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： 脑血流量(CBF)被精确控制，以满足神经元的代谢需求。激活神经元信号 通过多种神经血管耦合机制增加局部血流量 这种现象被称为功能性充血(FH)。充血反应增加了摩擦力 通过血流作用于小动脉和毛细血管的内皮细胞(ECs)。我们最近展示了 Piezo1通道是脑毛细血管内皮细胞的重要机械感受器，它在 对机械刺激的反应。然而，Piezo1信号对CBF控制的影响仍不清楚。在……里面 对美国国立卫生研究院特别关注通知(NOT-AT-21-002)“促进内感及其相关研究”的回应 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Piezo1介导的内部感觉 在CBF调节中起关键作用，而这一机制在高血压期间受到损害。建立在我们的 初步数据，我们的目标是检验脑血管Piezo1调节脑血流的主要假设。 局部毛细血管水平和扩展脑区的大规模水平。AIM 1将采用特定于EC的 基因编码的钙离子指示器小鼠，广域和双光子荧光成像来确定空间， 脑毛细血管中Piezo1介导的钙瞬变的时间和扩散特征。此外，我们还将 用遗传学和药理学方法确定Piezo1介导的钙信号是否偶联到 产生强有力的血管扩张剂一氧化氮，以增加局部毛细血管血流量。在目标2中，我们将 确定FH期间Piezo1的大规模激活如何触发阳离子电导，从而抑制 超极化介导的跳频，就像一个内置的刹车系统。为了实现这一目标，我们将使用基因 转基因小鼠在所有内皮细胞或脑内皮细胞中Piezo1活性降低，同时进行近红外激光成像， 和激光多谱勒流量计。在目标3中，我们将确定脑血管Piezo1信号是否在 高血压以及Piezo1通道病样效应是否最终导致CBF缺陷。我们会直接 测量两种高血压小鼠模型和基因工程小鼠的Piezo1通道活性和脑血流量 携带人类Piezo1突变的转基因小鼠。这种突变的使用与临床相关，因为PIEZO1 突变在非裔美国人中很普遍，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 其活性改变是脑血流量下降的一个新的危险因素。这项工作将进一步提供新的治疗靶点。 用于改善心血管疾病的脑血流。