0178 : The activation function-1 (AF1) of estrogen receptor α prevents arterial neointima through a direct effect on smooth muscle cells

Abstract

Estradiol (E2) regulates gene transcription through nuclear Estrogen Receptor alpha (ERα) thanks to two Activation Functions, AF-1 and AF- 2, but can activate membrane ERαand thereby rapid « non genomic » signals. Some tissue-specific stimulatory roles of these ERα functions have already been described: for instance ERα AF1 and membrane ERα activation are each necessary and sufficient to induce endometrial epithelial proliferation and to accelerate endothelial healing respectively in response to E2. E2 can also inhibit vascular smooth muscle cell proliferation, but the mechanisms of this action are poorly recognized. Using a mouse model of femoral artery injury, we found that 1) E2 prevents intimal smooth muscle hyperplasia. 2) Selective inactivation of ERαin smooth muscle cells abrogates this protective action, whereas its endothelial and hematopoietic inactivation did not alter this effect. 3) Estrogen dendrimer conjugate, a selective activator of membrane ERa, fail to prevent intimal hyperplasia. 4) E2 does not inhibit post-injury arterial smooth muscle cell proliferation in mice selectively deficient in ERαAF1 (through deletion of the N-terminal A/B domain which harbors this function), demonstrating that ERαAF1 is necessary to mediate this effect, 5) Finally, tamoxifen, a selective partial AF-1 activator of ERα, is sufficient to prevent the hyperplasia. Altogether, we demonstrate here, for the first time, that ERαAF1 activation is both necessary and sufficient to prevent post-injury arterial smooth muscle cell proliferation, in striking contrast to its stimulatory action on the endometrial epithelium. This underlines the exquisite tissue-specific actions of ERαsubfunctions as well as of selective ER modulators, and shed some light on one of the most intriguing mysteries of biology of estrogens.