Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms

Estrogen receptors (ERs) are widely held to mediate the ability of 17 beta -estradiol (estradiol) to attenuate injury-induced proliferation of vascula r smooth muscle cells (VSMCs) leading to vascular lesions. However, recent findings that estradiol prevents injury-induced vascular lesion formation i n knockout mice lacking either ER alpha or ER beta seriously challenge this concept. Here we report that the local metabolism of estradiol to methoxye stradiols, endogenous metabolites of estradiol with no affinity for ERs, is responsible for the ER-independent inhibitory effects of locally applied e stradiol on rat VSMC growth. These finding imply that local vascular estrad iol metabolism may be an important determinant of the cardiovascular protec tive effects of circulating estradiol. Thus, interindividual differences, e ither genetic or acquired, in the vascular metabolism of estradiol may defi ne a given female's risk of cardiovascular disease and influence the cardio vascular benefit she receives from estradiol replacement therapy in the pos tmenopausal state. These findings also imply that nonfeminizing estradiol m etabolites may confer cardiovascular protection in both women and men. (C) 2000 Academic Press.