Abstract-Pathophysiological aldosterone (aldo)/mineralocorticoid receptor signaling has a major impact on the cardiovascular system, resulting in hypertension and vascular remodeling. Mineralocorticoids induce endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine and increasing the response to vasoconstrictors. Activation of the epidermal growth factor receptor (EGFR) is thought to mediate the vascular effects of aldo, but this has yet to be demonstrated in vivo. In this study, we analyzed the molecular and functional vascular consequences of aldo-salt challenge in the waved 2 mouse, a genetic model with a partial loss of EGFR tyrosine kinase activity. Deficient EGFR activity is associated with global oxidative stress and endothelial dysfunction. A decrease in EGFR activity did not affect the arterial wall remodeling process induced by aldo-salt. By contrast, normal EGFR activity was required for the aldo-induced enhancement of phenylephrine-and angiotensin II-mediated vasoconstriction. In conclusion, this in vivo study demonstrates that EGFR plays a key role in aldosterone-mediated vascular reactivity. Clinical trials (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study and Randomized Aldactone Evaluation Study) have demonstrated the beneficial effects of administering low doses of pharmacological antagonists of the mineralocorticoid receptor (MR; the receptor of the mineralocorticoid hormone aldosterone [aldo]) to patients with heart failure, with improvements in survival rate and morbidity. 1,2 These clinical benefits may partly result from improved vascular function. 3 The MR is expressed in both endothelium and smooth muscle, 4 and the vessels are now considered to be direct targets of aldo. 5 In the mouse, the 11-hydroxysteroid dehydrogenase type II enzyme is expressed in the endothelium but not in the smooth muscle, 4,6 at variance with humans. 7 Therefore, in the mouse, aldo is the specific ligand of the MR in the endothelium but not in the smooth muscle, where glucocorticoids could also activate MR. MR activation affects endothelial function and vascular tone: aldo infusion induces endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine (Ach), and increasing the response to various vasoconstrictors. 5,8,9 We showed recently that an increase in MR signaling in the endothelium is associated with an increase in blood pressure and altered vascular tone. 4 Moreover, patients with primary aldosteronism have a higher aortic wall thickness than those with primary hypertension. 10 Aldo is, thus, recognized as a cardiovascular risk factor that exacerbates vascular injury, 3 although the underlying mechanisms remain unclear.It has been suggested that the epidermal growth factor receptor (EGFR) could play a key role in the cardiovascular effects of aldo. 11 In cultured cells, downstream EGFR signaling cascades are induced by aldo or prevented by MR blockade on aldo stimulation. 12 Increases in EGFR expression and/or activation have...
