Stroke in females with metabolic syndrome, a vascular perspective

代谢综合征(METS)与中风风险增加和预后不良有关，但 这种健康困境背后的机制尚不清楚。高血压，一种旋转 甲硫氨酸的并发症，扰乱脑血管调节机制，增加 大脑对缺血性损伤的易感性，在绝经后妇女中更为普遍。 新出现的证据表明，甲状旁腺素综合征患者的侧支状态较差 在急性缺血性中风期间。我们最近的数据显示，携带甲硫氨酸的雌性小鼠表现出 卒中时侧支状态较差，MCAO后卒中面积较大。患有甲硫氨酸的小鼠也 穿透小动脉的血流量减少和微血管血流障碍 动力学。大量证据将糖尿病与血管扩张受损联系在一起，这可归因于 内皮型一氧化氮合酶的磷酸化；然而，内皮型一氧化氮合酶在介导软脑膜和穿透小动脉中的作用 一次又一次的流动从来没有得到适当的解决。鉴于已知的雌激素对 ENOS活性增加和T2 DM与雌激素减少相关的事实尚不清楚 蛋氨酸致衰老雌性小鼠侧支循环障碍是否归因于减少 ENOS活性。临床证据还表明，蛋氨酸诱导的高凝状态 女性比男性对不良血管事件的影响更大，包括缺血的风险 卒中。胞外囊泡(EV)和外切体被认为是 心血管和代谢性疾病，以及血小板衍生的EV在 调节血栓形成事件，可能会增加中风的风险和恶化血流。这个 拟议的研究将调查血液灌注量减少和 内皮型一氧化氮合酶受损及EV介导的血小板活化/凝血功能增加 服用蛋氨酸的生殖衰老雌性小鼠。包括多普勒在内的尖端技术 将使用光学相干层析成像和多光子激光扫描显微镜 检测硬膜动脉和穿透小动脉以及毛细血管、血栓的血流动力学 中风前后血小板-白细胞聚集物的形成。转基因敲入小鼠 拟磷化eNOS的表达将用于确定血管扩张在调节中的作用 Db/db女性的侧支循环。EVS在增加凝血和引起侧支循环中的作用 通过向Met和Normal的颈静脉注射分离的EV，将在体内测试失败 老鼠。本申请中提议的研究将为深入了解人类免疫缺陷病毒的复杂生物学提供帮助。 血液灌注率低，特别是患有甲状旁腺功能亢进症且有未来概念验证数据的女性 络脉疗法的发展。

Metabolic syndrome (MetS) is associated with an increased risk of stroke and poor outcome, yet the mechanisms underlying this health predicament are unclear. Hypertension, a revolving complication of MetS, disrupts cerebral vasoregulatory mechanisms and increases the susceptibility of the brain to ischemic injury, is more prevalent in postmenopausal women. Emerging evidence suggests that patients with MetS are associated with poor collateral status during acute ischemic stroke. Our recent data showed that female mice with MetS exhibited poor collateral status during stroke and larger stroke size after MCAO. Mice with MetS also have reduced blood flow in penetrating arterioles and impairment in microvascular flow dynamics. Ample evidence links diabetes to impaired vasodilation that is attributable to reduced eNOS phosphorylation; however, the role of eNOS in mediating pial and penetrating arteriole flow after stroke has never been properly addressed. Given the known effect of estrogen on increasing eNOS activity and the fact that T2DM associated reduction in estrogen, it is unclear whether the impaired collateral flow in the aged female mice with MetS is attributed to reduced eNOS activity. Clinical evidence also suggests that MetS induced-hypercoagulability has a greater impact on adverse vascular events in women than in men including the risk of ischemic stroke. Extracellular vesicles (EV) and exosomes are recognized as key players in cardiovascular and metabolic diseases, and platelet-derived EVs are particularly important in mediating thrombotic events that can potentiate the risk of stroke and worsen blood flow. The proposed study will investigate the causal relationship between reduced blood perfusion and impaired eNOS as well as EV-mediated increase in platelet activation/coagulation in reproductively senescent female mice with MetS. Cutting-edge technology including Doppler Optical Coherence Tomography and Multiphoton Laser Scanning Microscopy will be employed to detect blood flow dynamics in pial and penetrating arterioles as well as capillary vessels, clot and platelet-leukocyte aggregates formation before and after stroke. Transgenic knock-in mice expressing phosphomimetic eNOS will be used to ascertain the role of vasodilation in regulating collateral flow in db/db females. The role of EVs in increasing clotting and causing collateral failure will be tested in vivo by injecting Isolated EVs into the jugular vein of MetS and normal mice. The proposed studies in this application will provide insights into the complex biology of poor blood perfusion especially in women with MetS with proof-of-concept data for future development of collateral therapy.