Vascular collagen accumulation & mechanical mechanisms in pulmonary hypertension

肺血管重构是肺动脉高压的结果，可导致右心室肥厚。 心室衰竭然而，重塑导致心室衰竭的机制尚不清楚。 以前的传统想法是小动脉肌肉化导致管腔直径减小， 增加稳定的心室作功，但最近的证据挑战了这一观点。我们的总体 假设肺血管胶原积聚是导致搏动性心室肌收缩增加的原因， 工作，这严重损害功能，并通过动脉硬化。在体循环中，动脉 硬化被认为是心血管死亡的独立危险因素。的影响 动脉硬化对右心室功能的影响代表了该领域的主要知识空白。在这里，我们寻求 为了检验肺动脉高压时血管胶原蛋白的积聚 (1)增加肺动脉硬度，（2）增加肺动脉脉搏波反射，和（3） 损害右心室功能。此外，我们试图表明，恢复正常动脉， 恢复期间的血液动力学和心室功能依赖于胶原蛋白的降解， 预防血管胶原蛋白积聚（用新型抗纤维化治疗剂）可防止进展。 我们将用最先进的野生型生物力学和血液动力学实验来验证我们的假设 和基因工程小鼠。我们还将在临床研究中探索这些终点的临床相关性。 试点研究。我们的具体目标是： 1.为了确定血管胶原积聚在肺动脉硬化中的作用-通过压力- 离体肺动脉和肺血管网的直径测量。 2.确定血管胶原积聚在肺动脉波反射中的作用-通过 在隔离的、通气的和灌注的肺中的脉动压力-流量测量。 3.为了确定血管胶原积聚在右心室功能中的作用-通过压力- 原位活体小鼠右心室的体积测量。 4.目的：检测肺动脉高压患者的肺血管血流动力学和右心功能， 肺动脉高压，重点是那些过度胶原蛋白积累。 该项目的成功完成将产生重要的见解，治疗进展， 以及肺动脉高压的恢复此外，这些研究将回答关键问题， 关于肺血管病变继发右心功能不全的力学机制， 肺动脉高压的重塑

Pulmonary vascular remodeling is a consequence of pulmonary hypertension that can lead to right ventricular failure. However, the mechanisms by which remodeling causes ventricular failure are unknown. Previous conventional thinking was that arteriolar muscularization led to reduced lumen diameters and increased steady ventricular work, but recent evidence has challenged that view. Our overarching hypothesis is that pulmonary vascular collagen accumulation is responsible for increased pulsatile ventricular work, which severely impairs function, and does so via arterial stiffening. In the systemic circulation, arterial stiffening has been recognized as an independent risk factor for cardiovascular mortality. The impact of arterial stiffening on right ventricular function represents a major knowledge gap in the field. Here, we seek to test the specific hypotheses that vascular collagen accumulation in response to pulmonary hypertension (1) increases pulmonary arterial stiffness, (2) increases pulmonary arterial pulse wave reflections, and (3) impairs right ventricular function. Furthermore, we seek to show that the return to normal arterial, hemodynamic and ventricular function during recovery is dependent on the degradation of collagen and that preventing vascular collagen accumulation (with a novel anti-fibrotic treatment agent) prevents progression. We will test our hypotheses with state-of-the-art biomechanical and hemodynamic experiments on wild type and genetically-engineered mice. We will also explore the clinical correlates of these endpoints in a clinical pilot study. Our specific aimsare: 1. To determine the role of vascular collagen accumulation in pulmonary arterial stiffening - via pressure- diameter measurements in isolated pulmonary arteries and the pulmonary vascular network. 2. To determine the role of vascular collagen accumulation in pulmonary arterial wave reflections - via pulsatile pressure-flow measurements in isolated, ventilated and perfused lungs. 3. To determine the role of vascular collagen accumulation in right ventricular function - via pressure- volume measurements in the right ventricle of live mice in situ. 4. To examine the pulmonary vascular hemodynamics and right ventricular function of patients with pulmonary hypertension, focusing on those with excessive collagen accumulation. The successful completion of this project will yield important insights into the progression of, treatment for and recovery from pulmonary hypertension. Furthermore, these studies will answer critical questions regarding the mechanical mechanisms of right ventricular dysfunction secondary to pulmonary vascular remodeling in pulmonary hypertension.