Endogenous Metabolites of Estradiol Inhibit Endothelin Synthesis by Coronary Artery Endothelial Cells Via Estrogen Receptor (ER) Indepedent Mechanism
Estradiol (E) inhibits endothelin (ET) synthesis via estrogen receptor (ER)-dependent pathway and this may,in part, mediate the protective effects of E against coronary artery disease (CAD)in postmenopausal women. However, recent findings that E inhibits neointima formation in mice lacking α and β ER, suggests that the protective effects of E may be mediated via an ER independent mechanism. Because endogenous metabolites of E (2-hydroxyestradiol [2OHE] and 2-methoxyestradiol [2MeOE]) with little/no affinity for ERs, are more potent than E in inhibiting SMC growth, we investigated whether these metabolites also inhibit ET synthesis via an ER-independent mechanism. Treatment of porcine coronary artery endothelial cells (ECs)for 12-48 hrs with .001-1μM of 2OHE or 2MeOE concentration-dependently inhibited basal as well as TNFα (10ng/ml) and thrombin (.1U/ml) stimulated ET synthesis and these effects were not blocked in presence of ER-antagonist ICI182780 (50μM; ICI). The effects of 2OHE and 2MeOE on ET synthesis was also mimicked by various clinically used estrogens (E valerate, E cypionate, ethinyl E) which are metabolized in vivo and by cultured cells. Our finding that 2OHE and 2MeOE inhibit basal and stimulated ET synthesis suggests that endogenous metabolism of E to 2OHE and 2MeOE may mediate the anti-vasoocclusive effects of E via an ER-independent mechanism. Moreover, endogenous metabolism of E to 2OHE and 2MeOE may be responsible for the decreased incidence of CAD in premenopausal women. In conclusion, both ER-dependent and -independent mechansims may mediate the endogenous effects of E on ET synthesis.