Estrogen Receptor- Mediates the Protective Effects of Estrogen Against Vascular Injury

Blood vessel cells express the 2 known estrogen receptors, and (ER , ER ), which are thought to mediate estrogen inhibition of vascular injury and atherosclerosis, but the relative role of ER and ER 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 ER (ER KOChapel Hill [ER KOCH]) and ER (ER KOChapel Hill [ER KOCH]). In double gene knockout mice generated by crossing these animals (ER , KOCH), 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 ER , KOCH mice could be due either to the presence of a novel, unidentified estrogen receptor or to functional expression of an estrogen receptorsplice variant in the parental ER KOCH mice. To distinguish between these possibilities, we studied recently generated mice fully null for estrogen receptor (ER KOStrasbourg [ER KOSt]) and examined the effect of estrogen on the response to vascular injury. In the present study, we show that after vascular injury in ovariectomized ER KOSt 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 receptormediates the protective effects of estrogen on the response to vascular injury. (Circ Res. 2002;90:1087-1092.)