Central Role of eNOS in the Maintenance of Endothelial Homeostasis

Abstract

Significance: Disruption of endothelial function is considered a key event in the development and progression of atherosclerosis. Endothelial nitric oxide synthase (eNOS) is a central regulator of cellular function that is important to maintain endothelial homeostasis. Recent Advances: Endothelial homeostasis encompasses acute responses such as adaption of flow to tissue's demand and more sustained responses to injury such as reendothelialization and sprouting of endothelial cells (ECs) and attraction of circulating angiogenic cells (CAC), both of which support repair of damaged endothelium. The balance and the intensity of endothelial damage and repair might be reflected by changes in circulating endothelial microparticles (EMP) and CAC. Flow-mediated vasodilation (FMD) is a generally accepted clinical read-out of NO-dependent vasodilation, whereas EMP are upcoming prognostically validated markers of endothelial injury and CAC are reflective of the regenerative capacity with both expressing a functional eNOS. These markers can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity with NO representing a central signaling molecule. Critical Issues: Improvements of reproducibility and observer independence of FMD measurements and definitions of relevant EMP and CAC subpopulations warrant further research. Future Directions: Endothelial homeostasis may be a clinical therapeutic target for cardiovascular health maintenance. Antioxid. Redox Signal. 22, 1230Signal. 22, -1242

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“…It is expressed in the endothelium of large arteries, and its expression decreases in small resistance arteries and veins and is virtually absent in the capillaries [15]. The laminar blood flow and the related endothelial shear stress are the major eNOS activators.…”

“…2). Consequently, the reported effects of vascular O 2 -overproduction (as associated with the CVD risk-factors) included: (i) impaired vascular NO bioavailability (seen as the endothelial dysfunction in the FMD test); (ii) vascular overproduction of the toxic peroxynitrite (ONOO -) mediating BH 4 inactivation, the eNOS uncoupling and further impairment of the NO availability, and (iii) decreased S-nitrosothiol and NO 2 -production and impairment of their signalisation [15]. Peroxynitrite may cause nitration of protein tyrosine residues to form 3-nitrotyrosine (Fig.…”

“…These interactions are mediated mainly by endothelium-derived autacoids such as NO and O 2 -, but also by prostaglandins, endothelin-1, and others. The endothelial homeostasis is disrupted in CVD and states such as ischaemia-reperfusion, and the resulting changes in the endothelial phenotype can be identified as: (ii) a pro-inflammatory state; (iii) a pro-thrombotic state, and (iv) a state promoting arterial wall proliferation [15,24].…”

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“…NO synthesized freshly, travels to the neighbouring cells. Then in the vessel walls, inside the cells, NO binds to guanylate cyclase (GC), thus cyclic guanosine monophosphate (cGMP) concentration increase, Ca 2+ channels start to open and when calcium inflows the smooth muscle relaxation is triggered [7].…”

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“…Its ability to generate nitric oxide (NO) allows for control of vascular tone along with preventing inflammation and proliferation of the surrounding vascular smooth muscle cells (SMC) [185][186][187] . Alterations in eNOS activity or expression are linked to a number of cardiovascular pathologies that exhibit endothelial dysfunction, such as hypertension and inflammation 188,189 .…”