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相关，但 造成这种健康困境的机制尚不清楚。高血压，一个旋转的 代谢综合征的并发症，破坏脑血管调节机制，并增加 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，代谢综合征患者与不良的侧支循环状态有关 急性缺血性中风我们最近的数据显示，患有MetS的雌性小鼠表现出 卒中时侧支循环状态差，MCAO后卒中面积较大。具有MetS的小鼠也 穿透性小动脉的血流减少，微血管血流受损 动力学大量证据表明糖尿病与血管舒张功能受损有关， eNOS磷酸化;然而，eNOS在介导软脑膜和穿透小动脉中的作用 中风后的血流从未得到适当的解决。考虑到雌激素对 eNOS活性增加和T2 DM相关雌激素减少的事实，目前尚不清楚 患有MetS的老年雌性小鼠侧支循环血流受损是否归因于减少 eNOS活性。临床证据还表明，MetS诱导的高凝状态具有显著的 对女性不良血管事件的影响大于男性，包括缺血性 中风细胞外囊泡（EV）和外泌体被认为是细胞内的关键参与者。 心血管疾病和代谢疾病，血小板衍生的EV在 介导血栓形成事件，可增强中风风险并使血流恶化。的 拟议的研究将调查血液灌注减少与 eNOS受损以及EV介导的血小板活化/凝血增加， 用MetS处理生殖衰老雌性小鼠。包括多普勒在内的尖端技术 将采用光学相干层析成像和多光子激光扫描显微镜 为了检测软脑膜和穿透性小动脉以及毛细血管中的血流动力学， 以及中风前后血小板-白细胞聚集体的形成。转基因敲入小鼠 表达拟磷酸化eNOS将被用于确定血管舒张在调节内皮细胞凋亡中的作用。 db/db雌性中的侧支血流。EV在增加凝血和引起侧支循环中的作用 通过将分离的EV注射到MetS和正常的颈静脉中， 小鼠本申请中提出的研究将为人类的复杂生物学提供见解。 血液灌注不良，尤其是MetS女性，未来有概念验证数据 络疗法的发展。

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.