Structure-function relationship of estrogen receptors in cardiovascular pathophysiological models

The ancestral status of estrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of estrogens, and in particular of 17β-estradiol (E2). Indeed, in addition to their well described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes several highly beneficial effects such as prevention of osteoporosis, atheroma and type 2 diabetes,…However, estrogens also promotes two deleterious actions : the stimulation of the proliferation of the epithelium of two sex targets : uterus and breast, favoring an increase in risk of epithelial cancer in these two tissues.These actions are mediated by the activation of ER alpha (ERα) and beta (ERβ), which regulate target gene transcription (genomic action) through two independent activation functions AF-1 and AF-2, but can also elicit rapid membrane initiated steroid signals. Although ERβ plays an important role in the central nervous system and in the heart, ERα appears to play a prominent role in most of the other tissues.One major challenge consists in uncoupling some beneficial actions from other deleterious ones, i.e. selective ER modulation. Tamoxifen and raloxifen are beneficial to prevent the recurrence of breast cancer, and mimic estrogen action mainly on bone, but their effets on atheroma and on type 2 diabetes are if any marginal.These last years, several labs, and in particular our lab, have attempted:1)To perform an in vivo molecular “dissection” of ERα, allowing the uncoupling of some of its actions, and potentially paving the way to optimized selective ER modulators. (reviewed in Arnal JF, et al. Br J Pharmacol. 2012;165:57-66).2)To describe an unexpected action of E2 treatment at the level of platelet responses in mice, that protects the animals from thromboembolism through the haematopoietic ERα. (Valéra MC et al. Blood. 2012, in press).