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.

新兴证据确定血压可变性（IBPV）是血管的强有力预测指标认知障碍和痴呆症的成分，但是IBPV如何导致认知能力下降。神经血管单元的成分，包括内皮细胞和星形胶质细胞表达最近发现的机械敏感的Ca2+ - 可渗透阳离子通道，在炎症和阿尔茨海默氏病中实施的压电。我们的小组显示，通过增强的星形胶质细胞CA2+和肌源性血管收缩。该项目测试了IBPV引起放大压电介导的中心假设内皮细胞和星形胶质细胞CA2+反应，会损害脑血管功能并诱导认知衰退。研究将在慢性IBPV的新型鼠模型中进行，该模型由脉动血管紧张素II诱导输注与有意识小鼠的连续血压测量相结合。目标1-3将测试假设：1）通过增加的Piezo1激活来升高神经血管单位的机械刺激。导致灌注不足和认知能力下降； 2）增加内皮细胞和星形胶质细胞Ca2+，通过增加压电激活，减少脑血流的感觉诱发的增加，3）压电1诱导的星形胶质细胞CA2+过载将星形细胞种群转移到促炎A1表型中。两者都使用在体内和原位方法中，我们将宏观心血管变量与微观细胞事件联系起来在NVU和评估中，IBPV如何逐渐损害血管，神经胶质和神经元功能。关系在IBPV和认知能力下降以及CA2+动力学之间，将使用纵向方法评估。在星形胶质细胞和内皮细胞中表达Ca2+指示剂GCAMP6的小鼠将用于跟踪 IBPV和异常CA2+事件之间的关联。药物和遗传方法将用于测试压电1个细胞通路的机制炎症（神经胶质）。调查结果将建立压电频道，为IBPV-的分子播放器诱发了NVU功能障碍，并证明了其作为治疗靶点的潜力。我们提出了增强血压变异性加速了神经胶质病，从而增强了NVU功能障碍，这反过来又有助于血管认知障碍和痴呆症。