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 ⍺ (ER⍺) in atheroprotective effect of E2 as this action was completely abolished in mice deficient both in Low Density Lipoprotein receptor (LDLr) and in ER⍺. Comparison of LDLr-/- mice transplanted with either ER⍺+/+ or ER⍺-/- bone marrow showed that functional ER⍺ in the hematopoietic lineage is not required for E2 atheroprotection. We then showed that ER⍺ floxed mice (ER⍺flox/flox) bred with the Tie2-Cre mice on the LDLr-/- background had a complete inactivation of ER⍺ both in bone marrow and in endothelial cells. Remarkably, in this mouse model, the E2 atheroprotective action was completely abolished.
Altogether, this is the first in vivo demonstration that endothelial ER⍺ represents a key target of the atheroprotective effect of E2, whereas the hematopoietic ER⍺ is dispensable 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.Le texte complet de cet article est disponible en PDF.