Endothelial Dysfunction: From Molecular Mechanisms to Measurement, Clinical Implications, and Therapeutic Opportunities

Health Faculty, UHI Millennium Institute, Inverness, University of Edinburgh, Edinburgh, Scotland.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 10/2008; 10(9):1631-74. DOI: 10.1089/ars.2007.2013
Source: PubMed


Endothelial dysfunction has been implicated as a key factor in the development of a wide range of cardiovascular diseases, but its definition and mechanisms vary greatly between different disease processes. This review combines evidence from cell-culture experiments, in vitro and in vivo animal models, and clinical studies to identify the variety of mechanisms involved in endothelial dysfunction in its broadest sense. Several prominent disease states, including hypertension, heart failure, and atherosclerosis, are used to illustrate the different manifestations of endothelial dysfunction and to establish its clinical implications in the context of the range of mechanisms involved in its development. The size of the literature relating to this subject precludes a comprehensive survey; this review aims to cover the key elements of endothelial dysfunction in cardiovascular disease and to highlight the importance of the process across many different conditions.

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    • "Functional diagnosis of endothelial dysfunction includes tests of endothelium dependent vasorelaxation, arterial stiffness and pulse wave propagation. Flow-mediated vasodilatation which uses high resolution ultrasound equipment to measure the post-occlusive increase in diameter and flow of brachial or radial arteries is reflective of the shear stress-stimulated production of nitric oxide (NO).[16] "
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    ABSTRACT: Migraine is a neurovascular disorder and any interventions improving endothelial function may contribute to its treatment and prevention of vascular complications like ischemic stroke. Yoga has been shown to have several beneficial effects on cardiovascular systems. However, no randomized controlled studies to date have investigated its effects on endothelial function of migraineurs. A total of 42 women patients with migraine were enrolled and randomized into either a Yoga exercise group or a control group. The control group received only medication for 12 weeks and the Yoga group was placed in yoga training program in addition to the same medical treatment. Blood test was given from all patients in order to measure plasma levels intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) after yoga training program. Totally 32 patients were participated in the final analyses (yoga: n = 18, control: n = 14). By analyzing data between yoga and control groups after the treatment period, there was a significant decreased in plasma level of VCAM in yoga group compare with the control group (15.29 ± 2.1 ng/ml vs. 21.70 ± 3.0 ng/ml, P < 0.05), whereas there was no significant difference in ICAM level between groups (19.1 ± 1.8 ng/ml vs. 20.97 ± 1.9 ng/ml P > 0.05). It seems that yoga exercises, as a complementary treatment beside pharmacological treatments, can be potentially an effective way of improving vascular functions in migraineurs.
    International journal of preventive medicine 04/2014; 5(4):424-9.
    • "In its reduced form, GSH has a wide variety of functions, from antioxidant protection to protein thiolation and drug detoxification, often supported by specific enzymes (Fig. 2). Oxidative stress is a critical process that is implicit in the aetiology of a wide range of diseases, including cardiovascular disease (Le Brocq et al., 2008), diabetes (Stadler, 2012) and cancer (Sosa et al., 2013). GSH is a critical intracellular antioxidant that helps to limit the impact of oxidative stress and to protect vital cellular components (lipids, proteins, DNA) against harmful peroxidation. "
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    ABSTRACT: N-acetyl-L-cysteine (NAC) has long been used therapeutically for treatment of acetaminophen (paracetamol) overdose, acting as a precursor for the substrate (L-cysteine) in synthesis of hepatic glutathione (GSH) depleted through drug conjugation. Other therapeutic uses of NAC have also emerged, including the alleviation of clinical symptoms of cystic fibrosis through cysteine-mediated disruption of disulfide cross-bridges in the glycoprotein matrix in mucus. More recently, however, a wide range of clinical studies have reported on the use of NAC as an antioxidant, most notably in protection against contrast-induced nephropathy and thrombosis. The results from these studies are conflicting and a consensus is yet to be reached regarding the merits or otherwise of NAC in the antioxidant setting. This review seeks to re-evaluate the mechanism of action of NAC as a precursor for GSH synthesis in the context of its activity as an "antioxidant". Results from recent studies are examined to establish whether the pre-requisites for effective NAC-induced antioxidant activity (i.e. GSH depletion and the presence of functional metabolic pathways for conversion of NAC to GSH) have received adequate consideration in interpretation of the data. A key conclusion is a reinforcement of the concept that NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH in deficient cells and it is likely to be ineffective in cells replete in GSH.
    Pharmacology [?] Therapeutics 09/2013; 141(2). DOI:10.1016/j.pharmthera.2013.09.006 · 9.72 Impact Factor
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    • "In addition, they express high levels of adhesion molecules involved in the recruitment and attachment of inflammatory cells [17]. Endothelial senescence has been implicated in endothelial dysfunction, which is characterized by phenotypic and hemodynamic changes in blood vessels that increase the risk of cardiovascular disease (CVD), such as atherosclerosis, and associated myocardial infarction and stroke [18], [19]. Therefore, better understanding of the molecular mechanisms underlying endothelial dysfunction is crucial to improve early detection and prognosis of CVD. "
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    ABSTRACT: The proto-oncogene c-Myc is vital for vascular development and promotes tumor angiogenesis, but the mechanisms by which it controls blood vessel growth remain unclear. In the present work we investigated the effects of c-Myc knockdown in endothelial cell functions essential for angiogenesis to define its role in the vasculature. We provide the first evidence that reduction in c-Myc expression in endothelial cells leads to a pro-inflammatory senescent phenotype, features typically observed during vascular aging and pathologies associated with endothelial dysfunction. c-Myc knockdown in human umbilical vein endothelial cells using lentivirus expressing specific anti-c-Myc shRNA reduced proliferation and tube formation. These functional defects were associated with morphological changes, increase in senescence-associated-β-galactosidase activity, upregulation of cell cycle inhibitors and accumulation of c-Myc-deficient cells in G1-phase, indicating that c-Myc knockdown in endothelial cells induces senescence. Gene expression analysis of c-Myc-deficient endothelial cells showed that senescent phenotype was accompanied by significant upregulation of growth factors, adhesion molecules, extracellular-matrix components and remodeling proteins, and a cluster of pro-inflammatory mediators, which include Angptl4, Cxcl12, Mdk, Tgfb2 and Tnfsf15. At the peak of expression of these cytokines, transcription factors known to be involved in growth control (E2f1, Id1 and Myb) were downregulated, while those involved in inflammatory responses (RelB, Stat1, Stat2 and Stat4) were upregulated. Our results demonstrate a novel role for c-Myc in the prevention of vascular pro-inflammatory phenotype, supporting an important physiological function as a central regulator of inflammation and endothelial dysfunction.
    PLoS ONE 09/2013; 8(9):e73146. DOI:10.1371/journal.pone.0073146 · 3.23 Impact Factor
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