Metabolite ligands of estrogen receptor-{beta} reduce primate coronary hyperreactivity

1 Dimera, Incorporated, and 3 Oregon Health and Science University, Portland, Oregon; 2 University of Southern California, Los Angeles, California; 4 University of Alabama Birmingham, Birmingham, Alabama; and 5 University of Illinois Urbana-Champaign, Urbana, Illinois Submitted 9 May 2005 ; accepted in final form 24 August 2005 Previous reports showed that 17 -estradiol implants attenuate in vivo coronary hyperreactivity (CH), characterized by long-duration vasoconstrictions (in coronary angiographic experiments), in menopausal rhesus monkeys. Prolonged Ca 2+ 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 17 -estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor- (ER- ) binding activity, estriol (E 3 ), 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 E 3 attenuated late Ca 2+ signals. This reduction of late Ca 2+ signals also appeared after >72 h of treatment with subnanomolar 5 -androstane-3 ,17 -diol (3 -Adiol), an endogenous dihydrotestosterone metabolite with ER- binding activity. R,R-tetrahydrochrysene, a selective ER- antagonist, significantly blocked the E 3 - and 3 -Adiol-mediated attenuation of late Ca 2+ signal increases. ER- and thromboxane-prostanoid receptor (TPR) were coexpressed in coronary arteries and aorta. In vivo E 3 treatment attenuated aortic TPR expression. Furthermore, in vitro treatment with E 3 or 3 -Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. E 3 - and 3 -Adiol-mediated reduction in persistent Ca 2+ signals is associated with ER- -mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle. menopause; calcium; thromboxane-prostanoid receptor; angiography Address for reprint requests and other correspondence: R. K. Hermsmeyer, Dimera Incorporated, 2525 NW Lovejoy, Suite 311, Portland, OR 97210 (e-mail: rkh{at}dimera.net )