Enhanced epithelial sodium channel signaling in endothelial cells promotes arterial stiffness

Abstract

Excessive epithelial sodium channel (ENaC) activation in endothelial cells (EnNaC) has been reported to increase oxidative stress and induce inflammation with associated cardiovascular abnormalities. Our previous research has demonstrated that global inhibition of ENaC signaling with amiloride prevented Western diet (WD)‐induced inflammation, fibrosis, endothelial dysfunction and vascular stiffness in mesenteric and coronary resistance arteries and aorta. However, the role of endothelium specific EnNaC activation in the pathogenesis of vascular stiffness has not been investigated. We posited that EnNaC activation promotes obesity‐ and mineralocorticoid receptor‐mediated vascular stiffness. Accordingly, we sought to determine if endothelium specific EnNaC alpha subunit KO would prevent vascular inflammation, vascular stiffness, and impairment of endothelium dependent relaxation. Female EnNaC and wild‐type littermate mice were fed with WD high in refined carbohydrates and saturated fat or a standard chow diet for 12 weeks. In a separate study, female mice were treated with aldosterone (250 μg/kg/day) via osmotic minipumps for 3 weeks. Selective deletion of EnNaC significantly mitigated WD‐induced ex vivo endothelial stiffness measured by atomic force microscopy and – impaired aortic endothelium dependent relaxation in response to acetylcholine (10−9–10−4 mol/L). In addition to reducing mineralocorticoid receptor mediated endothelial stiffness, EnNaC KO also mitigated aldosterone‐induced inward Na+ currents and EnNaC activity in isolated endothelial cells. Furthermore, EnNaC KO attenuated aldosterone‐induced endothelium permeability, vascular inflammation, endothelial stiffness, as well as aortic endothelium dependent relaxation. These data indicate that endothelial specific EnNaC activation mediates vascular endothelium dysfunction and prompts vascular stiffening.Support or Funding InformationJRS received funding from NIH (R01 HL73101‐01A and R01 HL107910‐01) and the Veterans Affairs Merit System (0018). Dr. Jia received funding from American Diabetes Association (Innovative Basic Science Award #1‐17‐IBS‐201).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.