Aorta

Arterial stiffness

Endocrinology

Endothelium

Vasodilation

Smooth muscle

Endothelial dysfunction

Blood pressure

Renin–angiotensin system

Aldosterone

Oxidative stress

Angiotensin II

Internal medicine

Vascular smooth muscle

Medicine

Chemistry

Hypertension

Arterial stiffness is an independent risk factor for the development and progression of cardiovascular and kidney disease. Inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) is seen in obesity and contributes significantly to development of arterial stiffness, vascular dysfunction and hypertension. We have recently observed that aldosterone increases the presence of epithelial sodium channels on endothelial cells (EnNaC), which results in stiffening of the endothelial cortical surface (glycocalyx) of the aorta. Accordingly, we posited that deletion of the critical alpha catalytic subunit of EnNaC would decrease Ang II induced arterial stiffening and vascular relaxation responses, in part, via decreases in oxidative stress. To investigate, we used mice with EC cell specific deletion of EnNaC, by serially crossing floxed” EnNaC mice with Tie 2-Cre transgene mice. EnNaC expression was markedly decreased in ECs from EnNaC KO mice while macrophage expression of EnNaC was unaffected. Ang II (500 ng/kg/min) was administered by infusion to 9 month old wild (WT) and EnNaC KO mice for three weeks with or without administration of the antioxidant tempol (2mM/day) in drinking water. Whole cell Na+ currents in ECs, as evaluated by patch clamp, were significantly increased by Ang II infusion, and this was markedly attenuated in EnNAC KO and tempol treated mice. Further, aortic endothelial stiffness as determined by atomic force microscopy was significantly increased in Ang II infused mice and this increase was attenuated in EnNaC KO mice. EnNaC deletion also attenuated impaired acetylcholine (eNOS)-mediated vasorelaxation. Thus, treatment with the antioxidant tempol reduced Ang II induced vascular stiffness and prevented impairment of NO mediated vascular relaxation. Moreover, tempol administration to Ang II infused EnNaC KO mice had similar effects in both Ang II-tempol and Ang II-EnNaC KO groups. Arterial stiffness was significantly decreased by EnNaC deletion or treatment with the antioxidant tempol in femoral vessels as well. These results are consistent with an important role for oxidative stress in Ang II promotion of EnNaC activation, endothelial stiffness and impaired eNOS mediated vascular relaxation.

Abstract 111: Endothelial Sodium Channel Activation Promotes Angiotensin II Induced Arterial Stiffness and Endothelial Dysfunction