Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta

Introduction: Blood pressure is lower in females than males. Angiotensin II type-2 receptor (AT₂R) induces vasodilation. This study determined whether sex differences in vascular AT₂R expression occur and if androgens exert control on AT₂R expression in the vasculature. Methods: AT₂Rs in the aorta of male and female Sprague-Dawley rats were examined following alteration in androgen levels by gonadectomy or hormone supplementation. Results: AT₂R mRNA and protein expression levels were lower in the aortas of males than females. In males, testosterone withdrawal by castration significantly elevated AT₂R mRNA and protein levels and testosterone replacement restored them. In females, increasing androgen levels decreased AT₂R mRNA and protein expression and this was attenuated by androgen receptor blocker flutamide. Ex vivo, dihydrotestosterone downregulated AT₂R in endothelium-intact but not endothelium-denuded aorta. Dihydrotestosterone-induced AT₂R downregulation in isolated aorta was blocked by an androgen receptor antagonist. Furthermore, blockade of ERK1/2 but not p38 MAP kinase or TGFβ signaling with specific inhibitors abolished dihydrotestosterone-induced AT₂R downregulation. Conclusion: Androgens downregulate AT₂R expression levels in aorta, in vivo and ex vivo. The androgen receptormediated ERK1/2 MAP kinase-signaling pathway may be a key mechanism by which testosterone downregulates AT₂R expression, implicating androgens' contributing role to gender differences in vascular AT₂R expression.