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

• 批准号: 8457865
• 负责人: Kristen Leanne Zuloaga
• 金额: $ 4.92万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457865
• 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; improved; in vivo; mRNA Expression; male; malignant breast neoplasm; men; microangiography; mortality; promoter; protective effect; protein expression; response; sex; sham surgery

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. PUBLIC HEALTH RELEVANCE: Aromatase inhibitors, which are in use clinically for the treatment of hormone positive breast cancer, have been linked to adverse cardiovascular effects. The proposed research will use a rodent model of stroke, the middle cerebral artery occlusion, to determine the protective effect of aromatase (the enzyme that produces estradiol) against endothelial dysfunction following cerebral ischemia, especially in females. Understanding endothelial cell specific regulation of aromatase may lead to therapeutic strategies for stroke 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，妇女的中风风险和死亡率较低。尽管某些保护似乎是通过卵巢雌激素介导的，但卵巢激素并不能说明女性在女性中看到的所有保护作用，因为即使在卵巢雌激素丧失后，女性保护仍然存在。在绝经后妇女中，雌激素的主要来源成为酶芳香酶对雌二醇的局部（外癌）合成。芳香酶在许多细胞类型中表达，包括血管内皮细胞（EC）。在雌性小鼠中，芳香酶基因缺失和药理抑制作用导致脑缺血后的预后较差，这表明芳香酶起保护作用。因此，要测试的假设是，与男性相比，由于内皮特异性芳香酶的表达和活性，女性免受脑缺血后脑功能障碍的保护。为了确定是否在那里 小鼠脑缺血后脑血管内皮功能障碍的性别差异是否在小鼠中对内皮依赖性血管舒张剂乙酰胆碱（ACH）的反应将在雄性和雌性小鼠中在短暂的中脑和雌性小鼠中使用，或使用中性脑部闭塞或之后使用（TMCAO）（TMCAO，1H）（TMCAO，1H）体内颅窗制备和光学显微镜成像。为了确定TMCAO后内皮依赖性扩张的性别差异是否是由芳香酶介导的，在TMCAO或假手术之前和之后的ACH反应将在两性的野生型和芳香酶敲除小鼠之间进行比较。最后，为了确定在EC特异性芳香酶表达和脑血管芳香酶活性中是否存在性别差异，EC特异性芳香酶mRNA和蛋白质表达以及蛋白质的表达以及脑血管芳香酶活性将在基线或TMCAO或TMCAO或TMCAO或TMCAO或TMCAO或雌性小鼠中分离的脑血管中进行比较。假手术。了解EC的芳香酶特定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，从而避免与全球雌激素给药相关的负副作用，但保持雌激素对脉管系统的保护作用。 公共卫生相关性：在临床上用于治疗激素阳性乳腺癌的芳香酶抑制剂与心血管不良影响有关。拟议的研究将使用中风模型，即脑部动脉闭塞，以确定芳香酶（产生雌二醇的酶）针对脑缺血后内皮功能障碍的保护作用，尤其是在女性中。了解芳香酶的内皮细胞特异性调节可能会导致中风的治疗策略，旨在增强内皮内的局部雌二醇产生 细胞，因此避免了与全球雌激素给药相关的负副作用，但保持雌激素对脉管系统的保护作用。