Metabolite ligands of estrogen receptor-β reduce primate coronary hyperreactivity

Rajesh G. Mishra, Frank Z. Stanczyk, Kenneth A. Burry, Suzanne Oparil, Benita S. Katzenellenbogen, Michele L. Nealen, John A. Katzenellenbogen, R. Kent Hermsmeyer

Research output: Contribution to journalArticle

Abstract

Previous reports showed that 17β-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 17β-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor-β (ER-β) binding activity, estriol (E3), suppresses in vivo and in vitro CH. E 3 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 5α-androstane-3β,17β-diol (3β-Adiol), an endogenous dihydrotestosterone metabolite with ER-β binding activity. R,R-tetrahydrochrysene, a selective ER-β antagonist, significantly blocked the E3- and 3β-Adiol-mediated attenuation of late Ca 2+ signal increases. ER-β 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 3β-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. E 3- and 3β-Adiol-mediated reduction in persistent Ca2+ signals is associated with ER-β-mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle.

Original languageEnglish (US)
Pages (from-to)H295-H303
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume290
Issue number1
DOIs
StatePublished - Jan 1 2006

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Keywords

  • Angiography
  • Calcium
  • Menopause
  • Thromboxane-prostanoid receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Mishra, R. G., Stanczyk, F. Z., Burry, K. A., Oparil, S., Katzenellenbogen, B. S., Nealen, M. L., Katzenellenbogen, J. A., & Hermsmeyer, R. K. (2006). Metabolite ligands of estrogen receptor-β reduce primate coronary hyperreactivity. American Journal of Physiology - Heart and Circulatory Physiology, 290(1), H295-H303. https://doi.org/10.1152/ajpheart.00468.2005