Increased 2-Methoxyestradiol Production in Human Coronary Artery Versus Aortic Smooth Muscle Cells: Potential Role in Mediating the Cardioprotective Effects of Estradiol
Estradiol (E) protects premenopausal women against coronary artery disease (CAD), however, the mechanisms involved remain unclear. Recent findings that E protects neointima formation in α and β estrogen receptor(ER) knockout mice suggest that the effects may be mediated via an ER independent mechanism. Because 2-methoxyestradiol(2MeOE),an endogenous metabolite of E with no affinity for ER, is more potent than E in inhibiting vascular smooth muscle cell (SMC) growth, it is feasible that 2MeOE mediates the protective effects of E. Since formation of 2MeOE involves the methylation of 2-hydroxyestradiol (2OHE; major estradiol metabolite)by COMT, the protective effects of estradiol on the coronary circulation may be due in part to the efficient conversion of E and 2OHE to 2MeOE in coronary vascular SMCs. To test this hypothesis, we compared the kinetics of 2MeOE synthesis in human aortic (A) versus coronary artery (CA) SMCs. Incubation of human ASMCs and CASMCs with 10μM 2OHE resulted in a time-dependent formation of 2MeOE. As compared to ASMCs, CASMCs were twice as effective in metabolizing 2OHE to 2MeOE and the Vmax and Km were 15.7±.7 vs 38.3±.9 pmol 2MeOE/106 cells/min and .35±.07 vs .12±.02 μM, respectively. Rat ASMCs and porcine aortic endothelial cells (ECs) also metabolized 2OHE to 2MeOE, the Vmax being 17.1±.8 and 14.22±.3 pmol/106cells/min, respectively, and Km of 0.48±.1 and 0.32±.04μM,respectively. Our findings indicate that vascular SMCs and ECs effectively metabolize 2OHE to 2MeOE and that as compared to ASMCs, CASMCs have increased COMT activity and 2MeOE formation.Thus, local metabolism of 2OHE to 2MeOE may mediate the anti-vasoocclusive effects of E via an ER-independent mechanism. Moreover, increased COMT activity may selectively protect the coronary artery by generating more 2MeOE and this may be responsible for the decreased incidence of CAD in premenopausal women.