MS general pharmacology—the vascular system Endothelial dysfunction in atherosclerosis

CoQ10 is an endogenous antioxidant produced in all cells that plays an essential role in energy metabolism and antioxidant protection. CoQ10 distribution is not uniform among different organs, and the highest concentration is observed in the heart, though its levels decrease with age. Advanced age is the major risk factor for cardiovascular disease and endothelial dysfunction triggered by oxidative stress that impairs mitochondrial bioenergetic and reduces NO bioavailability, thus affecting vasodilatation. The rationale of the use of CoQ10 in cardiovascular diseases is that the loss of contractile function due to an energy depletion status in the mitochondria and reduced levels of NO for vasodilatation has been associated with low endogenous CoQ10 levels. Clinical evidence shows that CoQ10 supplementation for prolonged periods is safe, well-tolerated and significantly increases the concentration of CoQ10 in plasma up to 3–5 µg/mL. CoQ10 supplementation reduces oxidative stress and mortality from cardiovascular causes and improves clinical outcome in patients undergoing coronary artery bypass graft surgery, prevents the accumulation of oxLDL in arteries, decreases vascular stiffness and hypertension, improves endothelial dysfunction by reducing the source of ROS in the vascular system and increases the NO levels for vasodilation.

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The Role of Uridine Adenosine Tetraphosphate in the Vascular System

Advances in Pharmacological Sciences ◽

10.1155/2011/435132 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Takayuki Matsumoto ◽

Rita C. Tostes ◽

R. Clinton Webb

Keyword(s):

Smooth Muscle ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Smooth Muscle Cells ◽

Vascular Function ◽

Purinergic Receptors ◽

Potential Role ◽

Vascular System

The endothelium plays a pivotal role in vascular homeostasis, and endothelial dysfunction is a major feature of cardiovascular diseases, such as arterial hypertension, atherosclerosis, and diabetes. Recently, uridine adenosine tetraphosphate (Up4A) has been identified as a novel and potent endothelium-derived contracting factor (EDCF). Up4A structurally contains both purine and pyrimidine moieties, which activate purinergic receptors. There is an accumulating body of evidence to show that Up4A modulates vascular function by actions on endothelial and smooth muscle cells. In this paper, we discuss the effects of Up4A on vascular function and a potential role for Up4A in cardiovascular diseases.

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Coagulation and endothelial dysfunction during longterm hyperdynamic porcine bacteremia – effects of selective inducible nitric oxide synthase inhibition

Thrombosis and Haemostasis ◽

10.1160/th06-09-0498 ◽

2007 ◽

Vol 97 (02) ◽

pp. 304-309 ◽

Cited By ~ 15

Author(s):

Ales Krouzecky ◽

Jaroslav Radej ◽

Richard Rokyta ◽

Hana Kralova ◽

Peter Radermacher ◽

...

Keyword(s):

Nitric Oxide ◽

Platelet Count ◽

Endothelial Dysfunction ◽

Continuous Infusion ◽

Plasminogen Activator ◽

Nitrosative Stress ◽

Vascular System ◽

Plasminogen Activator Inhibitor ◽

Inos Inhibition ◽

Pai 1

SummaryCoagulation abnormalities have been implicated in the pathogenesis of sepsis and organ dysfunction. Nitric oxide (NO) is regarded as a critical mediator of many vascular pathologies, including sepsis. However, limited evidence is available to document a relationship between NO generated by inducible NO synthase (iNOS) and hemostatic abnormalities in sepsis. Therefore, we evaluated the effects of selective iNOS inhibition on markers of endothelial and coagulation homeostasis in a clinically relevant model of porcine bacteremia induced and maintained for 24 hours (h) with a continuous infusion of live P. aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n = 7) or continuous infusion of selective iNOS inhibitor L-NIL (n=7). Before as well as 12, 18 and 24 h after starting P. aeruginosafollowing variables related to i) endothelial dysfunction (von Willebrand factor [vWf]; tissue plasminogen activator activity [t-PA]; ii) coagulation (thrombin-antithrombin complexes [TAT]; platelet count); iii) fibrinolysis (t-PA activity, activity of plasminogen activator inhibitor type 1 (PAI-1 act); and iv) oxidative/ nitrosative stress (isoprostanes, nitrate/nitrite levels) were measured. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite and isoprostanes concentrations, prevented hypotension and acidosis. L-NIL significantly attenuated sepsisinduced rise in plasma vWF and TAT. P. aeruginosa-induced drop in t-PA activity was blunted by iNOS inhibition, while increased PAI-1 and reduced platelet count were not reversed by the treatment. In conclusion, selective iNOS inhibition was associated with attenuation of sepsis-induced coagulation and endothelial dysfunction suggesting the interplay between mediators of vascular system and hemostatic balance. Reduction of oxidative stress probably contributes to the beneficial effects afforded by iNOS blockade.

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Possibilities of optimization of pregnancy preparation in the presence of conditions accompanied by endothelial dysfunction

Medical Council ◽

10.21518/2079-701x-2020-3-68-73 ◽

2020 ◽

pp. 68-73

Author(s):

M. A. Vinogradova ◽

T. V. Kirsanova ◽

D. S. Serebriyskaya

Keyword(s):

Endothelial Dysfunction ◽

Vascular System ◽

Vascular Complications ◽

Reproductive Function ◽

Risk Groups ◽

Adverse Outcomes ◽

Chronic Venous Disease ◽

Venous Disease ◽

Autoimmune Pathology ◽

Main Components

The implementation of the reproductive function is one of the main components of women’s quality of life. Despite significant progress in the treatment of infertility and prevention of reproductive losses, these problems are still relevant. It is also important to timely diagnose various pathological processes in order to determine the tactics of preparing women for pregnancy and its further management, taking into account the pathogenetic characteristics of diseases. Various attempts have been made to optimize both diagnostic and therapeutic approaches. Special attention is paid to identifying risk groups and ensuring the most effective preparation for pregnancy, taking into account possible risk factors for adverse outcomes. Adequate diagnostics of background pathology and the use of proven effective methods of pregravid preparation can significantly improve pregnancy outcomes. Peculiarities of the vascular system functioning may affect both the life of the woman in general and the outcome of pregnancy. Endothelial dysfunction is a component of pathogenesis of many nosologies (diabetes mellitus, chronic venous disease, hypertension, autoimmune pathology, etc.). Restoration of vascular endothelial dysfunction and, as a consequence, prevention of probable vascular complications is one of the new goals in the preventive approach to pregnancy. The promising center of this approach is considered to be the drug sulodexide. The three main effects of this drug – antithrombotic, anti-inflammatory and defensive in relation to endothelium – provide a significant increase in pregnancy preparation possibilities in many nosologies. This review presents its main features and areas of use.

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Reversibility of endothelial dysfunction in diabetes: role of polyphenols

British Journal Of Nutrition ◽

10.1017/s0007114516001884 ◽

2016 ◽

Vol 116 (2) ◽

pp. 223-246 ◽

Cited By ~ 45

Author(s):

N. Suganya ◽

E. Bhakkiyalakshmi ◽

D. V. L. Sarada ◽

K. M. Ramkumar

Keyword(s):

Endothelial Cells ◽

Endothelial Dysfunction ◽

Vessel Wall ◽

Molecular Mechanisms ◽

Vascular System ◽

Microvascular Complications ◽

Arterial Disease ◽

Cellular Adhesion ◽

Vascular Homeostasis

AbstractThe endothelium, a thin single sheet of endothelial cells, is a metabolically active layer that coats the inner surface of blood vessels and acts as an interface between the circulating blood and the vessel wall. The endothelium through the secretion of vasodilators and vasoconstrictors serves as a critical mediator of vascular homeostasis. During the development of the vascular system, it regulates cellular adhesion and vessel wall inflammation in addition to maintaining vasculogenesis and angiogenesis. A shift in the functions of the endothelium towards vasoconstriction, proinflammatory and prothrombic states characterise improper functioning of these cells, leading to endothelial dysfunction (ED), implicated in the pathogenesis of many diseases including diabetes. Major mechanisms of ED include the down-regulation of endothelial nitric oxide synthase levels, differential expression of vascular endothelial growth factor, endoplasmic reticulum stress, inflammatory pathways and oxidative stress. ED tends to be the initial event in macrovascular complications such as coronary artery disease, peripheral arterial disease, stroke and microvascular complications such as nephropathy, neuropathy and retinopathy. Numerous strategies have been developed to protect endothelial cells against various stimuli, of which the role of polyphenolic compounds in modulating the differentially regulated pathways and thus maintaining vascular homeostasis has been proven to be beneficial. This review addresses the factors stimulating ED in diabetes and the molecular mechanisms of natural polyphenol antioxidants in maintaining vascular homeostasis.

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Exploring the Antihypertensive and Vascular-Protective Effects of Blueberries in Middle-Aged/Older Men: Study Protocol

Current Developments in Nutrition ◽

10.1093/cdn/nzaa065_010 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1745-1745

Author(s):

Emily Woolf ◽

Allegra Vazquez ◽

Sarah Johnson

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Arterial Stiffness ◽

Endothelial Function ◽

Vascular System ◽

Oxidized Ldl ◽

Reactive Hyperemia ◽

Protective Effects ◽

Freeze Dried ◽

Stage 1

Abstract Objectives Previous research has demonstrated the antihypertensive and vascular-protective effects of blueberries in postmenopausal women with elevated blood pressure (BP) or stage 1-hypertension (HTN). However, this has not been explored in men with elevated BP or HTN. The objective of the present study is to examine effects of blueberry (BB) on BP, endothelial function, and arterial stiffness in men with elevated BP or stage 1-HTN, and baseline endothelial dysfunction, as well as to investigate possible mechanisms involved with BB on vascular health. Methods In a randomized, double-blind, placebo-controlled, parallel-arm trial, men with elevated BP or stage 1-HTN (systolic BP of 120–139 mmHg, and a diastolic BP < 90 mmHg), and endothelial dysfunction (reactive hyperemia index, RHI) <1.67, but otherwise healthy, will be randomized to receive either 22 g/day of freeze-dried wild BB powder or 22 g/day of placebo powder for 12 weeks. Primary outcomes for this study are BP and RHI, which is a measure of vascular endothelial function assessed using peripheral arterial tonometry. Secondary outcomes include analysis of arterial stiffness, measured by pulse wave velocity (PWV), as well as blood biomarkers of cardiovascular and metabolic health that include blood lipids, hemoglobin A1c, oxidized LDL, nitric oxide, and adhesion molecules. Furthermore, endothelial cells will be biopsied to provide mechanistic insight on how BB consumption might affect the vascular system by utilizing quantitative immunofluorescence. Results We hypothesize that 22 g/day of BB consumption (∼1 cup) for 12 weeks will improve endothelial function, arterial stiffness, and BP in men with elevated BP and/or stage 1-HTN. We also hypothesize that these improvements will be mediated by reductions in vascular oxidative stress and inflammation, and increased nitric oxide bioavailability. Conclusions This study has potential to provide unique in vivo (functional) and ex vivo (molecular) support for the hypothesis that BB consumption may attenuate endothelial dysfunction, arterial stiffness, and high BP that occurs with aging. Funding Sources Wild Blueberry Association of North America.

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Endothelial progenitor cells in pregnancy

Reproduction ◽

10.1530/rep-06-0219 ◽

2007 ◽

Vol 133 (1) ◽

pp. 1-9 ◽

Cited By ~ 32

Author(s):

Amy O Robb ◽

Nicholas L Mills ◽

David E Newby ◽

Fiona C Denison

Keyword(s):

Endothelial Dysfunction ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Progenitor Cell ◽

Mononuclear Cells ◽

Vascular System ◽

Specific Reference ◽

Vascular Repair ◽

Endothelial Progenitor ◽

Cell Numbers

The discovery of endothelial progenitor cells has generated considerable interest in the field of vascular biology. These cells arise from a population of circulating mononuclear cells and have the capacity to form new blood vessels and contribute to vascular repair. Circulating endothelial progenitor cell numbers are reduced in patients with cardiovascular risk factors and in the presence of endothelial dysfunction, but are increased in response to ischaemia, oestrogens and drug therapy. They have been studied in pathologies from cardiovascular and renal disease to rheumatoid arthritis and pre-eclampsia. Pregnancy is a challenge to the maternal vascular system, requiring systemic adaptation and pronounced local changes in the uterus. Diseases of pregnancy such as pre-eclampsia and gestational diabetes increase the risk of pregnancy complications and are associated with endothelial dysfunction. We propose that endothelial progenitor cells have an important role in the regulation and maintenance of the vasculature during pregnancy. This review summarises our current understanding of endothelial progenitor cells, with specific reference to their role in angiogenesis and human pregnancy.

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Inflammatory markers, endothelial function and cardiovascular risk

Jornal Vascular Brasileiro ◽

10.1590/jvb.2014.054 ◽

2014 ◽

Vol 13 (2) ◽

pp. 108-115 ◽

Cited By ~ 22

Author(s):

Bruno Costa Teixeira ◽

André Luiz Lopes ◽

Rodrigo Cauduro Oliveira Macedo ◽

Cleiton Silva Correa ◽

Thiago Rozales Ramis ◽

...

Keyword(s):

Nitric Oxide ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Inflammatory Markers ◽

Cardiovascular Events ◽

Vascular System ◽

Systematic Analysis ◽

Reactive Protein ◽

Endothelial Nitric Oxide

The need to study cardiovascular diseases (CVD) has become more and more relevant as their prevalence has increased over the years. An intact endothelial wall is essential to vascular health. Certain factors are responsible for maintaining this tissue intact, including nitric oxide (NO), which provokes dilation of blood vessels in response to shear stress. Expression of the endothelial nitric oxide synthase (eNOS) enzyme, which produces nitric oxide in response to increases in blood flow, is of fundamental importance to maintenance of the vascular system. When this enzyme is inhibited, nitric oxide production is reduced, causing endothelial dysfunction. Since C-reactive protein inhibits production of nitric oxide by the eNOS enzyme, it is one of the causes of endothelial dysfunction and cardiovascular events. The objective of the present study was to review scientific articles in the literature related to the subject 'inflammatory markers and endothelial function'. A wide-ranging review of the current literature was conducted, using systematic analysis of bibliographic references indexed in PubMed, Scielo, Medline and LILACS database, for the years 1992 to 2013. The studies reviewed show that increases in inflammation causes reductions in NO and increases in cardiovascular events. Increased inflammation is associated with higher incidence of cardiovascular diseases.

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Vascular senescence and ageing: a role for the MEOX proteins in promoting endothelial dysfunction

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0149 ◽

2017 ◽

Vol 95 (10) ◽

pp. 1067-1077 ◽

Cited By ~ 7

Author(s):

Josette M. Northcott ◽

Michael P. Czubryt ◽

Jeffrey T. Wigle

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Vascular Disease ◽

Vascular Function ◽

Vascular System ◽

Vascular Dysfunction ◽

Enos Expression ◽

Angiogenic Potential ◽

Protein Levels ◽

Increased Risk

In the vascular system, ageing is accompanied by the accrual of senescent cells and is associated with an increased risk of vascular disease. Endothelial cell (EC) dysfunction is a hallmark of vascular disease and is characterized by decreased angiogenic potential, reduced nitric oxide bioavailability, impaired vasodilation, increased production of ROS, and enhanced inflammation. In ECs, the major producer of nitric oxide is the endothelial nitric oxide synthase (eNOS) enzyme that is encoded by the NOS3 gene. NOS3/eNOS function is tightly regulated at both the transcriptional and post-transcriptional levels to maintain normal vascular function. A key transcriptional regulator of eNOS expression is p53, which has been shown to play a central role in mediating cellular senescence and thereby vascular dysfunction. Herein, we show that, in ECs, the MEOX homeodomain transcription factors decrease the expression of genes involved in angiogenesis, repress eNOS expression at the mRNA and protein levels, and increase the expression of p53. These findings support a role for the MEOX proteins in promoting endothelial dysfunction.

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Glycosylation with O-linked β-N-acetylglucosamine induces vascular dysfunction via production of superoxide anion/reactive oxygen species

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0225 ◽

2018 ◽

Vol 96 (3) ◽

pp. 232-240

Author(s):

Leonardo Souza-Silva ◽

Rheure Alves-Lopes ◽

Jéssica Silva Miguez ◽

Vanessa Dela Justina ◽

Karla Bianca Neves ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Endothelial Dysfunction ◽

Nadph Oxidase ◽

Protein Expression ◽

Vascular Function ◽

Superoxide Anion ◽

Vascular System ◽

Reactive Oxygen ◽

Oxygen Species ◽

Endothelium Dependent Relaxation

Overproduction of superoxide anion (•O2−) and O-linked β-N-acetylglucosamine (O-GlcNAc) modification in the vascular system are contributors to endothelial dysfunction. This study tested the hypothesis that increased levels of O-GlcNAc-modified proteins contribute to •O2− production via activation of NADPH oxidase, resulting in impaired vasodilation. Rat aortic segments and vascular smooth muscle cells (VSMCs) were incubated with vehicle (methanol) or O-(2-acetamido-2-deoxy-d-glucopyranosylidenamino) N-phenylcarbamate (PUGNAc) (100 μM). PUGNAc produced a time-dependent increase in O-GlcNAc levels in VSMC and decreased endothelium-dependent relaxation, which was prevented by apocynin and tiron, suggesting that •O2− contributes to endothelial dysfunction under augmented O-GlcNAc levels. Aortic segments incubated with PUGNAc also exhibited increased levels of reactive oxygen species, assessed by dihydroethidium fluorescence, and augmented •O2− production, determined by lucigenin-enhanced chemiluminescence. Additionally, PUGNAc treatment increased Nox-1 and Nox-4 protein expression in aortas and VSMCs. Translocation of the p47phox subunit from the cytosol to the membrane was greater in aortas incubated with PUGNAc. VSMCs displayed increased p22phox protein expression after PUGNAc incubation, suggesting that NADPH oxidase is activated in conditions where O-GlcNAc protein levels are increased. In conclusion, O-GlcNAc levels reduce endothelium-dependent relaxation by overproduction of •O2− via activation of NADPH oxidase. This may represent an additional mechanism by which augmented O-GlcNAc levels impair vascular function.

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