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

Jay S. Mishra, Gary Hankins, Sathish Kumar

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJRAAS - Journal of the Renin-Angiotensin-Aldosterone System
Volume17
Issue number4
DOIs
StatePublished - 2016

Keywords

  • Blood pressure
  • Endothelium
  • ERK
  • Gender difference
  • Testosterone
  • Vascular

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology

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