Mechanism of Vascular Dysfunction after Stroke in Postmenopausal Female

描述(由申请人提供)：绝经后女性中风风险增加和中风相关脑损伤的潜在机制尚不清楚。我们将检验这一假说，即绝经后卵巢激素的丢失会加剧中风后的脑损伤，这是由于脑血管内皮细胞保护机制的丧失，使绝经后女性的内皮细胞(ECs)非常容易受到缺血性损伤和内皮功能障碍的影响。我们将使用血管血流的体内光学成像来评估体内的EC功能，并确定16月龄中年雌性小鼠在生殖衰老(RS)后卵巢激素的丢失是否会加剧EC的损伤和功能障碍，导致大脑中动脉闭塞(MCAO)后的血流灌注不足和脑损伤加重。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细胞色素P450(CYP)二十碳二烯酸(EETs)信号减少有关。利用内皮特异性高表达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雌性小鼠卒中后EC损伤、灌流不足和内皮细胞功能降低是否与EEH上调和EETs丢失有关。我们还将使用内皮特异性信号转导和转录激活因子3缺失的小鼠(Tie2-CRE/Flox-STAT3)来确定RS雌性患者的sEH上调是否与脑血管内皮细胞中STAT3信号的丢失有关。这项拟议的研究考察了一种在绝经后女性血管中特定诱导的损伤机制。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，并且对绝经后女性特别有效，绝经后女性是中风发生率和死亡率最高的年龄段。

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.