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机制尚不清楚。我们将验证以下假设：由于脑血管内皮保护机制的丧失，绝经后女性卵巢激素的减少会加剧脑卒中后的脑损伤，使内皮细胞（ECs）极易受到缺血性损伤和内皮功能障碍的影响。我们将使用体内血管灌注光学成像来评估EC在体内的功能，并确定16月龄中年雌性小鼠生殖衰老（RS）后卵巢激素的丧失是否会加剧EC损伤和功能障碍，导致大脑中动脉闭塞（MCAO）后的灌注缺陷和脑损伤恶化。在机制上，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来源的细胞色素P450 （CYP）二十烷类化合物（环氧二碳三烯酸（EETs））信号传导减少有关。通过内皮特异性过表达EETs合成酶CYP2J2 （Tie2-2J2）和EETs代谢酶可溶性环氧化物水解酶（Tie2-sEH）的转基因小鼠，我们将确定RS雌性小鼠脑卒中后EC损伤、灌注缺陷和内皮细胞功能降低是否与sEH上调和EETs丧失有关。我们还将使用内皮特异性缺失信号传感器和转录激活子-3 （Tie2- Cre/Flox-STAT3）的小鼠来确定RS女性的sEH上调是否与脑血管内皮中STAT3信号的缺失有关。提出的研究探讨了绝经后女性血管损伤的机制。选择性靶向sEH可能是一种专门针对绝经后女性的治疗策略，尤其有效，绝经后女性是卒中发病率和死亡率最高的年龄组。

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.