Arterial Stiffness in the Pathogenesis of Human Pulmonary Arterial Hypertension

动脉僵硬度在人肺动脉高压发病机制中的作用

• 批准号: 8516592
• 负责人: LAURA ELIZABETH FREDENBURGH
• 金额: $ 8.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516592
• 关键词: Anabolism; Apoptosis; Atomic Force Microscopy; BMPR2 gene; Behavior; Biology; Blood Vessels; Cell Proliferation; Cells; Cessation of life; Collagen; Cytoskeleton; Deposition; Development; Disease; Distal; Employee Strikes; Endothelin-1; Environment; Epoprostenol; Equilibrium; Failure; Feedback; Goals; Heart; Heart failure; Human; Hypoxia; Inflammation; Lead; Lung; Measures; Mechanics; Mediator of activation protein; Modeling; Monocrotaline; Mutation; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Prostaglandins; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Regulation; Research; Resistance; Resources; Right Ventricular Function; Role; SU 5416; Side; Smooth Muscle Myocytes; Structure of parenchyma of lung; Testing; Tissues; Traction; Vascular remodeling; Ventricular; arterial stiffness; attenuation; cell growth; cyclooxygenase 2; hemodynamics; insight; mortality; novel; novel therapeutic intervention; polyacrylamide; polyacrylamide gels; prevent; pulmonary arterial hypertension; pulmonary artery endothelial cell; response

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a severe disease characterized by excessive proliferation of apoptosis-resistant pulmonary artery endothelial cells (PAEC) and smooth muscle cells (PASMC), progressive pulmonary arterial (PA) stiffening, and ultimately right heart failure and death. Recent studies suggest that increased PA stiffness contributes significantly to increased right ventricular afterload and is associated with increased mortality in PAH patients, however the role of PA stiffening in the pathogenesis of PAH has not yet been fully elucidated. We have used atomic force microscopy (AFM) microindentation to mechanically characterize the stiffness of pulmonary arteries at an unprecedented micro-scale level in experimental PAH. Our preliminary findings demonstrate that distal pulmonary arteries develop significant increases in matrix stiffness by more than three-fold in the rat models of SU5416/hypoxia and monocrotaline (MCT)-induced PAH. Furthermore, human PASMC and PAEC grown on polyacrylamide substrates with the stiffness of remodeled pulmonary arteries develop a striking hyperproliferative phenotype, decreased expression of cyclooxygenase (COX)-2, reduced prostaglandin I2 synthesis, and increased secretion of endothelin-1. Taken together, our findings suggest that matrix remodeling in the PA wall fundamentally biases cellular behavior towards progressive vascular remodeling via previously unrecognized effects of matrix stiffening. We hypothesize that increases in PA stiffness are not merely a consequence of pathological alterations in the vessel wall, but rather that increases in matrix stiffness trigger a "remodeling phenotype" characterized by enhanced cellular proliferation and matrix deposition in pulmonary arteries, promoting mechanobiological feedback amplification of vascular remodeling. To test our hypothesis, we propose two specific aims. In Specific Aim 1, we will investigate the magnitude and distribution of pathological increases in pulmonary arterial stiffness at the micron spatial scale in human PAH tissue. We will use AFM microindentation to characterize the mechanical environment of remodeled pulmonary arteries in lung tissue derived from subjects with WHO Group I PAH and secondary pulmonary hypertension compared with normal vessels in lung tissue from control subjects. In Specific Aim 2, we will elucidate the mechanisms by which the mechanical environment promotes pathologic remodeling behaviors in PASMC and PAEC derived from subjects with PAH. We will investigate whether matrix stiffness regulates the biology of proximal and distal PASMC and PAEC derived from subjects with PAH compared with control subjects. We will also determine whether stiffness-dependent attenuation of COX-2- derived prostanoid biosynthesis drives progressive vascular remodeling in a mechanobiological feedback loop. The proposed studies will provide novel insights into the role of the mechanical environment in pulmonary vascular remodeling in human PAH and will elucidate the mechanisms activating the stiffness-dependent "switch" to a remodeling cellular phenotype in human PASMC and PAEC.

描述（申请人提供）：肺动脉高压（PAH）是一种严重的疾病，其特征是抗凋亡的肺动脉内皮细胞（PAEC）和平滑肌细胞（PASMC）过度增殖，进行性肺动脉（PA）硬化，最终导致右心衰竭和死亡。最近的研究表明，PA 僵硬增加会显着增加右心室后负荷，并与 PAH 患者死亡率增加相关，但 PA 僵硬在 PAH 发病机制中的作用尚未完全阐明。我们使用原子力显微镜 (AFM) 显微压痕在实验性 PAH 中以前所未有的微观尺度机械表征肺动脉的硬度。我们的初步研究结果表明，在 SU5416/缺氧和野百合碱 (MCT) 诱导的 PAH 大鼠模型中，远端肺动脉基质硬度显着增加三倍以上。此外，在具有重塑肺动脉硬度的聚丙烯酰胺基质上生长的人 PASMC 和 PAEC 会出现显着的过度增殖表型，环加氧酶 (COX)-2 的表达减少，前列腺素 I2 合成减少，内皮素-1 分泌增加。总而言之，我们的研究结果表明，PA 壁中的基质重塑从根本上使细胞行为偏向于通过以前未认识到的基质硬化效应进行渐进性血管重塑。我们假设PA硬度的增加不仅仅是血管壁病理改变的结果，而且基质硬度的增加触发了一种“重塑表型”，其特征是肺动脉中细胞增殖和基质沉积增强，促进血管重塑的机械生物学反馈放大。为了检验我们的假设，我们提出了两个具体目标。在具体目标 1 中，我们将研究人类 PAH 组织中微米空间尺度肺动脉硬度病理性增加的幅度和分布。我们将使用 AFM 显微压痕来表征 WHO I 组 PAH 和继发性肺动脉高压受试者肺组织中重塑肺动脉的机械环境，并与对照受试者肺组织中的正常血管进行比较。在具体目标 2 中，我们将阐明机械环境促进来自 PAH 受试者的 PASMC 和 PAEC 病理重塑行为的机制。我们将研究与对照受试者相比，基质刚度是否调节来自 PAH 受试者的近端和远端 PASMC 和 PAEC 的生物学。我们还将确定 COX-2 衍生的前列腺素生物合成的硬度依赖性衰减是否驱动机械生物学反馈回路中的渐进性血管重塑。拟议的研究将为机械环境在人类 PAH 肺血管重塑中的作用提供新的见解，并将阐明激活人类 PASMC 和 PAEC 中刚度依赖性“转换”至重塑细胞表型的机制。