Metabolite ligands of estrogen receptor-beta reduce primate coronary hyperreactivity

Metabolite ligands of estrogen receptor-beta reduce primate coronary hyperreactivity. Am J Physiol Heart Circ Physiol 290: H295 - H303, 2006. First published September 30, 2005; doi: 10.1152/ajpheart. 00468.2005. - Previous reports showed that 17 beta-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 17 beta-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor-beta (ER-beta) 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 Ca2+ signals. This reduction of late Ca2+ signals also appeared after > 72 h of treatment with subnanomolar 5 alpha-androstane-3 beta,17 beta-diol (3 beta-Adiol), an endogenous dihydrotestosterone metabolite with ER-beta binding activity. R, R-tetrahydrochrysene, a selective ER-beta antagonist, significantly blocked the E-3- and 3 beta-Adiol-mediated attenuation of late Ca2+ signal increases. ER-beta 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 beta-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R, R-tetrahydrochrysene. E-3- and 3 beta-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.