Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors α and β

Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors α and β

^*University of Turku, Institute of Biomedicine and MediCity Research Laboratory, Kiinamyllynkatu 10, FIN-20520 Turku, Finland; ^†Center for Nutrition and Toxicology, Department of Biosciences, Karolinska Institute, NOVUM, S-141 57 Huddinge, Sweden; ^‡Transplantation Laboratory, The Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 3, FIN-00014 Helsinki, Finland; and ^¶Department of Medical Nutrition, Karolinska Institute, NOVUM, S-141 86 Huddinge, Sweden

Communicated by Elwood V. Jensen, Karolinska Institute, Huddinge, Sweden (received for review December 17, 1998)

Abstract

Estrogen-based drug therapy in cardiovascular diseases has been difficult because it has not been possible to separate the wanted vasculoprotective effect from the unwanted effects of the hormone to the reproductive system. Here, we demonstrate that, after endothelial denudation of rat carotid artery, the mRNA of the classical estrogen receptor (ERα) is constitutively expressed at a low level whereas the expression of the novel ERβ mRNA increases >40-fold. Under in situ hybridization and immunohistochemistry, ERβ mRNA and protein colocalize with the smooth muscle cells in the media and neointima. Treatment of ovariectomized female rats with the isoflavone phytoestrogen genistein, which shows 20-fold higher binding affinity to ERβ than to ERα, or with 17β-estradiol, which does not differentiate between the two receptors, provides similar dose-dependent vasculoprotective effect in rat carotid injury model. In addition in concentrations <10 μM, both ligands are equally inhibitory to the replication and migration of smooth muscle cells in vitro. However, only treatment with 17β-estradiol, but not with genistein, is accompanied with a dose-dependent uterotrophic effect. The results suggest that preferential targeting to ERβ will provide vasculoprotective estrogen analogs devoid of effects to the reproductive system.

Footnotes

¶ To whom reprint requests should be addressed at: Transplantation Laboratory, The Haartman Institute, University of Helsinki, P.O. Box 21, Haartmaninkatu 3, FIN 00014, Helsinki, Finland. e-mail: pekka.hayry{at}helsinki.fi.
ABBREVIATIONS:

ER,

estrogen receptor;

17β-E2,

17-estradiol;

SMC,

(vascular) smooth muscle cell;

PDGF-B,

platelet-derived growth factor-B