Metabolite ligands of estrogen receptor-β reduce primate coronary hyperreactivity

Abstract

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 2ϩ contraction signals that correspond with CH in coronary vascular muscle cells (VMC) to the same dual-constrictor stimulus, serotonin ϩ the thromboxane analog U-46619, in estrogen-deprived VMC were suppressed by Ͼ72 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 ϩ U-46619 challenge. In vitro treatment of rhesus coronary VMC for Ͼ72 h with nanomolar E 3 attenuated late Ca 2ϩ signals. This reduction of late Ca 2ϩ signals also appeared after Ͼ72 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 2ϩ signal increases. ER-␤ 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 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 2ϩ 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 CARDIOVASCULAR PHYSIOLOGY is profoundly regulated by multiple endocrine signals via nuclear and cell surface receptors, and age-related hormonal decline may increase the risk of cardiovascular disease (1). Current controversy regarding cardiovascular effects of hormone therapy (35, 38) emphasizes the need for research to enhance our understanding of steroid hormone actions on structural and functional changes in the blood vessel wall (7). Growing evidence suggests a role for estrogen receptors (ER) in regulation of vascular healing and proliferation following injury as well as ER-mediated regulation of endothelial-dependent vasodilator reactivity responses (23). However, published data on ER-mediated effects on coronary vasoconstrictor reactivity responses are sparse.Despite a large body of evidence on the biological actions of 17␤-estradiol (E 2 ) (33), there is a paucity of information on the biological actions of metabolites of E 2 , such as the endogenous ER ligand estriol (E 3 ), which can be present at significant concentrations at the tissue level (5,11,19). E 3 is abundantly produced during late-stage pregnancy and, thus, is present in conjugated equine estrogen preparations, which are kno...

Age and sex differences in vascular responsiveness in healthy and trauma patients: contribution of estrogen receptor-mediated Rho kinase and PKC pathways

“…Three subtypes of the ER have been identified: ER-␣, ER-␤, and GPR30 (3,7,29,39,43). Some studies have shown that the ERs have different patterns of expression and different effects at different ages (12,14).…”

Vascular Actions of Estrogens: Functional Implications

“…Few studies have examined transdermal preparations of estrogen metabolites, for example, estriol (Mishra et al, 2006), or transdermal preparations of compounded formulations of estriol and estrone sulfate. These latter preparations have gained popularity as more natural, bioidentical formulations, but data supporting their superiority over other estrogenic formulations are scant in regard to specific measures of vascular physiology.…”

Dihydrotestosterone attenuates hypoxia inducible factor-1α and cyclooxygenase-2 in cerebral arteries during hypoxia or hypoxia with glucose deprivation

“…Both androgens and estrogens are generally credited with anti-inflammatory effects (26,32,34,49), although some proinflammatory effects have been reported for androgens (6,28). Furthermore, 5␣-androstane-3␤,17␤-diol (3␤-diol), an estrogen receptor (ER)-␤ agonist derived from the potent androgen dihydrotestosterone (DHT), has been shown to reduce levels of inflammatory markers in rhesus monkey vascular smooth muscle cells and human umbilical vein endothelial cells (29,31). In addition, the androgen dehydroepiandrosterone has been shown to decrease HIF-1␣ accumulation during hypoxia in human pulmonary smooth muscle cells (8).…”