The protective effects of estrogen in the cardiovascular system result from both systemic effects and direct actions of the hormone on the vasculature. Two estrogen receptors have been identified, ER␣ and ER␤. We demonstrated previously that estrogen inhibits the response to vascular injury in both wild-type and ER␣-deficient mice, and that ER␤ is expressed in the blood vessels of each, suggesting a role for ER␤ in the vascular protective effects of estrogen. In the present study, we examined the effect of estrogen administration on mouse carotid arterial injury in ER␤-deficient mice. Surprisingly, in ovariectomized female wild-type and ER␤ knockout mice, 17␤-estradiol markedly and equally inhibited the increase in vascular medial area and the proliferation of vascular smooth muscle cells after vascular injury. These data demonstrate that ER␤ is not required for estrogenmediated inhibition of the response to vascular injury, and suggest that either of the two known estrogen receptors is sufficient to protect against vascular injury, or that another unidentified estrogen receptor mediates the vascular protective effects of estrogen.17␤-estradiol ͉ vascular smooth muscle T he cardiovascular protective effects of estrogen are well established, and the direct effects of the hormone on vascular tissues are now well recognized (1, 2). Using a model of carotid arterial injury in a mouse, we have shown previously that administration of physiologic levels of 17␤-estradiol (E2) completely inhibits the vascular injury response in ovariectomized female wild-type (w.t.) mice (3,4). Subsequent studies demonstrated that E2 continues to protect against vascular injury in ER␣ knockout mice (␣ERKO) (4), indicating that estrogen can inhibit the vascular injury response by an ER␣-independent pathway. Another estrogen receptor, termed ER␤, was identified recently (5), suggesting the possibility that ER␤ mediates the protective effects of E2 on the vasculature. Studies demonstrating that ER␤ is expressed in vascular cells and tissues (4, 6-11), and, in contrast to ER␣, that ER␤ mRNA expression increases in vascular endothelial and smooth muscle cells after vascular injury (11, 12), prompted widespread speculation that ER␤ may place a central role in mediating the cardiovascular effects of E2 (10,13,14). To test directly the hypothesis that ER␤ mediates the vasoprotective effects of estrogen, we have now developed knockout mice in which the ER␤ gene is disrupted by gene targeting (␤ERKO) (15). In the present study, we examine the effect of estrogen on the response to vascular injury in these ␤ERKO mice. MethodsAnimals. The ␤ERKO mice were generated by targeted disruption of exon three of the ER␤ gene as described (15). The ␤ERKO mice are normal in appearance, but the females are subfertile because of impaired ovarian function (15). For vascular injury studies, 3-to 4-month-old F 2 littermates bred from heterozygote matings of F 1 animals (129 ϫ C57BL͞6J) were used. The mice were fed a normal diet ad libitum, as previously described (3...

We conclude that hyperglycemia itself can influence immune function in some phagocytic cells, which may be an important factor in postsurgical infection.