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.

项目概要/摘要 粘附连接（AJ）水平的肺内皮屏障完整性是肺液稳态所必需的。 在肺病等疾病中导致内皮屏障完整性丧失的关键机制 水肿是肺毛细血管对高压的“应激衰竭”。 由 VE-钙粘蛋白和相关连环蛋白组成，限制内皮细胞通透性，但目前对其知之甚少 机械力（特别是血管壁张力）如何控制内皮通透性和肺水肿。 我们的支持数据描述了微血管静水压在激活中的潜在重要作用 内皮细胞 (EC) 中的机械传感器 Piezo1 和增加内皮屏障通透性。 观察到 Piezo1 的激活诱导细胞内 Ca2+ 信号传导，进而导致 这些发现首次将 VE-钙粘蛋白与微血管通透性增加联系起来。 EC 暴露于 Piezo1 激活和 AJ 解体的张力下，导致 基本问题“Piezo1 在 EC 质膜上感知到的张力如何激活 VE- 钙粘蛋白磷酸化从而破坏 AJ？在目标 1 中，我们将确定微血管的作用 压力激活肺 EC 中的机械传感器通道 Piezo1 以及 Piezo1 的调节作用 我们将确定 Src 是否依赖于内皮通透性和肺液平衡。 Piezo1 是 EC 中 Piezo1 激活 Ca2+ 信号传导所必需的，因此这是否介导增加 在目标 2 中，我们将确定 Piezo1 信号传导在介导分解中的作用。 在这里，我们将通过 VE-钙粘蛋白的磷酸化来增加 AJ 的活性，并增加内皮细胞的通透性。 鉴定诱导 VE-钙粘蛋白磷酸化的 Piezo1 激活下游信号通路 VE-钙粘蛋白内吞作用，从而分解 AJ。在目标 3 中，我们将确定 Piezo1 在其中的作用。 调节肺血管渗透性过高（“应激性衰竭”）和与左心衰竭相关的水肿 (LHF)。这些研究将解决 Piezo1 在肺损伤机制中的病理生理学相关性。 LHF 引起的肺微血管压力增加导致的水肿上述研究至关重要。 了解 Piezo1 在增加肺微血管通透性方面的作用，目的是识别新的 高压引起的肺水肿的治疗目标。