Increased 2-methoxyestradiol production in human coronary versus aortic vascular cells

Estradiol may be cardioprotective; however, the mechanisms involved remain unclear. Recent findings that estradiol attenuates neointima formation in e strogen 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 inhibiti ng vascular smooth muscle cell growth, it is feasible that 2-methoxyestradi ol mediates in part the cardioprotective effects of estradiol. To address t his 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 19 +/-0.69 pmol . min(-1) pe r 10(6) cells, 0.52 +/-0.085 mu mol/L, and 44 +/-4.9 pmol . min(-1) . mu mo l/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-hyelroxyeshadiol to 2-methoxyestradiol were 16 +/-0.59 pmol . min(-1) pe r 10(6) cells, 0.23 +/-0.011 mu mol/L, and 69 +/-3.6 pmol . min(-1) . mu mo l/L per 10(6) cells, respectively (all values significantly different compa red with human aortic smooth muscle cells). Also, in human aortic versus co ronary artery endothelial cells, the V-max (33 +/-0.24 versus 22 +/-0.33 pm ol . min(-1) per 10(6) cells, respectively), K-m (0.20 +/-0.010 versus 0.09 9 +/-0.014 mu mol/L, respectively), and V-max/K-m (163 +/-7.7 versus 243 +/ - 41 pmol . min(-1) . mu mol/L per 10(6) cells, respectively) values were s ignificantly different, Our results indicate that vascular smooth muscle an d endothelial cells effectively metabolize 2-hydroxyestradiol to 2-methoxye stradiol. 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-hydroxyestrad iol to 2-methoxyestradiol in the coronary circulation at low levels of 2-hy droxyestradiol.