Mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure

左心衰竭继发肺动脉高压的力学生物学机制

• 批准号: 10414922
• 负责人: Naomi C Chesler
• 金额: $ 57.69万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414922
• 关键词: Adult; Animal Model; Arteries; Biological; Biological Assay; Biomechanics; Blood Vessels; Blood capillaries; CD31 Antigens; Cardiac Output; Cells; Cessation of life; Chronic; Computer Models; Development; Diagnosis; Disease; Disease Progression; Due Process; EFRAC; Endothelial Cells; Endothelin; Endothelin-1; Endothelium; Equilibrium; Genetic; Goals; Heart Atrium; Heart failure; Homeostasis; Human; Impairment; In Vitro; Knock-out; Knowledge; Left; Lung; Measures; Mechanics; Mediator of activation protein; Metabolic; Modeling; Morbidity - disease rate; Mus; NOS3 gene; Patient-Focused Outcomes; Process; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Pulmonary veins; Right Ventricular Function; Role; Secondary to; Signal Transduction; Stimulus; Stretching; Structure; System; Testing; Text; Therapeutic; Thinking; Time; Veins; Venous; arterial stiffness; hemodynamics; improved outcome; individual patient; mechanical stimulus; mechanotransduction; mortality; mouse model; multimodality; novel; novel therapeutics; porcine model; preservation; pressure; pulmonary arterial pressure; pulmonary vascular remodeling; right ventricular failure; sex; shear stress; targeted treatment; vasoconstriction

SUMMARY/ABSTRACT Pulmonary hypertension due to left heart failure (PH-LHF) is associated with high mortality. Current thinking is that PH-LHF begins as a passive process due to elevated left atrial filling pressures that increase pressures in the pulmonary veins. This early stage is termed isolated post-capillary PH (Ipc-PH) and is diagnosed by elevated mean pulmonary artery pressure with normal pulmonary vascular resistance (PVR). Combined post- and pre-capillary PH (Cpc-PH) is diagnosed when PVR is increased in this setting and confers an additional increase in mortality. Mechanisms underlying disease development and progression are poorly understood. Our overarching goal in this proposal is to discover the mechanical and biological mechanisms that drive transition from Ipc-PH to Cpc-PH and the development of (RV) right ventricular failure. Aim 1: To investigate the biomechanical and mechanobiological progression of Ipc-PH to Cpc-PH and RVF. In an established mouse model, we will quantify pulmonary vascular and RV biomechanics during disease progression as well as expression of mediators altered by shear stress and stretch. In two swine models, using a unique and comprehensive suite of invasive and noninvasive assays, we will quantify flow and pressure waveforms, and pulmonary vascular and RV biomechanics and mechanobiology, including RV-pulmonary vascular interactions and expression of mechanotransducers ET-1, eNOS, PECAM-1, and Twist1. Aim 2: To determine the roles of mechanical stimuli and mechanotransduction in disease progression. Using an existing computational model of the pulmonary circulation and a novel capillary sheet flow model, we will predict the impact of LHF-induced changes in pulmonary vascular pressures, flow, and biomechanics on shear stress and stretch in each compartment of the pulmonary vasculature, including the capillaries. Then, using well-established systems for imposing shear stress and stretch on cells in vitro, we will test the hypothesis that these mechanical stimuli drive key aspects of remodeling in human pulmonary endothelial cells. Finally, to investigate the balance between adaptive and maladaptive remodeling driven by ET-1 mechanotransduction, we will study disease progression in mice with endothelial cell specific knockout of ET-1.

摘要/摘要 左心力衰竭（pH-LHF）引起的肺动脉高压与高死亡率有关。当前的思维是 该pH-LHF作为一个被动过程，是由于较高的左心房填充压力增加的，以增加压力 肺静脉。该早期阶段被称为孤立的毛细血管后pH（IPC-PH），并被诊断 较高的肺动脉压力升高，正常肺血管耐药性（PVR）。结合后 当PVR增加在这种情况下，诊断出毛细血管前pH（CPC-PH）并授予额外 死亡率增加。疾病发展和进展的机制知之甚少。 我们在此提案中的总体目标是发现驱动的机械和生物学机制 从IPC-PH到CPC-PH的过渡以及（RV）右心衰竭的发展。 目标1：研究IPC-PH到CPC-PH的生物力学和机械生物学进展 RVF。在既定的小鼠模型中，我们将在疾病期间量化肺血管和RV生物力学 剪切应力和拉伸改变的进展以及介体的表达。在两个猪模型中，使用 我们将量化流动和压力的独特而全面的侵入性和无创测 波形，肺血管和RV生物力学和机械生物学，包括RV-Pulonary 机械转换器ET-1，ENOS，PECAM-1和Twist1的血管相互作用和表达。 目的2：确定机械刺激和机械转导在疾病进展中的作用。 使用肺循环的现有计算模型和新型的毛细血管流量模型，我们 将预测LHF诱导的肺血管压力，流量和生物力学变化的影响 包括毛细血管在内的肺脉管系统的每个隔室中的剪切应力和拉伸。然后， 使用公认的系统施加剪切应力并在体外伸展细胞，我们将检验假设 这些机械刺激驱动了人类肺部内皮细胞中重塑的关键方面。最后，到 研究由ET-1机械转导驱动的自适应和适应不良重塑之间的平衡， 我们将研究ET-1的内皮细胞特异性敲除小鼠的疾病进展。