Mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure

总结/摘要 左心衰竭所致肺动脉高压（PH-LHF）与高死亡率相关。目前的想法是 PH-LHF开始时是一个被动过程，由于左心房充盈压升高， 肺静脉这种早期阶段被称为孤立性毛细血管后PH（Ipc-PH），并通过以下方法诊断： 平均肺动脉压升高，肺血管阻力（PVR）正常。联合员额 和毛细血管前PH（Cpc-PH）诊断时，PVR增加，在这种情况下，并赋予额外的 死亡率上升。疾病发展和进展的机制知之甚少。 我们在这个提案中的首要目标是发现驱动这些生物的机械和生物机制。 从Ipc-PH转变为Cpc-PH，并发生（RV）右心室衰竭。 目的1：研究Ipc-PH到Cpc-PH的生物力学和机械生物学进展， 裂谷热。在建立的小鼠模型中，我们将量化疾病期间的肺血管和RV生物力学， 进展以及介质的表达被剪切应力和拉伸改变。在两个猪模型中，使用 一套独特而全面的侵入性和非侵入性检测，我们将量化流量和压力 波形，肺血管和RV生物力学和机械生物学，包括RV肺 血管相互作用和机械转换器ET-1、eNOS、PECAM-1和Twist 1的表达。 目的2：确定机械刺激和机械转导在疾病进展中的作用。 使用现有的肺循环计算模型和一种新的毛细血管薄层流模型，我们 将预测LHF引起的肺血管压力、流量和生物力学变化对 包括毛细血管在内的肺血管系统的每个隔室中的剪切应力和拉伸。然后， 我们将使用成熟的系统对体外细胞施加剪切应力和拉伸，来检验这一假设 这些机械刺激驱动了人类肺内皮细胞重塑的关键方面。最后为 研究由ET-1机械转导驱动的适应性和适应不良重塑之间的平衡， 我们将研究内皮细胞特异性敲除ET-1的小鼠的疾病进展。

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.