Metabolite ligands of estrogen receptor-beta reduce primate coronary hyperreactivity

Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H295-303. doi: 10.1152/ajpheart.00468.2005. Epub 2005 Sep 30.

Abstract

Previous reports showed that 17beta-estradiol implants attenuate in vivo coronary hyperreactivity (CH), characterized by long-duration vasoconstrictions (in coronary angiographic experiments), in menopausal rhesus monkeys. Prolonged Ca2+ contraction signals that correspond with CH in coronary vascular muscle cells (VMC) to the same dual-constrictor stimulus, serotonin + the thromboxane analog U-46619, in estrogen-deprived VMC were suppressed by >72 h in 17beta-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor-beta (ER-beta) binding activity, estriol (E3), suppresses in vivo and in vitro CH. E3 treatment in vivo for 4 wk significantly attenuated the angiographically evaluated vasoconstrictor response to intracoronary serotonin + U-46619 challenge. In vitro treatment of rhesus coronary VMC for >72 h with nanomolar E3 attenuated late Ca2+ signals. This reduction of late Ca2+ signals also appeared after >72 h of treatment with subnanomolar 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), an endogenous dihydrotestosterone metabolite with ER-beta binding activity. R,R-tetrahydrochrysene, a selective ER-beta antagonist, significantly blocked the E3- and 3beta-Adiol-mediated attenuation of late Ca2+ signal increases. ER-beta and thromboxane-prostanoid receptor (TPR) were coexpressed in coronary arteries and aorta. In vivo E3 treatment attenuated aortic TPR expression. Furthermore, in vitro treatment with E3 or 3beta-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. E3- and 3beta-Adiol-mediated reduction in persistent Ca2+ signals is associated with ER-beta-mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
  • Administration, Cutaneous
  • Androstane-3,17-diol / pharmacology
  • Animals
  • Calcium Signaling / drug effects
  • Chrysenes / pharmacology
  • Coronary Vasospasm / chemically induced
  • Coronary Vasospasm / drug therapy*
  • Estriol / administration & dosage
  • Estriol / pharmacology
  • Estriol / therapeutic use*
  • Estrogen Receptor beta / agonists
  • Estrogen Receptor beta / antagonists & inhibitors
  • Estrogen Receptor beta / metabolism*
  • Female
  • Gene Expression / drug effects
  • Genistein / pharmacology
  • Macaca mulatta
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Nitriles / pharmacology
  • Propionates / pharmacology
  • Receptors, Thromboxane / biosynthesis
  • Serotonin / pharmacology
  • Vasoconstriction / drug effects

Substances

  • 2,3-bis(4-hydroxyphenyl)-propionitrile
  • Chrysenes
  • Estrogen Receptor beta
  • Nitriles
  • Propionates
  • Receptors, Thromboxane
  • Androstane-3,17-diol
  • Serotonin
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Genistein
  • Estriol