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Endothelial Dysfunction: Role in Vascular Disease

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Under physiological conditions, the major function of endothelium is to dynamically regulate arterial vascular tone by maintaining a homeostasis between vasodilation and vasoconstriction in response to physiologic stimuli. Endothelial cells produce and release nitric oxide, which diffuses to surrounding ...

Under physiological conditions, the major function of endothelium is to dynamically regulate arterial vascular tone by maintaining a homeostasis between vasodilation and vasoconstriction in response to physiologic stimuli. Endothelial cells produce and release nitric oxide, which diffuses to surrounding tissue and smooth muscle cells and exerts vasodilation. Numerous cardiovascular risk factors contribute to reduced activity of the endothelium and endothelial dysfunction (ED) is one of the key events that occur in several pathological conditions leading to the acceleration of cardiovascular mortality and morbidity. ROS-mediated oxidative stress is one of the known factors to cause eNOS uncoupling and subsequent ED, resulting in decreased NO signaling and increased superoxide production. Supplementation with antioxidants such as glutathione, N-acetyl cysteine, and vitamin C has been shown to reverse ED in coronary and peripheral arteries.
Nitric oxide (NO) signaling is compromised prior to the development of ED and this correlates with a decrease in L-arginine levels. The mechanism by which the decrease in L-arginine occurs is complex and involves both an increase in its degradation (through activation of arginase activity) and a reduction in its production through the citrulline-NO cycle. In the latter pathway, L-citrulline produced in the conversion of arginine to NO is recycled to arginine by the sequential activity of argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). Further, L-arginine regeneration from citrulline-NO cycle is thought to play a key role in providing the L-arginine required for endothelial NO production. Thus, the L-arginine pool resulting from the Citrulline-NO cycle is likely an important control point for the NO signaling. However, little is known regarding the role of arginine recycling in impaired NO signaling associated with cardiovascular diseases.
Endothelial dysfunction is a major mechanism that leads towards coronary artery disease (CAD), and other atherosclerotic diseases. In the CAD, the vascular endothelium plays a critical role in modulating both the inflammatory response and vasomotor abnormalities. In peripheral blood vessels, hypercholesterolemia and other risk factors for atherosclerosis are associated with ED. Diabetes-associated changes in the endothelium are modifications of lipoproteins, formation of advanced glycation end-products, alteration of the NO pathway, and elevated levels of homocysteine. Since insulin regulates the endothelial NOS activity through the phosphorylation by AKT, insulin resistance is one of major factors associated with the ED in obesity and diabetes. Previous studies have established that ED is closely associated with the development of diabetic complications such as retinopathy and nephropathy in both type I and II diabetes.
This Research Topic will focus on articles that can discuss and identify the molecular mechanisms responsible for the development of ED-mediated cardiovascular pathologies as well as focus on therapies to ameliorate ED.


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