title: Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  Androgens downregulate AT2R 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 AT2R expression, implicating androgens' contributing role to gender differences in vascular AT2R expression.
authors.affiliation: Division of Reproductive Endocrinology, University of Texas Medical Branch at Galveston, Texas, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Mishra
authors.affiliation: Division of Reproductive Endocrinology, University of Texas Medical Branch at Galveston, Texas, USA.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hankins
authors.affiliation: Division of Reproductive Endocrinology, University of Texas Medical Branch at Galveston, Texas, USA kusathis@utmb.edu.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000728:Androgens / Q000097:blood; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000728:Androgens; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone
keywords: ERK; Endothelium; blood pressure; gender difference; testosterone; vascular