Metabolite ligands of estrogen receptor-beta reduce primate coronary hyperreactivity.
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.
Mishra
Rajesh G
RG
Dimera Incorporated, 2525 NW Lovejoy, Suite 311, Portland, OR 97210, USA.
Stanczyk
Frank Z
FZ
Burry
Kenneth A
KA
Oparil
Suzanne
S
Katzenellenbogen
Benita S
BS
Nealen
Michele L
ML
Katzenellenbogen
John A
JA
Hermsmeyer
R Kent
RK
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000279:Administration, Cutaneous; D015113:Androstane-3,17-diol / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002911:Chrysenes / Q000494:pharmacology; D003329:Coronary Vasospasm / Q000139:chemically induced / Q000188:drug therapy*; D004964:Estriol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D008253:Macaca mulatta; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000096:biosynthesis; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D002911:Chrysenes; D047629:Estrogen Receptor beta; D009570:Nitriles; D011422:Propionates; D017482:Receptors, Thromboxane; D015113:Androstane-3,17-diol; D012701:Serotonin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019833:Genistein; D004964:Estriol