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）的特征是抗细胞凋亡的过度增殖肺部动脉内皮细胞（PAEC），平滑肌细胞（PASMC）和外在成纤维细胞（PAAF）导致肺血管抗性的逐渐增加，并最终正确的心力衰竭和死亡。最近的研究表明，肺动脉（PA）刚度与死亡率增加有关 PAH患者；但是，PA僵硬的发病机理和进展涉及的机制 PAH尚未完全阐明。我们已经发现，远端血管基质僵硬在早期发展肺动脉高压（pH）的模型和触发局部机械生物学反馈回路，该回路会放大血管重塑并加速疾病进展。这些发现表明PA刚度不是仅是血管壁中病理变化的结果，但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中的机械活化。我们的初步发现表明，通过YAP/TAZ驱动器进行机械信号血管细胞通过抑制环氧合酶（COX）-2衍生的前列腺素的产生和骨形态发生蛋白（BMP）信号传导。在PASMC和PAEC中对YAP/TAZ的沉默可消除刚度依赖性增加，基质沉积和牵引力产生，并挽救抑制前列腺素的产生和BMP信号传导。此外，PASMC过表达了一个定位的突变体TAZ 构成对核的组成型在COX-2衍生的前列腺素的产生和BMP中有显着降低信号传导导致高增殖性重塑表型。我们假设YAP/TAZ被激活驱动促造成细胞反应并促进基质僵硬的机械环境不利的反馈回路通过抑制PAH中的前类动物产生和BMP信号传导。在AIM 1中，我们将研究YAP/TAZ在调节COX-2依赖性前列腺素生产和血管中扮演的作用对PAH的矩阵僵硬的响应。我们将确定YAP/TAZ依赖性抑制的机制 COX-2的刚度依赖性收缩力和基质合成的调节和Paaf。在AIM 2中，我们将研究YAP/TAZ控制TGF-的机制！和BMP依赖性 SMAD信号传导，抑制ID1表达并调节PAH中对BMP信号的细胞生长反应。我们将确定YAP/TAZ活动对增殖，凋亡耐药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AIM 3中，我们将确定 YAP/TAZ的失活是否会阻止PA僵硬，减弱血管重塑并防止正确实验pH中的心室（RV）功能障碍。我们将使用鼠模型和药理方法调节YAP/TAZ活性，并评估YAP/TAZ失活对PA僵硬，血液动力学的影响 RV功能障碍，血管重塑以及pH模型中的前类动物和BMP途径的调节。