Endothelial Piezo1 channel and cerebral blood flow control

内皮Piezo1通道与脑血流控制

基本信息

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
项目类别：
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

项目摘要

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：精确控制脑血流量（CBF）以满足神经元信号的活跃代谢需求。通过多种神经血管耦合机制进入脉管系统，以增加局部血流量称为功能性充血（FH）的现象。充血反应会增加摩擦力。我们最近证明了血流对小动脉和毛细血管内皮细胞（EC）的影响。 Piezo1 通道是脑毛细血管内皮细胞中至关重要的机械传感器，并且它介导 Ca2+ 信号然而，Piezo1 信号对 CBF 控制的影响仍然未知。对 NIH 特别关注通知 (NOT-AT-21-002)“促进内感受及其研究”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，证明 Piezo1 介导的内感受在 CBF 调节中至关重要，并且这种机制在高血压期间会受到损害。初步数据，我们的目的是测试脑血管 Piezo1 调节 CBF 的总体假设目标 1 将采用特定于 EC 的局部毛细血管水平和扩展大脑区域的大规模水平。基因编码的 Ca2+ 指示小鼠，宽场和双光子荧光成像以确定空间，此外，我们还将研究 Piezo1 介导的 Ca2+ 瞬变在脑毛细血管中的时间和传播特征。使用遗传和药理学方法来确定 Piezo1 介导的 Ca2+ 信号是否与产生强效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 期间大规模 Piezo1 激活如何触发阳离子电导，从而抑制超极化介导的 FH，很像内置制动系统为了实现这一目标，我们将使用基因。工程小鼠的所有 EC 或大脑 EC 中的 Piezo1 活性均降低，并进行近红外激光成像，在目标 3 中，我们将确定脑血管 Piezo1 信号传导是否受到损害。高血压以及 Piezo1 通道病样效应是否最终导致 CBF 缺陷我们将直接进行。测量两种高血压小鼠模型和基因工程小鼠中的 Piezo1 通道活性和 CBF 携带人类 Piezo1 突变的转基因小鼠，该突变的使用具有临床意义，即 PIEZO1。突变在非裔美国人中普遍存在，这是高血压患病率最高的人群该项目的完成将支持 Piezo1 在 CBF 监管中至关重要的概念。其活性的改变是 CBF 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。改善心血管疾病的 CBF。