Mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure

摘要/摘要 左心衰竭所致的肺动脉高压(PH-LHF)与高死亡率相关。目前的想法是 PH-LHF开始是一种被动的过程，原因是左心房充盈压力升高，从而增加了 肺静脉。这一早期阶段称为孤立性毛细血管后肺高压(IPC-PH)，由 平均肺动脉压升高，肺血管阻力(PVR)正常。组合岗位-- 在这种情况下，当PVR增加时，诊断为毛细血管前PH(CPC-PH)，并给予额外的 死亡率的增加。疾病发生和发展的潜在机制还知之甚少。 我们在这项提议中的首要目标是发现驱动 IPC-PH向CPC-PH过渡与(RV)右心衰竭的发展 目的1：研究IPC-PH向CPC-PH转化的生物力学和力学生物学进展。 RVF。在已建立的小鼠模型中，我们将量化疾病期间的肺血管和右肺生物力学。 剪应力和拉伸改变了中介体的进程和表达。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，我们将对流量和压力进行量化 波形，以及肺血管和右肺生物力学和机械生物学，包括右肺 血管相互作用与力学转导因子ET-1、eNOS、PECAM-1和Twist1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。 利用现有的肺循环计算模型和一种新的毛细血管薄片流动模型，我们 将预测LHF引起的肺血管压力、流量和生物力学变化对 肺血管各隔室，包括毛细血管的切应力和拉伸。然后, 使用在体外对细胞施加剪应力和拉伸的成熟系统，我们将检验这一假设。 这些机械刺激驱动了人肺内皮细胞重塑的关键方面。最后，为了 研究ET-1机械转导驱动的适应性和适应性不良重构之间的平衡， 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.