Molecular mechanisms underlying the activation of eNOS

Abstract

Endothelial cells situated at the interface between blood and the vessel wall play a crucial role in controlling vascular tone and homeostasis, particularly in determining the expression of pro- and anti-atherosclerotic genes. Many of these effects are mediated by changes in the generation and release of the vasodilator nitric oxide (NO) in response to hemodynamic stimuli exerted on the luminal surface of endothelial cells by the streaming blood (shear stress) and the cyclic strain of the vascular wall. The endothelial NO synthase (eNOS) is activated in response to fluid shear stress and numerous agonists via cellular events such as; increased intracellular Ca(2+), interaction with substrate and co-factors, as well as adaptor and regulatory proteins, protein phosphorylation, and through shuttling between distinct sub-cellular domains. Dysregulation of these processes leads to attenuated eNOS activity and reduced NO output which is a characteristic feature of numerous patho-physiological disorders such as diabetes and atherosclerosis. This review summarizes some of the recent findings relating to the molecular events regulating eNOS activity.

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

“…G q/11 mediates activation of the calmodulin-dependent enzyme eNOS through both mechanisms of Ca 2+ mobilization and Akt-mediated eNOS phosphorylation. 35 Hence, the study by Korhonen et al 27 and our study together suggest that the PAF receptor, which is a G q/11 -coupled receptor, Cui 20 mediates an increase in vascular permeability through eNOS stimulation whereas S1P 2 counteracts this G q/11 -mediated action through G 12/13 -mediated suppression of the Akt-eNOS pathway.…”

“…35 S1pr2 deficiency augmented activation of Akt as well as eNOS in the vasculature (Fig 2). Therefore, it is likely that increased Akt activity at least in part mediates enhanced eNOS phosphorylation in S1pr2 -/-mice.…”

Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation

“…One function of the endothelium is vasomotor control via the release of vasoactive substances such as nitric oxide (NO) gas, a potent vasodilator. In physiological conditions, acetylcholine (7), flow-related shear stress (8) and mechanical deformation of the vessel wall (9) induce NO production by the endothelial nitric oxide synthase (eNOS) (10). Increases in flow induce vasodilation by up-regulating the transcription factor Kruppel-like factor 2 (KLF2) expression and its downstream effectors (eNOS and thrombomodulin) promoting NO production (11).…”

Endothelial Nitric-oxide Synthase Activation Generates an Inducible Nitric-oxide Synthase-like Output of Nitric Oxide in Inflamed Endothelium

“…eNOS activation in bovine aortic endothelial cells and human umbilical vein endothelial cells has been well characterized (20,26). However, B2R-stimulated NO production has not been studied in endothelial cells under inflammatory conditions that are classically associated with activation of the kallikrein-kinin system and generation of B2R agonist kinins (15,16).…”

“…Phosphorylation modulates eNOS activity by altering enzyme localization, facilitating protein-protein interactions, or inducing conformational changes that abet or impede efficient flow of electrons between the reductase and oxygenase domains (23,24). The best characterized phosphorylation sites on eNOS modified in response to BK (and many other agonists) stimulation in control endothelial cells include dephosphorylation of the inhibitory Thr(P) 495 by calcineurin and phosphorylation at the stimulatory Ser 1177 by Akt (primarily) and also protein kinase A (PKA) and calcium-calmodulin-dependent kinase II (25,26). Additionally, B2R activation alters phosphorylation at Tyr 81 , Ser 615 , and Ser 633 but not Ser 114 (27)(28)(29).…”