Effects of estrogen on the vascular injury response in estrogen receptor alpha,beta (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 exte nt in female wild-type (WT), ERa knockout (ER alpha KOCH), and ER beta knoc kout (ER beta KOCH) mice. We generated mice harboring disruptions of both E R 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 ovariecto mized female ER alpha,beta KOCH mice and WT littermates. E2 inhibited incre ases 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 kno wn estrogen receptors are necessary and sufficient to mediate estrogen inhi bition of a component of the vascular injury response. Surprisingly, as in WT littermates, E2 still significantly increased uterine weight and inhibit ed vascular smooth muscle cell (VSMC) proliferation following injury in the ER alpha,beta KOCH mice. These data support that the role of estrogen rece ptors differs for specific components of the vascular injury response in th e ER alpha,beta KOCH mice. The results leave unresolved whether E2 inhibiti on 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 th e parental ER alpha KOCH mice. These possibilities may be resolved by studi es of mice in which ER alpha has been fully disrupted (ER alpha KOSt), whic h are in progress.