Estradiol may be cardioprotective; however, the mechanisms involved remain unclear. Recent findings that estradiol attenuates neointima formation in estrogen receptor knockout mice suggest that the cardioprotective effects of estradiol may be mediated through estrogen receptor-independent mechanisms. Because 2-methoxyestradiol, an endogenous metabolite of estradiol with no affinity for estrogen receptors, is more potent than estradiol in inhibiting vascular smooth muscle cell growth, it is

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... ble that 2-methoxyestradiol mediates in part the cardioprotective effects of estradiol. To address this hypothesis, we examined the kinetics of 2-methoxyestradiol synthesis in vascular smooth muscle cells and endothelial cells. In human aortic smooth muscle cells, the V max , K m , and V max /K m ratio values for conversion of 2-hydroxyestradiol to 2-methoxyestradiol were 19Ϯ0.69 pmol ⅐ min Ϫ1 per 10 6 cells, 0.52Ϯ0.085 mol/L, and 44Ϯ4.9 pmol ⅐ min Ϫ1 ⅐ mol/L per 10 6 cells, respectively. In human coronary artery vascular smooth muscle cells, the V max , K m , and V max /K m ratio values for conversion of 2-hydroxyestradiol to 2-methoxyestradiol were 16Ϯ0.59 pmol ⅐ min Ϫ1 per 10 6 cells, 0.23Ϯ0.011 mol/L, and 69Ϯ3.6 pmol ⅐ min Ϫ1 ⅐ mol/L per 10 6 cells, respectively (all values significantly different compared with human aortic smooth muscle cells). Also, in human aortic versus coronary artery endothelial cells, the V max (33Ϯ0.24 versus 22Ϯ0.33 pmol ⅐ min Ϫ1 per 10 6 cells, respectively), K m (0.20Ϯ0.010 versus 0.099Ϯ0.014 mol/L, respectively), and V max /K m (163Ϯ7.7 versus 243Ϯ41 pmol ⅐ min Ϫ1 ⅐ mol/L per 10 6 cells, respectively) values were significantly different. Our results indicate that vascular smooth muscle and endothelial cells effectively metabolize 2-hydroxyestradiol to 2-methoxyestradiol. The lower K m and higher V max /K m ratio of human coronary versus aortic cells indicate a faster rate of local metabolism of 2-hydroxyestradiol to 2-methoxyestradiol in the coronary circulation at low levels of 2-hydroxyestradiol. (Hypertension. 2001;37[part 2]:658-662.)