Effects of Estrogen on the Vascular Injury Response in Estrogen Receptor a,b (Double) Knockout Mice

The two known estrogen receptors, ERa and ERb, 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 (ERaKOCH), and ERb knockout (ERbKOCH) mice. We generated mice harboring disruptions of both ERa and ERb genes (ERa,bKOCH) by breeding and studied the effect of 17b-estradiol (E2) on vascular injury responses in ovariectomized female ERa,bKOCH mice and WT littermates. E2 inhibited increases in vascular medial area following injury in the WT mice but not in the ERa,bKOCH 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 ERa,bKOCH mice. These data support that the role of estrogen receptors differs for specific components of the vascular injury response in the ERa,bKOCH mice. The results leave unresolved whether E2 inhibition of VSMC proliferation in ERa,bKOCH mice is caused by a receptor-independent mechanism, an unidentified receptor responsive to estrogen, or residual activity of the ERa splice variant reported previously in the parental ERaKOCH mice. These possibilities may be resolved by studies of mice in which ERa has been fully disrupted (ERaKOSt), which are in progress. (Circ Res. 2001;89:534-539.)