253 Endothelial Estrogen Receptor α mediates the atheroprotective action of 17β-Eestradiol in LDLr deficient mice

Background Although estrogen administration to hysterectomized menopausal women did not prevent the occurence of myocardial infarction in a randomized controlled trial (WHI 2004), epidemiological studies suggest and experimental results clearly demonstrate a major atheroprotective action of estrogens. The goal of the present study was to identify the cellular target(s) accounting for the estradiol (E2) beneficial action on fatty streak development. Methods and Results We first confirmed the key role of estrogen receptor α (ERα) in atheroprotective effect of E2 as this action was completely abolished in mice deficient both in Low Density Lipoprotein receptor (LDLr) and in ERα. Comparison of LDLr–/– mice transplanted with either ERα+/+ or ERα–/– bone marrow showed that functional ERα in the hematopoietic lineage is not required for E2 atheroprotection. We then showed that ERα floxed mice (ER_lox/flox) bred with the Tie2-Cre mice on the LDLr–/–- background had a complete inactivation of ERα both in bone marrow and in endothelial cells. Remarkably, in this mouse model, the E2 atheroprotective action was completely abolished. Conclusions Altogether, this is the first in vivo demonstration that endothelial ERα represents a key target of the atheroprotective effect of E2, whereas the hematopoietic ERα isdispensable for the protective action. Selective estrogen receptor modulators that mimic this endothelial action of E2 should now be considered in hormonal treatment as well as in atheroprotection.