Endothelial Aromatase in Sex-Specific Cerebrovascular Dysfunction After Ischemia

内皮芳香酶在缺血后性别特异性脑血管功能障碍中的作用

基本信息

批准号：
8927748
负责人：
Kristen Leanne Zuloaga
金额：
$ 1.71万
依托单位：
REGENERATIVE RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2016-01-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927748
关键词：
Accounting Acetylcholine Adverse effects Age Aromatase Aromatase Inhibitors Breast Cancer Treatment Caliber Cardiovascular system Cephalic Cerebral Ischemia Cerebrovascular Circulation Cerebrum Cytochrome P450 Endothelial Cells Endothelium Endothelium-Dependent Relaxing Factors Enzymes Estradiol Estrogens Female Functional disorder Gene Deletion Hormones Image Ischemia Ischemic Brain Injury Knockout Mice Lead Link Mediating Menopause Middle Cerebral Artery Occlusion Monitor Mus Optics Outcome Ovarian Ovarian hormone Perfusion Play Postmenopause Preparation Production Regulation Relative (related person)Research Risk Rodent Model Role Sex Characteristics Source Stroke Testing Therapeutic Tissues Vascular Endothelial Cell Vasodilation Vasodilator Agents Woman cell type cerebrovascular endothelial dysfunction improved in vivo mRNA Expression male malignant breast neoplasm men microangiography mortality promoter protective effect protein expression response sex sham surgery

项目摘要

ABSTRACT 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.

抽象的与年龄匹配的男性相比，女性中风风险和死亡率较低。卵巢激素似乎是通过卵巢雌激素介导的在女性保护阶段后，在卵巢雌激素丢失时，女性的保护仍然存在。更年期妇女，雌激素的主要来源是雌二醇的局部（外部）合成（外部）的合成。酶芳香酶以多种细胞类型表达，包括血管内皮细胞（EC）。在雌性小鼠中，芳香化酶基因缺失和药理学抑制作用导致结果较差脑缺血表明芳香酶起保护作用。比较脑缺血后，女性免受脑血管功能障碍的保护由于较高的表达和活性，以确定是否有性别小鼠脑缺血后的脑弯曲骨质内皮功能障碍的差异，有些在雄性和雌性小鼠之前和经过体内颅颅窗口，经过跨性脑动脉阻塞（TMCAO，1H）或假手术后制备和光学的微读成像。 TMCAO后的扩张是通过芳香酶介导的，TMCAO或假手术后的ACH反应Willl 在两性的野生型和芳香酶敲除小鼠之间进行比较。 EC的性别差异 - 特异性芳香酶芳香酶表达和脑血管芳香酶活性，EC特异性芳香酶mRNA和蛋白质表达和脑血管芳香酶活性将在脑中进行比较从基线或TMCAO或假手术后从雄性和雌性小鼠分离的血管。芳香酶的特定调节可能导致旨在增强局部雌二醇的治疗策略生产规范规范规范在希森特细胞中，因此避免了与全局相关的负面副作用雌激素给药，但在脉管系统上保持保护性雌激素。