanced contractility and might thereby moderate COVID-19 complications.

scholarly journals Kidney dysfunction in the low-birth weight murine adult: implications of oxidative stress

2018 ◽  
Vol 315 (3) ◽  
pp. F583-F594 ◽  
Author(s):  
Wasan Abdulmahdi ◽  
May M. Rabadi ◽  
Edson Jules ◽  
Yara Marghani ◽  
Noor Marji ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Birth Weight ◽  
Endothelial Dysfunction ◽  
Low Birth Weight ◽  
Vascular Dysfunction ◽  
Vascular Density ◽  
Immunofluorescence Analysis ◽  
Doppler Flowmetry ◽  
Maternal Undernutrition ◽  
Nephron Endowment

Maternal undernutrition (MUN) during pregnancy leads to low-birth weight (LBW) neonates that have a reduced kidney nephron endowment and higher morbidity as adults. Using a severe combined caloric and protein-restricted mouse model of MUN to generate LBW mice, we examined the progression of renal insufficiency in LBW adults. Through 6 mo of age, LBW males experienced greater albuminuria (ELISA analysis), a more rapid onset of glomerular hypertrophy, and a worse survival rate than LBW females. In contrast, both sexes experienced a comparable progressive decline in renal vascular density (immunofluorescence analysis), renal blood flow (Laser-Doppler flowmetry analysis), glomerular filtration rate (FITC-sinistrin clearance analysis), and a progressive increase in systemic blood pressure (measured via tail-cuff method). Isolated aortas from both LBW sexes demonstrated reduced vasodilation in response to ACh, indicative of reduced nitric oxide bioavailability and endothelial dysfunction. ELISA and immunofluorescence analysis revealed a significant increase of circulating reactive oxygen species and NADPH oxidase type 4 (NOX4) expression in both LBW sexes, although these increases were more pronounced in males. Although more effective in males, chronic tempol treatment did improve all observed pathologies in both sexes of LBW mice. Chronic NOX4 inhibition with GKT137831 was more effective than tempol in preventing pathologies in LBW males. In conclusion, despite some minor differences, LBW female and male adults have a reduced nephron endowment comparable with progressive renal and vascular dysfunction, which is associated with increased oxidative stress and subsequent endothelial dysfunction. Tempol treatment and/or NOX4 inhibition attenuates renal and vascular dysfunction in LBW adults.

scholarly journals Unacylated Ghrelin Improves Vascular Dysfunction and Attenuates Atherosclerosis during High-Fat Diet Consumption in Rodents

2019 ◽  
Vol 20 (3) ◽  
pp. 499 ◽  
Author(s):  
Michela Zanetti ◽  
Gianluca Gortan Cappellari ◽  
Andrea Graziani ◽  
Rocco Barazzoni
Keyword(s):  
Oxidative Stress ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
High Fat ◽  
Enos Expression ◽  
Unacylated Ghrelin ◽  
Vascular Oxidative Stress ◽  
Expression And Activity

Unacylated ghrelin (UnGhr) exerts several beneficial actions on vascular function. The aim of this study was to assess the effects of UnGhr on high-fat induced endothelial dysfunction and its underlying mechanisms. Thoracic aortas from transgenic mice, which were overexpressing UnGhr and being control fed either a standard control diet (CD) or a high-fat diet (HFD) for 16 weeks, were harvested and used for the assessment of vascular reactivity, endothelial nitric oxide synthase (eNOS) expression and activity, thiobarbituric acid reactive substances (TBARS) and glutathione levels, and aortic lipid accumulation by Oil Red O staining. Relaxations due to acetylcholine and to DEA-NONOate were reduced (p < 0.05) in the HFD control aortas compared to vessels from the CD animals. Overexpression of UnGhr prevented HFD-induced vascular dysfunction, while eNOS expression and activity were similar in all vessels. HFD-induced vascular oxidative stress was demonstrated by increased (p < 0.05) aortic TBARS and glutathione in wild type (Wt) mice; however, this was not seen in UnGhr mice. Moreover, increased (p < 0.05) HFD-induced lipid accumulation in vessels from Wt mice was prevented by UnGhr overexpression. In conclusion, chronic UnGhr overexpression results in improved vascular function and reduced plaque formation through decreased vascular oxidative stress, without affecting the eNOS pathway. This research may provide new insight into the mechanisms underlying the beneficial effects of UnGhr on the vascular dysfunction associated with obesity and the metabolic syndrome.

Oxidative stress and endothelial dysfunction

2007 ◽  
Vol 27 (01) ◽  
pp. 5-12 ◽  
Author(s):  
G. Muller ◽  
C. Goettsch ◽  
H. Morawietz
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vessel Wall ◽  
Clinical Implications ◽  
Oxygen Species ◽  
Vascular Oxidative Stress ◽  
Arteries And Veins ◽  
Different Sources

SummaryThis review focuses on the role of vascular oxidative stress in the development and progression of endothelial dysfunction. We discuss different sources of oxidative stress in the vessel wall, oxidative stress and coagulation, the role of oxidative stress and vascular function in arteries and veins, the flow-dependent regulation of reactive oxygen species, the putative impact of oxidative stress on atherosclerosis, the interaction of angiotensin II, oxidative stress and endothelial dysfunction, and clinical implications.

scholarly journals Differential contribution of Nox1, Nox2 and Nox4 to kidney vascular oxidative stress and endothelial dysfunction in obesity

Redox Biology ◽  
2020 ◽  
Vol 28 ◽  
pp. 101330 ◽  
Author(s):  
Mercedes Muñoz ◽  
Maria Elvira López-Oliva ◽  
Claudia Rodríguez ◽  
María Pilar Martínez ◽  
Javier Sáenz-Medina ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Vascular Oxidative Stress ◽  
Differential Contribution

scholarly journals Contribution of monoamine oxidases to vascular oxidative stress in patients with end-stage renal disease requiring hemodialysis

2017 ◽  
Vol 95 (11) ◽  
pp. 1383-1388 ◽  
Author(s):  
Diana Uțu ◽  
Stelian Pantea ◽  
Oana M. Duicu ◽  
Danina M. Muntean ◽  
Adrian Sturza
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Renal Disease ◽  
Vascular Access ◽  
End Stage Renal Disease ◽  
Mao Inhibitors ◽  
Monoamine Oxidases ◽  
Stage Renal Disease ◽  
End Stage ◽  
Vascular Oxidative Stress

Arteriovenous fistula (AVF) is the “lifeline” for patients with end-stage renal disease (ESRD) undergoing hemodialysis. AVF maturation failure is a poorly understood process, one of the contributors being endothelial dysfunction due to oxidative stress. Monoamine oxidases (MAOs) A and B were recently identified as novel sources of vascular oxidative stress. The aim of the present study was to assess the contribution of MAOs to the endothelial dysfunction in patients with ESDR with indication of hemodialysis. Fragments of brachial artery collaterals were harvested from ESRD patients during the surgical procedure aimed at creating the vascular access in the cubital fossa. The effect of increasing concentrations (10, 30, 100 μmol/L) of the irreversible MAO-A inhibitor, clorgyline, and MAO-B inhibitor, selegiline, on endothelial-dependent relaxation (EDR) in response to cumulative doses of acetylcholine was studied in isolated phenylephrine-preconstricted vascular rings. Hydrogen peroxide (H2O2) production was assessed using ferrous oxidation xylenol orange assay. We showed that incubation of brachial rings with MAO inhibitors significantly improved EDR and attenuated H2O2 generation in patients with ESRD. MAO-related oxidative stress might contribute to the primary dysfunction/non-maturation of the AVF and MAO inhibitors could improve maturation and long-term patency of the vascular access in dialysis patients.

scholarly journals Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats

2004 ◽  
Vol 558 (1) ◽  
pp. 239-248 ◽  
Author(s):  
Maria do Carmo P. Franco ◽  
Zuleica B. Fortes ◽  
Eliana H. Akamine ◽  
Elisa M. Kawamoto ◽  
Cristoforo Scavone ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Vascular Oxidative Stress
Sign in / Sign up

Export Citation Format

Share Document