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: 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
• 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

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.

摘要 与年龄匹配的男性相比，女性的中风风险和死亡率较低。虽然有些保护措施 似乎是通过卵巢雌激素介导的，卵巢激素并不能解释所有的保护作用。 这在女性中很常见，因为即使在绝经后，当卵巢雌激素丢失时，女性的保护作用仍然存在。在后- 绝经期妇女，雌激素的主要来源成为局部（性腺外）的雌二醇合成， 芳香酶芳香化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，芳香化酶基因缺失和药物抑制均导致以下结果更差： 脑缺血，提示芳香化酶起保护作用。因此，要检验的假设是 与男性相比，女性在脑缺血后不会发生脑血管功能障碍 这是由于内皮特异性芳香酶的较高表达和活性。为了确定是否有性行为 小鼠脑缺血后脑血管内皮功能障碍的差异， 内皮依赖性血管扩张剂乙酰胆碱（ACh）将在雄性和雌性小鼠中进行比较， 短暂性大脑中动脉闭塞（tMCAO，1小时）或使用体内颅窗进行假手术后 制备和光学微血管造影成像。为了确定内皮依赖性的性别差异是否 tMCAO后的扩张是由芳香化酶介导的，tMCAO或假手术前后的ACh反应将 在两种性别的野生型和芳香酶敲除小鼠之间进行比较。最后，为了确定是否有 EC特异性芳香化酶表达和脑血管芳香化酶活性的性别差异， 芳香化酶mRNA和蛋白质表达以及脑血管芳香化酶活性将在脑梗死患者中进行比较。 在基线或tMCAO或假手术后从雄性和雌性小鼠分离的血管。了解EC 芳香化酶的特异性调节可能导致旨在增强局部雌二醇的治疗策略 特别是在内皮细胞内的生产，从而避免了与全球相关的负面副作用。 雌激素给药，但维持雌激素对脉管系统的保护作用。