Stroke in females with metabolic syndrome, a vascular perspective

代谢综合征女性中风的血管视角

• 批准号: 10358508
• 负责人: JIALING LIU
• 金额: $ 32.66万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358508
• 关键词: Acute; Address; Age; Age-Months; Animal Model; Area; Arterial Fatty Streak; Biology; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Blood capillaries; Blood coagulation; Blood flow; Brain; Cardiovascular Diseases; Cardiovascular system; Cell Aggregation; Cells; Cerebrum; Characteristics; Clinical; Clinical Research; Coagulation Process; Collateral Circulation; Complex; Complication; Data; Development; Diabetes Mellitus; Distal; Drug resistance; Drug usage; Epidemic; Erythrocytes; Estradiol; Estrogens; Event; Exhibits; Failure; Female; Fibrinogen; Financial compensation; Future; Genetic; Genotype; Health; Heart Diseases; Hemostatic function; Hormones; Hyperglycemia; Hyperlipidemia; Hypertension; Impairment; Incidence; Infarction; Inflammation; Ischemia; Ischemic Stroke; Knock-in; Knock-in Mouse; Laser Scanning Microscopy; Lesion; Leukocytes; Link; Mediating; Metabolic Diseases; Metabolic syndrome; Middle Cerebral Artery Occlusion; Modeling; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Optical Coherence Tomography; Outcome; Pathologic; Patients; Perfusion; Persons; Phosphorylation; Plasma; Plasminogen Activator Inhibitor 1; Platelet Activation; Play; Postmenopause; Predisposition; Prevalence; Process; Production; Reporting; Risk; Risk Factors; Role; Severities; Stream; Stroke; Structure of jugular vein; System; Technology; Thrombelastography; Thrombophilia; Time; Transgenic Organisms; Vascular blood supply; Vasodilation; Velocimetries; Woman; aged; arteriole; artery occlusion; blood perfusion; clinical practice; db/db mouse; diabetic; exosome; experience; experimental study; extracellular vesicles; functional disability; improved; in vivo; in vivo evaluation; insight; ischemic injury; leptin receptor; male; men; microvesicles; negative affect; neutrophil; particle; post stroke; reproductive; response; restoration; senescence; stroke model; stroke outcome; stroke risk; stroke therapy; thrombotic

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.

代谢综合征（METS）与中风和预后不佳的风险增加有关 这种健康困境的基础机制尚不清楚。高血压，旋转 大都会的并发症，破坏脑血管调节机制，并增加 大脑对缺血性损伤的敏感性，在绝经后妇女中更为普遍。 新兴的证据表明，大都会患者与抵押状况差有关 在急性缺血性中风期间。我们最近的数据表明，具有Mets的雌性小鼠表现出 MCAO后，中风期间的抵押状态差。大都会的小鼠也 渗透动脉中的血液流量降低，微血管流动障碍 动力学。充分的证据将糖尿病与损害的血管舒张相关，这归因于减少 eNOS磷酸化；但是，eNOS在介导PIAL和穿透动脉中的作用 中风后的流量从未得到正确解决。鉴于雌激素对 eNOS活性增加以及T2DM相关的雌激素减少的事实尚不清楚 年龄雌性小鼠的侧支流量是否归因于减少 eNOS活动。临床证据还表明，MetS引起的Hyperogulability具有 对女性不良血管事件的影响要比男性的影响更大 中风。细胞外囊泡（EV）和外泌体被认为是主要参与者 心血管和代谢性疾病以及血小板衍生的电动汽车在 介导可以增强中风风险并加剧血液流动的血栓性事件。这 拟议的研究将研究减少血液灌注与 eNOS受损以及EV介导的血小板激活/凝结的增加 生殖衰老的雌性小鼠。包括多普勒在内的尖端技术 光学相干断层扫描和多光子激光扫描显微镜将被使用 为了检测沿海和穿透动脉和毛细管血管中的血流动力学，凝块 中风前后的血小板 - 白细胞聚集体形成。转基因敲入小鼠 表达磷酸化ENOS将用于确定血管舒张在调节中的作用 DB/DB女性的侧支流。电动汽车在增加凝结和引起抵押品中的作用 通过将分离的EV注射到MetS的颈静脉和正常状态，将在体内测试故障 老鼠。本应用程序中提出的研究将提供有关对复杂生物学的见解 血液灌注不良，尤其是在有概念证明数据的大都会女性中 抵押疗法的发展。

项目成果

Use of Botulinum Toxin for Limb Immobilization for Rehabilitation in Rats with Experimental Stroke.

• DOI: 10.3390/biom13030512
• 发表时间: 2023-03-10
• 期刊: Biomolecules
• 影响因子: 5.5

Local field potentials identify features of cortico-hippocampal communication impacted by stroke and environmental enrichment therapy.

• DOI: 10.1088/1741-2552/ac0a54
• 发表时间: 2021-07-06
• 期刊: Journal of neural engineering
• 影响因子: 4
• 作者: Ip Z;Rabiller G;He JW;Chavan S;Nishijima Y;Akamatsu Y;Liu J;Yazdan-Shahmorad A
• 通讯作者: Yazdan-Shahmorad A