Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors alpha and beta

Estrogen-based drug therapy in cardiovascular diseases has been difficult b ecause it has not been possible to separate the wanted vasculoprotective ef fect from the unwanted effects of the hormone to the reproductive system. H ere, we demonstrate that, after endothelial denudation of rat carotid arter y, the mRNA of the classical estrogen receptor (ER alpha) is constitutively expressed at a low level whereas the expression of the novel ER beta mRNA increases >40-fold. Under in situ hybridization and immunohistochemistry, E R beta mRNA and protein colocalize with the smooth muscle cells in the medi a and neointima. Treatment of ovariectomized female rats with the isoflavon e phytoestrogen genistein, which shows 20-fold higher binding affinity to E R beta than to ER alpha, or with 17 beta-estradiol, which does not differen tiate between the two receptors, provides similar dose-dependent vasculopro tective effect in rat carotid injury model. In addition in concentrations < 10 mu M, both ligands are equally inhibitory to the replication and migrati on of smooth muscle cells in vitro. However, only treatment with 17 beta-es tradiol, but not with genistein, is accompanied with a dose-dependent utero trophic effect. The results suggest that preferential targeting to ER beta will provide vasculoprotective estrogen analogs devoid of effects to the re productive system.