The impact of blood pressure variability on neurovascular function

血压变异性对神经血管功能的影响

基本信息

批准号：
10419670
负责人：
JESSICA A FILOSA
金额：
$ 52.97万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10419670
关键词：
Acute Agonist Alzheimer&apos s Disease Angiotensins Astrocytes Blood Flow Velocity Blood Pressure Blood Vessels Brain Calcium Cardiovascular system Cations Cells Cerebrovascular Circulation Cerebrum Chronic Cognition Disorders Conscious Coupled Data Dementia Diastolic blood pressure Endothelial Cells Event Functional disorder Genetic Gliosis Heart Rate Homeostasis Hypertension Immunohistochemistry Impaired cognition Impairment Implant In Situ Inflammation Inflammatory Infusion procedures Intracranial Pressure Intravenous Ion Channel Knockout Mice Lasers Link Measurement Measures Mediating Microscopic Modeling Molecular Mus Neuroglia Neurons Outcome Pathway interactions Perfusion Permeability Pharmacology Phenotype Piezo 1 ion channel Population Posture Process Pump Rest Role Saline Sensory Slice Telemetry Testing Tissues Unit of Measure Vascular Diseases Vascular resistance behavior test blood pressure variability cerebral hypoperfusion cerebral microvasculature cerebrovascular cognitive testing design genetic approach hemodynamics hypoperfusion in vivo in vivo two-photon imaging mechanotransduction mouse model neurovascular neurovascular coupling neurovascular unit novel parenchymal arterioles pressure programs response shear stress therapeutic target vascular cognitive impairment and dementia vascular factor vasoconstriction

项目摘要

Emerging evidence identifies increased blood pressure variability (IBPV) as a strong predictor of the vascular component of cognitive impairment and dementia, but how IBPV causes cognitive decline is not known. Components of the neurovascular unit, including endothelial cells and astrocytes express the recently discovered mechanosensitive Ca2+-permeable cation channel, Piezo1 implicated in inflammation and Alzheimer’s disease. Our group showed mechanotransduction to be enhanced in hypertension with augmented astrocyte Ca2+ and myogenic vasoconstriction. This project tests the central hypothesis that IBPV causes amplified Piezo1-mediated endothelial cell and astrocyte Ca2+ responses, which impairs cerebrovascular function and induces cognitive decline. Studies will be conducted in a novel murine model of chronic IBPV, induced by pulsatile angiotensin II infusion coupled with continuous blood pressure measurement in conscious mice. Aims 1-3 will test the hypothesis: 1) that elevated mechanostimulation at the neurovascular unit, via increased Piezo1 activation, results in hypoperfusion and cognitive decline; 2) that increased endothelial cell and astrocyte Ca2+, via increased Piezo1 activation, diminishes sensory-evoked increases in cerebral blood flow and 3) that Piezo1-induced astrocyte Ca2+ overload shifts the astrocytic population towards the proinflammatory A1 phenotype. Using both in vivo and in situ approaches, we will link macroscopic cardiovascular variables to microscopic cellular events at the NVU and assess how IBPV progressively impairs vascular, glial and neuronal function. The relationship between IBPV and cognitive decline, along with Ca2+ dynamics, will be assessed using a longitudinal approach. Mice expressing the Ca2+ indicator GCaMP6 in astrocytes and endothelial cells will be used to track the association between IBPV and aberrant Ca2+ events. A pharmacological and genetic approach will be used to test the mechanism of Piezo1 cellular pathways underlying pressure-driven vascular dysfunction and glia-driven inflammation (gliosis). Findings will establish the Piezo1 ion channel as the molecular player underlying IBPV- evoked NVU dysfunction and demonstrate its potential as a therapeutic target. We propose that augmented blood pressure variability accelerates gliosis, thereby enhancing NVU dysfunction, which, in turn, contributes to vascular cognitive impairment and dementia.

新出现的证据表明血压变异性（IBPV）增加是血管疾病的有力预测因素。认知功能障碍和痴呆的组成部分，但 IBPV 如何导致认知能力下降尚不清楚。神经血管单元的组成部分，包括内皮细胞和星形胶质细胞，表达最近发现的机械敏感性 Ca2+ 可渗透的阳离子通道，Piezo1 与炎症和阿尔茨海默氏病有关。我们的研究小组表明，通过增加星形胶质细胞 Ca2+ 和该项目测试了 IBPV 导致 Piezo1 介导的放大的中心假设。内皮细胞和星形胶质细胞 Ca2+ 反应，损害脑血管功能并诱发认知障碍研究将在由脉动血管紧张素 II 诱导的新型慢性 IBPV 小鼠模型中进行。目标 1-3 将测试清醒小鼠的输注和连续血压测量。假设：1) 通过增加 Piezo1 激活来提高神经血管单元的机械刺激，导致灌注不足和认知能力下降；2) 通过增加内皮细胞和星形胶质细胞 Ca2+ Piezo1 激活，减少感觉诱发的脑血流量增加，3) Piezo1 诱导的星形胶质细胞 Ca2+ 超载使星形胶质细胞群转向促炎 A1 表型。通过体内和原位方法，我们将宏观心血管变量与微观细胞事件联系起来在 NVU 进行评估，评估 IBPV 如何逐渐损害血管、神经胶质和神经元功能。 IBPV 和认知能力下降之间以及 Ca2+ 动态将使用纵向方法进行评估。在星形胶质细胞和内皮细胞中表达 Ca2+ 指示剂 GCaMP6 的小鼠将用于追踪 IBPV 与异常 Ca2+ 事件之间的关联将用于研究药理学和遗传学方法。测试压力驱动的血管功能障碍和神经胶质细胞驱动的 Piezo1 细胞通路的机制研究结果将确定 Piezo1 离子通道作为 IBPV- 的分子参与者。诱发 NVU 功能障碍并证明其作为治疗靶点的潜力。血压变异性会加速神经胶质增生，从而增强 NVU 功能障碍，进而导致血管性认知障碍和痴呆。