Piezo1 Mediated Adjustments in Lung Fluid Balance

Piezo1 介导的肺液平衡调整

• 批准号: 10091571
• 负责人: Yulia A Komarova
• 金额: $ 5.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-11 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091571
• 关键词: Address; Adherens Junction; Blood Vessels; Blood capillaries; Cadherins; Cell membrane; Cells; Cessation of life; Congestive Heart Failure; Data; Edema; Endocytosis; Endothelial Cells; Endothelium; Exposure to; Failure; Fluid Balance; Goals; Heart failure; Homeostasis; Hydrostatic Pressure; Lead; Left; Link; Liquid substance; Lung; Mediating; Medical; Microvascular Permeability; Patients; Permeability; Phosphorylation; Piezo 1 ion channel; Proteins; Pulmonary Edema; Research; Respiratory Failure; Role; Signal Pathway; Signal Transduction; Stress; Time; cadherin 5; mechanical force; new therapeutic target; pressure; response

PROJECT SUMMARY / ABSTRACT Lung endothelial barrier integrity at the level of adherens junctions (AJs) is required for lung fluid homeostasis. A crucial mechanism contributing to the loss of endothelial barrier integrity in conditions such as pulmonary edema is “stress failure” of pulmonary capillaries in response to high pressure. While it is known that AJs, comprised of VE-cadherin and associated catenin proteins, restrict endothelial permeability, little is known about how mechanical forces, specifically vessel wall tension, control endothelial permeability and pulmonary edema. Our Supporting Data describe the potentially important role of hydrostatic pressure in microvessels in activating the mechanosensor Piezo1 in endothelial cells (ECs) and in increasing endothelial barrier permeability. We observed that activation of Piezo1 induced intracellular Ca2+ signaling, which in turn, caused phosphorylation of VE-cadherin and increased microvascular permeability. These findings have for the first time linked increased tension to which ECs are exposed to the activation of Piezo1 and disassembly of AJs, leading to the fundamental question “how does tension sensed at the plasma membrane of ECs by Piezo1 activate VE- cadherin phosphorylation and thereby disrupt AJs?” In Aim 1, we will determine the role of microvessel pressure in activating the mechanosensor channel Piezo1 in lung ECs and Piezo1’s role in regulating endothelial permeability and lung fluid balance. We will determine whether Src dependent phosphorylation of Piezo1 is required for Piezo1 activated Ca2+ signaling in ECs and whether this thereby mediates increased endothelial permeability. In Aim 2, we will determine the role of Piezo1 signaling in mediating disassembly of AJs through phosphorylation of VE-cadherin, and in increasing endothelial permeability. Here, we will identify the signaling pathway downstream of Piezo1 activation that induces phosphorylation of VE-cadherin and VE-cadherin endocytosis and thus disassemble the AJs. In Aim 3, we will determine the role of Piezo1 in mediating lung vascular hyper-permeability (“stress failure”) and edema associated with left heart failure (LHF). These studies will address the pathophysiological relevance of Piezo1 in the mechanism of pulmonary edema resulting from LHF-induced increases in lung microvessel pressure. The above studies will be essential for understanding the role of Piezo1 in increasing lung microvessel permeability, with the goal of identifying new therapeutic targets for high pressure-induced pulmonary edema.

项目摘要 /摘要 肺部连接水平（AJS）的肺部内皮屏障完整性是肺部稳态需要的。 在肺部等疾病中导致内皮屏障完整性丧失的关键机制 水肿是响应高压的肺毛细血管的“应力衰竭”。虽然知道AJS，但 完成VE-钙粘蛋白和相关的catenin蛋白，限制了内皮渗透性，对 机械力，特定于容器壁张力，控制内皮渗透性和肺水肿的方式。 我们的支持数据描述了静液压在微血管激活中的潜在重要作用 内皮细胞（EC）中的机械力学压电和内皮屏障渗透性的增加。我们 观察到压电1的激活诱导了细胞内Ca2+信号传导，这又导致了磷酸化 VE-钙粘蛋白并增加微血管通透性。这些发现首次链接了 EC暴露于压电1的激活和AJ拆卸的张力，导致 基本问题：“在Piezo1激活VE-的ECS质膜处的张力如何激活VE- 钙粘蛋白磷酸化并因此破坏AJS？”在AIM 1中，我们将确定微血管的作用 激活肺ECS中的Mechanologensor通道Piezo1和Piezo1在调节中的作用的压力 内皮渗透性和肺液平衡。我们将确定SRC依赖磷酸化是否 在EC中激活Ca2+信号的Piezo1是必需的，以及这是否会增加 内皮渗透性。在AIM 2中，我们将确定压电1信号在中介拆卸中的作用 通过VE-钙粘着蛋白的磷酸化以及增加内皮渗透性的AJ。在这里，我们会的 确定诱导VE-钙粘着蛋白和 VE-钙粘蛋白内吞作用，从而拆卸AJ。在AIM 3中，我们将确定Piezo1在 介导肺血管过度过度性（“压力失败”）和与左心衰竭相关的水肿 （LHF）。这些研究将解决Piezo1在肺机理中的病理生理相关性 LHF诱导的肺微血管压力增加引起的水肿。以上研究将是必不可少的 了解压电1在增加肺微血管渗透性中的作用，目的是确定新的 高压诱导的肺水肿的治疗靶标。