Endothelial Piezo1 channel and cerebral blood flow control

内皮Piezo1通道与脑血流控制

• 批准号: 10719633
• 负责人: Osama F Harraz
• 金额: $ 59.32万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719633
• 关键词: Acceleration; Address; Affect; African American population; Angiotensin II; Animals; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain region; Capillary Endothelial Cell; Cardiovascular Diseases; Cations; Cells; Cerebrovascular Circulation; Cerebrovascular system; Characteristics; Chronic; Coupled; Cues; Data; Deceleration; Disease; Electrophysiology (science); Endothelial Cells; Endothelium; Engineering; Feedback; Foundations; Friction; Future; Genetic; Genetic Engineering; Genetically Engineered Mouse; Goals; Health; High Prevalence; Human; Hyperemia; Hypertension; Image; Interoception; Kinetics; Knock-out; Knockout Mice; Laser-Doppler Flowmetry; Lasers; Learning; Measurement; Measures; Mechanics; Mediating; Membrane Potentials; Memory; Metabolic; Monitor; Mus; Mutation; Neurons; Nitric Oxide; Outcome; Peripheral; Piezo 1 ion channel; Population; Positioning Attribute; Probability; Production; Proteins; Regional Blood Flow; Regulation; Relaxation; Reporting; Research; Risk Factors; Shapes; Signal Transduction; Stimulus; System; Testing; Transgenic Mice; Translating; United States National Institutes of Health; Vasodilator Agents; Vibrissae; Work; arteriole; behavior test; blood pressure regulation; brain endothelial cell; brain health; cerebral capillary; cerebrovascular; clinically relevant; druggable target; experience; fluorescence imaging; gain of function; gain of function mutation; hemodynamics; hypertensive; improved; in vivo; interest; mechanical drive; mechanical force; mechanical stimulus; mouse model; neural; neurotransmission; neurovascular coupling; new therapeutic target; novel; pharmacologic; prevent; response; shear stress; spatiotemporal; time use; two photon microscopy; two-photon

Project Summary/Abstract: Cerebral blood flow (CBF) is precisely controlled to satisfy neuronal metabolic demands. Active neurons signal to the vasculature via multiple neurovascular coupling mechanisms to increase regional blood flow in a phenomenon known as functional hyperemia (FH). The hyperemic response increases the frictional forces imposed by blood flow onto endothelial cells (ECs) of arterioles and capillaries. We have recently demonstrated that the Piezo1 channel is a crucial mechanosensor in brain capillary ECs, and that it mediates Ca2+ signals in response to mechanical stimuli. However, the impact of Piezo1 signaling on CBF control remains unknown. In response to the NIH Notice of Special Interest (NOT-AT-21-002) “Promoting Research on Interoception and Its Impact on Health and Disease,” we provide compelling preliminary evidence that Piezo1-mediated interoception is crucial in CBF regulation, and that this mechanism is compromised during hypertension. Building on our preliminary data, we aim to test the overarching hypothesis that cerebrovascular Piezo1 regulates CBF at the local capillary level and at the large-scale level in extended brain regions. Aim 1 will employ EC-specific genetically encoded Ca2+ indicator mice, widefield and two-photon fluorescence imaging to determine the spatial, temporal, and spread characteristics of Piezo1-mediated Ca2+ transients in brain capillaries. Moreover, we will use genetic and pharmacological approaches to determine if Ca2+ signaling mediated by Piezo1 is coupled to the production of the potent vasodilator nitric oxide to increase local capillary blood flow. In Aim 2, we will determine how large-scale Piezo1 activation during FH triggers a cationic conductance, which dampens hyperpolarization-mediated FH, much like a built-in brake system. To achieve this goal, we will use genetically engineered mice with reduced Piezo1 activity in all ECs or brain ECs, along with near infrared laser imaging, and laser doppler flowmetry. In Aim 3, we will determine if cerebrovascular Piezo1 signaling is compromised in hypertension and whether a Piezo1 channelopathy-like effect leads ultimately to CBF deficits. We will directly measure Piezo1 channel activity and CBF in two mouse models of hypertension and in genetically engineered transgenic mice that harbor a human Piezo1 mutation. Use of this mutation is clinically relevant, in that PIEZO1 mutations are prevalent in African Americans, a population with the highest prevalence of hypertension worldwide. Completion of this project will support the concept that Piezo1 is crucial in CBF regulation, and that alteration of its activity is a novel risk factor for CBF decline. This work will further provide new therapeutic targets for improving CBF in cardiovascular disease.

项目摘要/摘要： 精确控制脑血流（CBF）以满足神经元代谢需求。活性神经元信号 通过多种神经血管耦合机制来增加脉管系统，以增加A的区域血流 现象称为功能性充血（FH）。高血分的反应增加了摩擦力 血液流动到动脉和毛细血管的内皮细胞（EC）上。我们最近证明了 Piezo1通道是脑毛细管EC中的至关重要的机构，它介导了Ca2+信号 对机械刺激的反应。但是，压电1信号对CBF控制的影响仍然未知。在 对NIH特别关注通知的回应（非AT-21-002）” 对健康和疾病的影响，“我们提供了令人信服的初步证据，表明压电介导的感受 在CBF调节中至关重要，并且在高血压期间这种机制受到损害。建立在我们的基础上 初步数据，我们旨在检验总体假设，即脑血管压电调节CBF在 局部毛细血管水平以及大脑区域的大规模水平。 AIM 1将采用特定于EC的特定 遗传编码的Ca2+指示剂小鼠，广场和两光子荧光成像，以确定空间 脑毛细血管中压电1介导的Ca2+瞬变的临时和扩散特征。而且，我们会的 使用遗传和药物方法来确定压电1介导的Ca2+信号传导是否耦合到 潜在的血管舒张一氧化氮的产生以增加局部毛细血管血流。在AIM 2中，我们将 确定FH期间大规模的压电激活如何触发阳离子电导，从而减弱 超极化介导的FH，就像内置制动系统一样。为了实现这一目标，我们将一般使用 在所有ECS或脑EC中具有降低压电活性的工程小鼠，以及近红外激光成像， 和激光多普勒流量计。在AIM 3中，我们将确定脑血管压电是否在 高血压以及Piezo1通道疗法样效应是否最终导致CBF定义。我们将直接 在两种小鼠高血压模型和基因工程中测量压电通道活动和CBF 具有人类压电突变的转基因小鼠。该突变的使用在临床上是相关的，因为Piezo1 突变在非洲裔美国人中很普遍，这是高血压患病率最高的人群 全世界。该项目的完成将支持Piezo1在CBF监管中至关重要的概念，并且 其活性的改变是CBF下降的新风险因素。这项工作将进一步提供新的治疗目标 用于改善心血管疾病中的CBF。