Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury.
Blood vessel cells express the 2 known estrogen receptors, alpha and beta (ERalpha, ERbeta), which are thought to mediate estrogen inhibition of vascular injury and atherosclerosis, but the relative role of ERalpha and ERbeta in these events is controversial. Estrogen inhibits the vascular injury response to the same extent in ovariectomized female wild-type mice and in the original single gene knockout mice for ERalpha (ERalphaKO(Chapel Hill) [ERalphaKO(CH)]) and ERbeta (ERbetaKO(Chapel Hill) [ERbetaKO(CH)]). In double gene knockout mice generated by crossing these animals (ERalpha,betaKO(CH)), estrogen no longer inhibits medial thickening after vascular injury, but still inhibits vascular smooth muscle cell proliferation and increases uterine weight. The partial retention of estrogen responsiveness in ERalpha,betaKO(CH) mice could be due either to the presence of a novel, unidentified estrogen receptor or to functional expression of an estrogen receptor-alpha splice variant in the parental ERalphaKO(CH) mice. To distinguish between these possibilities, we studied recently generated mice fully null for estrogen receptor alpha (ERalphaKO(Strasbourg) [ERalphaKO(St)]) and examined the effect of estrogen on the response to vascular injury. In the present study, we show that after vascular injury in ovariectomized ERalphaKO(St) mice, estrogen has no detectable effect on any measure of vascular injury, including medial area, proteoglycan deposition, or smooth muscle cell proliferation. These data demonstrate that estrogen receptor-alpha mediates the protective effects of estrogen on the response to vascular injury.
Pare
Gary
G
Molecular Cardiology Research Institute, New England Medical Center, Boston, Massachusetts, USA.
Krust
Andrée
A
Karas
Richard H
RH
Dupont
Sonia
S
Aronovitz
Mark
M
Chambon
Pierre
P
Mendelsohn
Michael E
ME
D000818:Animals; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size; D011509:Proteoglycans / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D014599:Uterus / Q000473:pathology
D047628:Estrogen Receptor alpha; D011509:Proteoglycans; D011960:Receptors, Estrogen; D004958:Estradiol