Mechanism of Vascular Dysfunction after Stroke in Postmenopausal Female

描述（由申请人提供）：绝经后女性卒中风险增加和卒中相关脑损伤的潜在机制尚不清楚。我们将检验以下假设：绝经后卵巢激素的丧失会加重卒中后的脑损伤，这是由于脑血管内皮保护机制的丧失，使绝经后女性的内皮细胞（EC）极易受到缺血性损伤和内皮功能障碍的影响。我们将使用血管灌注的体内光学成像来评估体内EC功能，并确定中年16月龄雌性小鼠生殖衰老（RS）后卵巢激素的丧失是否加剧EC损伤和功能障碍，导致大脑中动脉闭塞（MCAO）后灌注不足和脑损伤恶化。从机制上讲，我们将确定生殖衰老小鼠的缺血后内皮损伤和功能障碍是否与内皮衍生的细胞色素P450（E450）称为环氧二十碳三烯酸（E450）的信号转导减少有关。使用内皮特异性过表达EETs合成酶CYP 2 J2（Tie 2 - 2 J2）和EETs代谢酶可溶性环氧化物水解酶（Tie 2-sEH）的转基因小鼠，我们将确定RS雌性小鼠中风后EC损伤、灌注不足和内皮细胞功能降低是否与sEH上调和EETs丢失有关。我们还将使用内皮特异性缺失信号转导子和转录激活子-3（Tie 2- Cre/Flox-STAT 3）的小鼠来确定RS女性中sEH上调是否与脑血管内皮中STAT 3信号转导的丧失有关。拟议的研究检查了绝经后女性血管特异性诱导的损伤机制。选择性靶向sEH可能代表了一种专门针对绝经后女性的治疗策略，并且在绝经后女性中特别有效，绝经后女性是中风率和死亡率最高的年龄组。 公共卫生相关性：包括中风在内的心血管疾病是全世界妇女死亡的最大单一原因。尽管最近认识到中风的机制在男性和女性之间是不同的，但目前还没有专门针对女性中风的治疗方法。我们已经确定了绝经后女性脑血管特异性损伤的机制，这可能是治疗绝经后女性中风特别有效的靶点。

DESCRIPTION (provided by applicant): The mechanisms underlying increased stroke risk and stroke-related brain damage in postmenopausal females are poorly understood. We will test the hypothesis that loss of ovarian hormones following menopause exacerbates brain damage after stroke, due to loss of cerebrovascular endothelial protective mechanisms, rendering endothelial cells (ECs) in postmenopausal women highly susceptible to ischemic injury and endothelial dysfunction. We will use in-vivo optical imaging of vascular perfusion to assess EC function in vivo, and determine if loss of ovarian hormones after reproductive senescence (RS) in middle-aged, 16-month old female mice exacerbates EC injury and dysfunction, leading to perfusion deficit and worsening brain damage after middle cerebral artery occlusion (MCAO). Mechanistically, we will determine if post-ischemic endothelial injury and dysfunction in reproductively senescent mice are linked to reduced signaling by endothelium-derived cytochrome P450 (CYP) eicosanoids called epoxyeicosatrienoic acids (EETs). Using transgenic mice with endothelial-specific overexpression of EETs-synthetic enzyme CYP2J2 (Tie2-2J2) and EETs-metabolizing enzyme soluble epoxide hydrolase (Tie2-sEH), we will determine if EC injury, perfusion deficit and reduced endothelial cell function after stroke in RS female mice are linked to sEH upregulation and loss of EETs. We will also use mice with endothelial-specific deletion of signal transducer and activator of transcription-3 (Tie2- Cre/Flox-STAT3) to determine if sEH upregulation in RS females is linked to loss of STAT3 signaling in cerebrovascular endothelium. The proposed studies examine a mechanism of injury specifically induced in postmenopausal female vessels. Selective targeting of sEH may represent a therapeutic strategy specifically tailored to and particularly effective in postmenopausal females, an age group with the highest stroke rate and mortality. PUBLIC HEALTH RELEVANCE: Cardiovascular disease, including stroke, is the largest single cause of death among women worldwide. Despite recent recognition that mechanisms of stroke are different between men and women, no therapy currently exists that specifically targets stroke in women. We have identified a mechanism of injury specifically induced in female brain vessels after menopause, which may serve as a target for stroke therapy particularly effective in post-menopausal females.