The mineralocorticoid receptor (MR) is a member of the steroid receptor family and a critical regulator of blood pressure (BP). For years the mechanism was thought to be exclusively mediated by the renal effects of the hormone aldosterone on sodium and water homeostasis. However, studies put forward the pathological role of vascular MR in cardiovascular diseases (CVD). Mice with specific deletion of MR in smooth muscle cells (SMC-MR-KO) exhibit decreased BP with aging, reduced myogenic tone and agonist-dependent contraction on resistance arteries, despite unchanged renal MR function; these data clearly supports a physiological role for SMC-MR in control of vascular tone and BP. Moreover, deletion of SMC-MR prevented the increase in SMC proliferation and fibrosis induced by aldosterone after wire-induced carotid injury suggesting that SMC-MR is also involved in vascular response to injury. However, the deletion of SMC-MR does not modulate the progression of plaque size and vascular inflammation induced by subpressor dosis of aldosterone in atherosclerosis-prone apolipoprotein E-knockout mice (ApoE-KO). These data support the hypothesis that there are BP-independent and SMC-MR-independent mechanisms contributing to aldosterone-induced atherosclerosis. NADPH oxidase activation and eNOS uncoupling induced by MR activation in endothelial cells (EC) are potential mechanisms mediating vascular oxidative stress and endothelial dysfunction (ED) in CVD. However, controversial effects of aldosterone on NO production have been reported; and if EC-MR affects vascular contractility, endothelial function and BP is not clear yet. In the present study we propose to use the first mouse model with specific deletion of MR in EC to address the role of EC-MR in mediating ED and oxidative stress in resistance arteries from CVD mouse models of hypertension and atherosclerosis.
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