Brain Capillary Mechanosensation by Piezo1 Channels in Health and Disease

脑血流量受到精确控制，以满足神经元的代谢需求。这种控制的一个基本特征是 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） 这是由多种神经血管耦合机制协调的。重要的是，剪切应力的增加， 对增强的血流的响应构成具有影响血管行为的潜力的机械力。一 越来越多的证据表明，高血压使FH减弱。值得注意的是，血液不受控制的升高 压力与施加在脉管系统上的血液动力学力的显著变化有关。但 脑循环的机械敏感特性受高血压影响的程度尚未被证实。 探讨了Piezo1是一种在血管内皮细胞中表达的Ca2 +/Na+渗透性机械敏感性通道， 大脑毛细血管中的主要机械传感器。有趣的是，PIEZO1基因中的功能获得性突变已经被发现。 在非洲裔美国人人群中报告，其显示出世界上高血压的最高患病率（> 40%）。 基于Piezo1通道的独特性质和内皮细胞Ca2+信号转导在FH中的重要作用，我将 评估以下假设：（1）脑毛细血管Piezo 1通道活性在高血压期间改变;和（2） Piezo 1功能的这种变化与高血压期间发生的FH缺陷有关。这些假设将 通过直接测量Piezo1通道活性和通过测量正常情况下的脑血流量进行测试 和高血压。我们将使用我们实验室引进的技术创新，包括尖端的 Piezo1活性增加或降低的基因工程小鼠模型和内皮特异性 基因编码的Ca2+指示剂。通过一种新的透镜将充血"反应"视为机械"刺激"， 所提出的研究设想正常和扰动（即，高血压）脑血流量从一个完全新鲜的 perspective.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.