The impact of blood pressure variability on neurovascular function

新出现的证据表明，血压变异性增加（IBPV）是血管病变的一个强有力的预测因子。 IBPV是认知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。 神经血管单位的组成部分，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Ca 2+渗透性阳离子通道，Piezo 1与炎症和阿尔茨海默病有关。 我们的研究小组显示，高血压患者的机械传导增强，星形胶质细胞Ca 2+增加， 肌源性血管收缩该项目测试了IBPV引起放大的Piezo 1介导的 内皮细胞和星形胶质细胞的Ca 2+反应，损害脑血管功能并诱导认知功能 下降研究将在脉动血管紧张素II诱导的慢性IBPV新型小鼠模型中进行 输注结合连续血压测量。目标1-3将测试 假设：1）通过增加Piezo 1激活， 导致低灌注和认知能力下降; 2）通过增加内皮细胞和星形胶质细胞的Ca 2+， Piezo 1激活，减少感觉诱发的脑血流量增加，3）Piezo 1诱导的 星形胶质细胞Ca 2+超载使星形胶质细胞群向促炎A1表型转移。同时使用 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， 并评估IBPV如何逐渐损害血管、神经胶质和神经元功能。的关系 IBPV和认知下降之间的关系，沿着Ca 2+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Ca 2+指示剂GCaMP 6的小鼠将用于追踪细胞内Ca 2+浓度。 IBPV和异常Ca 2+事件之间的关联。将采用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Piezo 1细胞通路的机制， 炎症（神经胶质增生）。研究结果将确定Piezo 1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。我们建议， 血压变异性加速神经胶质增生，从而增强NVU功能障碍，这反过来又有助于 血管性认知障碍和痴呆。

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.