Metabolite ligands of estrogen receptor-β reduce primate coronary hyperreactivity

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.