Estrogen Receptor-&agr; Mediates the Protective Effects of Estrogen Against Vascular Injury

Abstract

Blood vessel cells express the 2 known estrogen receptors, &agr; and &bgr; (ER&agr;, ER&bgr;), which are thought to mediate estrogen inhibition of vascular injury and atherosclerosis, but the relative role of ER&agr; and ER&bgr; 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&agr; (ER&agr;KOChapel Hill [ER&agr;KOCH]) and ER&bgr; (ER&bgr;KOChapel Hill [ER&bgr;KOCH]). In double gene knockout mice generated by crossing these animals (ER&agr;,&bgr;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&agr;,&bgr;KOCH mice could be due either to the presence of a novel, unidentified estrogen receptor or to functional expression of an estrogen receptor-&agr; splice variant in the parental ER&agr;KOCH mice. To distinguish between these possibilities, we studied recently generated mice fully null for estrogen receptor &agr; (ER&agr;KOStrasbourg [ER&agr;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&agr;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 receptor-&agr; mediates the protective effects of estrogen on the response to vascular injury.