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 (AT(2)R) induces vasodilation. This study determined whether sex differences in vascular AT(2)R expression occur and if androgens exert control on AT(2)R expression in the vasculature. METHODS: AT(2)Rs in the aorta of male and female Sprague-Dawley rats were examined following alteration in androgen levels by gonadectomy or hormone supplementation. RESULTS: AT(2)R mRNA and protein expression levels were lower in the aortas of males than females. In males, testosterone withdrawal by castration significantly elevated AT(2)R mRNA and protein levels and testosterone replacement restored them. In females, increasing androgen levels decreased AT(2)R mRNA and protein expression and this was attenuated by androgen receptor blocker flutamide. Ex vivo, dihydrotestosterone downregulated AT(2)R in endothelium-intact but not endothelium-denuded aorta. Dihydrotestosterone-induced AT(2)R 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 AT(2)R downregulation. CONCLUSION: Androgens downregulate AT(2)R expression levels in aorta, in vivo and ex vivo. The androgen receptor-mediated ERK1/2 MAP kinase-signaling pathway may be a key mechanism by which testosterone downregulates AT(2)R expression, implicating androgens’ contributing role to gender differences in vascular AT(2)R expression.