Brain Capillary Mechanosensation by Piezo1 Channels in Health and Disease

大脑血流量得到精确控制，以满足神经元的代谢需求。此控件的一个基本功能 是由神经活动触发的局部血流量的按需增加；这一过程称为功能性充血(FH) 这是由多个神经血管耦合机制协调的。重要的是，切应力的增加 对血流增强的反应构成机械力，有可能影响血管的行为。一个 越来越多的证据表明，高血压可以减轻FH。值得注意的是，血液的不受控制的升高 压力与施加在血管系统上的血液动力的戏剧性变化有关。然而， 高血压对脑循环机械敏感特性的影响程度尚未得到证实 探索过了。PIEZO1是一种在血管内皮细胞中表达的钙/钠离子通透性、机械敏感的通道，是 大脑毛细血管中的主要机械传感器。有趣的是，PIEZO1基因的功能获得突变 在非洲裔美国人中报告，这是世界上高血压患病率最高的人群(&gt；40%)。 基于Piezo1通道的独特特性和内皮细胞钙信号在FH中的重要作用，我将 评估以下假设：(1)脑毛细血管Piezo1通道活动在高血压期间改变；以及(2) Piezo1功能的这种变化与高血压期间FH的缺陷有关。这些假设将 通过直接测量Piezo1通道活动和在正常情况下测量脑血流量来进行测试 还有高血压。我们将使用我们实验室引进的包括尖端技术在内的技术创新 Piezo1活性升高或降低的基因工程小鼠模型和内皮特异性小鼠 基因编码的钙离子指示剂。通过使用一种新的透镜将充血的“反应”视为机械的“刺激”， 拟议的研究设想正常和扰动(即高血压)的脑血流来自完全新鲜的 透视。这个项目有可能深刻地改变我们对脑血流失调的理解 并可能揭示出迫切需要的新的治疗途径。

Cerebral blood flow is exquisitely controlled to satisfy neuronal metabolic demands. An essential feature of this control is the on-demand increase in local blood flow triggered by neural activity; a process termed functional hyperemia (FH) that is coordinated by multiple neurovascular coupling mechanisms. Importantly, the increases in shear stress in response to enhanced blood flow constitute mechanical forces with the potential to impact vascular behavior. A growing body of evidence indicates that hypertension attenuates FH. Notably, uncontrolled elevation of blood pressure is associated with dramatic alterations in the hemodynamic forces imposed on the vasculature. However, the extent to which mechanosensitive properties of the cerebral circulation are impacted by hypertension has not been explored. Piezo1, a Ca2+/Na+-permeable, mechanosensitive channel expressed in vascular endothelial cells, is the major mechanosensor in brain capillaries. Intriguingly, a gain-of-function mutation in the PIEZO1 gene has been reported in African Americans populations, which show the highest prevalence of hypertension in the world (>40%). Based on the unique properties of Piezo1 channels and the essential role of endothelial Ca2+ signaling in FH, I will evaluate the following hypotheses: (1) brain capillary Piezo1 channel activity is altered during hypertension; and (2) this change in Piezo1 function is implicated in the deficits in FH that occur during hypertension. These hypotheses will be tested by directly measuring Piezo1 channel activity and by measuring cerebral blood flow in the context of normal and high blood pressure. We will use technical innovations introduced by our laboratory that include cutting-edge genetically engineered mouse models with increased or decreased Piezo1 activity and mice with endothelial-specific genetically encoded Ca2+ indicators. By viewing hyperemic 'responses' through a new lens as mechanical 'stimuli', the proposed studies envision normal and perturbed (i.e., hypertension) cerebral blood flow from a completely fresh perspective. This project has the potential to profoundly alter our understanding of cerebral blood flow dysregulation during hypertension and may reveal sorely needed new paths to treatment.