Endothelial Aromatase in Sex-Specific Cerebrovascular Dysfunction After Ischemia

描述（由申请人提供）：与同龄男性相比，女性卒中风险和死亡率较低。虽然这种保护似乎是通过卵巢雌激素介导的，但卵巢激素并不能解释女性身上看到的所有保护作用，因为即使在卵巢雌激素消失后，女性的保护作用仍然存在。在绝经后的妇女，雌激素的主要来源变成局部（性腺外）合成雌二醇的酶芳香化酶。芳香酶在多种细胞类型中表达，包括血管内皮细胞（EC）。在雌性小鼠中，芳香酶基因缺失和药物抑制均导致脑缺血后预后恶化，提示芳香酶具有保护作用。因此，需要验证的假设是，与男性相比，由于内皮特异性芳香化酶的表达和活性更高，女性在脑缺血后免受脑血管功能障碍的影响。为了确定是否存在

DESCRIPTION (provided by applicant): Women have lower stroke risk and mortality compared to age-matched men. While some of this protection appears to be mediated via ovarian estrogen, ovarian hormones do not account for all of the protective effects seen in females since female protection persists even after menopause when ovarian estrogen is lost. In post- menopausal women, the major source of estrogen becomes local (extra-gonadal) synthesis of estradiol by the enzyme aromatase. Aromatase is expressed in numerous cell types, including vascular endothelial cells (EC). In female mice, both aromatase gene deletion and pharmacological inhibition lead to worse outcome following cerebral ischemia, suggesting that aromatase plays a protective role. Therefore, the hypothesis to be tested is that females are protected from cerebrovascular dysfunction following cerebral ischemia compared to males due to higher expression and activity of endothelial-specific aromatase. In order to determine if there are sex differences in cerebrovascular endothelial dysfunction following cerebral ischemia in mice, responses to the endothelium-dependent vasodilator acetylcholine (ACh) will be compared in male and female mice before and after transient middle cerebral artery occlusion (tMCAO, 1h) or sham surgery using an in vivo cranial window preparation and optical microangiography imaging. To determine if sex differences in endothelium-dependent dilation after tMCAO are mediated by aromatase, ACh responses before and after tMCAO or sham surgery will be compared between wild-type and aromatase knockout mice of both sexes. Finally, to determine if there are sex differences in EC-specific aromatase expression and cerebrovascular aromatase activity, EC-specific aromatase mRNA and protein expression and cerebrovascular aromatase activity will be compared in cerebral vessels isolated from male and female mice at baseline or after tMCAO or sham surgery. Understanding EC specific regulation of aromatase may lead to therapeutic strategies aimed at enhancing local estradiol production specifically within endothelial cells, thus avoiding the negative side effects associated with global estrogen administration, but maintaining the protective effects of estrogen on the vasculature.