Epithelial Sodium Channel in Aldosterone-Induced Endothelium Stiffness and Aortic Dysfunction

Enhanced activation of the endothelial mineralocorticoid receptor contributes to the development of arterial stiffness, which is an independent predictor of cardiovascular disease. Previously, we showed that enhanced endothelium mineralocorticoid receptor signaling in female mice prompts expression and translocation of the α-subunit of the epithelial sodium channel to the endothelial cell (EC) surface (EnNaC) inducing vascular fibrosis and stiffness. Further, amiloride, an epithelial sodium channel antagonist, inhibits vascular fibrosis, remodeling, and stiffness induced by feeding a Western diet high in saturated fat and refined carbohydrates. However, how this occurs remains unknown. Thereby, we hypothesized that endothelial cell-specific EnNaC activation is necessary for aldosterone-mediated endothelium stiffness. To address this notion, EnNaC α-subunit knockout (EnNaC^-/-) and wild-type littermate female mice were administrated aldosterone (250 µg/kg per day) via osmotic minipumps for 3 weeks beginning at 25 to 28 weeks of age. In isolated mouse endothelial cells, inward sodium currents were significantly reduced in amiloride controls, as well as in EnNaC^-/-. Likewise, aldosterone-induced endothelium stiffness was increased and endothelium-dependent relaxation less in EnNaC^-/- versus wild-type. Further, EnNaC^-/- mice exhibited attenuated responses to aldosterone infusion, including aortic endoplasmic reticulum stress, endothelium nitric oxide synthase activation, endothelium permeability, expression of proinflammatory cytokines, oxidative stress, and aortic collagen 1 deposition, supporting the notion that αEnNaC subunit activation contributes to these vascular responses.