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：
8770057
负责人：
Kristen Leanne Zuloaga
金额：
$ 5.6万
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 2016-02-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770057
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 Health 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

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.

描述（由申请人提供）：与年龄匹配的男性相比，女性的中风风险和死亡率较低。虽然这种保护作用的一部分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中所见的所有保护作用，因为即使在绝经后卵巢雌激素丧失时，女性保护作用仍然存在。在绝经后妇女中，雌激素的主要来源是通过芳香酶局部（性腺外）合成雌二醇。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都会导致脑缺血后的结果更差，这表明芳香酶发挥着保护作用。因此，要检验的假设是，与男性相比，女性由于内皮特异性芳香酶的表达和活性较高，因此可以免受脑缺血后脑血管功能障碍的影响。为了确定是否有由于小鼠脑缺血后脑血管内皮功能障碍存在性别差异，因此将在暂时性大脑中动脉闭塞（tMCAO，1小时）或假手术前后雄性和雌性小鼠对内皮依赖性血管扩张剂乙酰胆碱（ACh）的反应进行比较体内颅窗制备和光学微血管造影成像。为了确定 tMCAO 后内皮依赖性扩张的性别差异是否由芳香酶介导，将比较野生型和芳香酶敲除两性小鼠在 tMCAO 或假手术前后的 ACh 反应。最后，为了确定 EC 特异性芳香酶表达和脑血管芳香酶活性是否存在性别差异，将在基线或 tMCAO 或之后从雄性和雌性小鼠分离的脑血管中比较 EC 特异性芳香酶 mRNA 和蛋白表达以及脑血管芳香酶活性。假手术。了解 EC 对芳香酶的特异性调节可能会导致旨在增强内皮细胞内局部雌二醇产生的治疗策略，从而避免与整体雌激素给药相关的负面副作用，但保持雌激素对脉管系统的保护作用。