Mechanotransduction and YAP/TAZ Signaling in Pulmonary Arterial Hypertension

肺动脉高压中的机械转导和 YAP/TAZ 信号传导

基本信息

批准号：
9456950
负责人：
LAURA ELIZABETH FREDENBURGH
金额：
$ 66.99万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9456950
关键词：
Agonist Apoptosis Atomic Force Microscopy Attenuated BMPR2 gene Behavior Binding Biochemical Blood Vessels Bone Morphogenetic Proteins Cell Nucleus Cells Cessation of life Cyclic AMP Deposition Development Disease Disease Progression Distal Environment Experimental Models Failure Feedback Fibroblasts Generations Genetic Transcription Growth Heart Heart failure Human Hypoxia Knockout Mice Lung Mechanics Modeling Molecular Monocrotaline Mutation Myocardial dysfunction PTGS2 gene Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phenotype Physiological Plasminogen Activator Inhibitor 1 Play Production Prostaglandin Production Prostaglandin-Endoperoxide Synthase Prostaglandins Pulmonary Fibrosis Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Rattus Regulation Repression Research Resistance Resolution Right Ventricular Dysfunction Role SU 5416 Side Signal Pathway Signal Transduction Signaling Protein Smad Proteins Smooth Muscle Myocytes Stimulus Tamoxifen Testing Traction Vascular remodeling arterial stiffness cell growth hemodynamics knock-down lipid mediator mechanical properties mechanotransduction migration mortality mouse model mutant novel novel strategies overexpression prevent programs pulmonary arterial hypertension pulmonary artery endothelial cell response therapeutic target trafficking transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of apoptosis-resistant pulmonary artery endothelial cells (PAEC), smooth muscle cells (PASMC), and adventitial fibroblasts (PAAF) leading to progressive increases in pulmonary vascular resistance, and ultimately right heart failure and death. Recent studies suggest that pulmonary arterial (PA) stiffness is associated with increased mortality in patients with PAH; however, the mechanisms involved in the pathogenesis and progression of PA stiffening in PAH have yet to be fully elucidated. We have discovered that distal vascular matrix stiffening develops early in models of pulmonary hypertension (PH) and triggers a local mechanobiological feedback loop that amplifies vascular remodeling and accelerates disease progression. These findings suggest that PA stiffness is not merely a consequence of pathologic changes in the vessel wall, but can itself drive abnormal cellular behavior. We have identified YAP and TAZ as pivotal regulators of stiffness-dependent PASMC and PAEC mechanoactivation in PAH. Our preliminary findings suggest that mechanosignaling via YAP/TAZ drives vascular cell activation through suppression of cyclooxygenase (COX)-2-derived prostanoid production and bone morphogenetic protein (BMP) signaling. Silencing of YAP/TAZ in PASMC and PAEC abrogates stiffness- dependent increases in proliferation, matrix deposition, and traction force generation, and rescues suppression of prostanoid production and BMP signaling. Moreover, PASMC overexpressing a mutant TAZ that localizes constitutively to the nucleus have a dramatic reduction in COX-2-derived prostanoid production and BMP signaling leading to a hyperproliferative remodeling phenotype. We hypothesize that YAP/TAZ are activated by the mechanical environment to drive pro-remodeling cellular responses and promote matrix stiffening in an adverse feedback loop via suppression of prostanoid production and BMP signaling in PAH. In Aim 1, we will investigate the role that YAP/TAZ play in regulating COX-2-dependent prostaglandin production and vascular responses to matrix stiffening in PAH. We will determine the mechanisms of YAP/TAZ-dependent suppression of COX-2 and regulation of stiffness-dependent contractility and matrix synthesis in human PASMC, PAEC, and PAAF. In Aim 2, we will examine the mechanisms by which YAP/TAZ control TGF-! and BMP-dependent Smad signaling, suppress Id1 expression, and regulate cellular growth responses to BMP signaling in PAH. We will determine the impact of YAP/TAZ activity on proliferation, apoptosis resistance, and migration in PASMC, PAEC, and PAAF from PAH patients with and without BMPR2 mutations. In Aim 3, we will determine whether inactivation of YAP/TAZ arrests PA stiffening, attenuates vascular remodeling, and prevents right ventricular (RV) dysfunction in experimental PH. We will use murine models and pharmacologic approaches to modulate YAP/TAZ activity and assess the effects of YAP/TAZ inactivation on PA stiffening, hemodynamics, RV dysfunction, vascular remodeling, and regulation of the prostanoid and BMP pathways in models of PH.

项目摘要/摘要：肺动脉高压（PAH）的特点是抗凋亡细胞过度增殖肺动脉内皮细胞 (PAEC)、平滑肌细胞 (PASMC) 和外膜成纤维细胞 (PAAF) 导致肺血管阻力逐渐增加，最终导致右心衰竭和死亡。最近的研究表明，肺动脉（PA）僵硬度与死亡率增加有关肺动脉高压患者；然而，PA 硬化的发病机制和进展的机制 PAH 尚未完全阐明。我们发现远端血管基质硬化发生在早期肺动脉高压（PH）模型并触发局部机械生物学反馈回路，放大血管重塑并加速疾病进展。这些发现表明 PA 刚度并不这仅仅是血管壁病理变化的结果，但其本身可以驱动异常的细胞行为。我们已经确定 YAP 和 TAZ 是刚度依赖性 PASMC 和 PAEC 的关键调节剂 PAH 中的机械激活。我们的初步研究结果表明，通过 YAP/TAZ 驱动器进行机械信号传输通过抑制环氧合酶 (COX)-2 衍生的前列腺素生成来激活血管细胞骨形态发生蛋白 (BMP) 信号传导。 PASMC 和 PAEC 中 YAP/TAZ 的沉默消除了刚度增殖、基质沉积和牵引力产生的依赖性增加，并挽救抑制前列腺素生成和 BMP 信号传导。此外，PASMC 过表达突变 TAZ，该突变 TAZ 定位于细胞核内 COX-2 衍生的前列腺素生成和 BMP 显着减少信号传导导致过度增殖重塑表型。我们假设 YAP/TAZ 被激活驱动促重塑细胞反应并促进基质硬化的机械环境通过抑制 PAH 中前列腺素的产生和 BMP 信号传导产生不良反馈循环。在目标 1 中，我们将研究 YAP/TAZ 在调节 COX-2 依赖性前列腺素产生和血管中的作用对 PAH 中基质硬化的反应。我们将确定 YAP/TAZ 依赖性抑制的机制 COX-2 的调节以及人 PASMC、PAEC 中僵硬度依赖性收缩性和基质合成的调节，和PAAF。在目标 2 中，我们将研究 YAP/TAZ 控制 TGF-!和 BMP 依赖性 Smad 信号传导、抑制 Id1 表达并调节 PAH 中 BMP 信号传导的细胞生长反应。我们将确定 YAP/TAZ 活性对细胞增殖、凋亡抗性和迁移的影响来自有或没有 BMPR2 突变的 PAH 患者的 PASMC、PAEC 和 PAAF。在目标 3 中，我们将确定 YAP/TAZ 失活是否会阻止 PA 僵硬、减弱血管重塑并阻止右旋实验 PH 中的心室 (RV) 功能障碍。我们将使用小鼠模型和药理学方法调节 YAP/TAZ 活性并评估 YAP/TAZ 失活对 PA 硬化、血流动力学、 PH 模型中的 RV 功能障碍、血管重塑以及前列腺素和 BMP 通路的调节。