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Recent data have indicated that ENaC also exists in the cells of the vascular wall and contributes to the direct regulation of vascular function and blood pressure. The expression and activation of ENaC are both known to be regulated through mineralocorticoid receptor activation and serum glucocorticoid-regulated kinase 1. In addition, insulin metabolic signaling contributes to ENaC expression and activation. Other factors, including extracellular and intracellular sodium levels, protease-specific cleavage, lipids, ubiquitination and deubiquitination, advanced glycation end products, acetylation, and N-glycosylation, also play important roles in regulating ENaC expression and function. Related to ENaC activation, a number of pathophysiological abnormalities, including heightened salt-sensitive hypertension, excessive endothelial cell stiffening, dysregulation of the endothelial glycocalyx, impaired shear stress mechanosensation, and proinflammatory responses, appear to contribute to activated ENaC-induced vascular dysfunction and hypertension. Importantly, obesity and insulin resistance are associated with these pathophysiological processes. 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