Effects of estrogen on the vascular injury response in estrogen receptor α,β (double) knockout mice

The two known estrogen receptors, ER alpha and ER beta, mediate the effects of estrogen in all target tissues, including blood vessels. We have shown previously that estrogen inhibits vascular injury response to the same extent in female wild-type (WT), ERa knockout (ER alpha KOCH), and ER beta knockout (ER beta KOCH) mice. We generated mice harboring disruptions of both ER alpha and ER beta genes (ER alpha,beta KOCH) by breeding and studied the effect of 17 beta -estradiol (E2) on vascular injury responses in ovariectomized female ER alpha,beta KOCH mice and WT littermates. E2 inhibited increases in vascular medial area following injury in the WT mice but not in the ER alpha,beta KOCH mice, demonstrating for the first time that the two known estrogen receptors are necessary and sufficient to mediate estrogen inhibition of a component of the vascular injury response. Surprisingly, as in WT littermates, E2 still significantly increased uterine weight and inhibited vascular smooth muscle cell (VSMC) proliferation following injury in the ER alpha,beta KOCH mice. These data support that the role of estrogen receptors differs for specific components of the vascular injury response in the ER alpha,beta KOCH mice. The results leave unresolved whether E2 inhibition of VSMC proliferation in ER alpha,beta KOCH mice is caused by a receptor-independent mechanism, an unidentified receptor responsive to estrogen, or residual activity of the ER alpha splice variant reported previously in the parental ER alpha KOCH mice. These possibilities may be resolved by studies of mice in which ER alpha has been fully disrupted (ER alpha KOSt), which are in progress.