Collagen Accumulation & Mechanical Mechanisms in Pulmonary Hypertension

描述（由申请人提供）：肺动脉高压（PAH）是一种进行性和快速致命的疾病，即使采用现代治疗。死亡原因通常是右心室（RV）衰竭。小的远端肺动脉变窄是引起肺动脉高压的原因。最近，大的近端肺动脉（PAs）僵硬度增加被认为是PAH死亡率的一个强有力的预测因素。然而，远端和近端PA重塑对从健康右心室到失效右心室的关键转变的影响仍然是一个主要的知识缺口。在最初的资助期（2008-2012），我们重点研究了机械上重要的蛋白胶原对近端动脉硬化、肺血流动力学和缺氧引起的肺动脉高压（HPH）后右心室功能变化的血管影响。在这里，我们从三个重要的方面扩展了这项工作。首先，我们采用了新的方法来产生RV功能障碍和RV失败，这一直是小鼠PH模型的局限性，直到最近。其次，我们设计了一种新的实验方法来解耦，从而区分近端PA僵硬和远端PA狭窄的影响，这两种影响在临床上是紧密耦合的，但可能通过独立的机制损害右心室功能。第三，我们研究右心室胶原含量和交联在右心室功能障碍和向衰竭过渡中的作用。我们的目标是：为了证明轻度/中度肺动脉高压中适应性右心室肥大（右心室增厚但不衰竭）依赖于远端肺动脉狭窄和不依赖于近端肺动脉硬化，因为我们假设由于远端肺动脉狭窄导致平均肺动脉压升高是引起轻度至中度肺动脉高压中适应性右心室肥大的必要和充分条件。目标2。为了证明严重PAH中右心室重构不良（RV衰竭）依赖于远端肺动脉狭窄和近端肺动脉硬化的结合，因为我们假设平均肺动脉压的增加是必要的，但不足以导致严重PAH中右心室重构不良；我们假设近端动脉硬化引起的脉压增加也是必要的。目标3。为了研究右心室功能与右心室纤维化之间的关系，我们假设纤维化程度较高的右心室比纤维化程度较低的右心室更容易受到远端右心室狭窄和近端右心室硬化的损害。临床和科学

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a progressive and rapidly fatal disease, even with modern therapies. The cause of death is typically right ventricular (RV) failure. Narrowing of the small, distal pulmonary arteries is know to cause PAH. Recently, increased stiffness of the large, proximal pulmonary arteries (PAs) was identified as a powerful predictor of mortality in PAH. However, the impact of distal and proximal PA remodeling on the critical transition from a healthy RV to a failing RV remains a major knowledge gap. Over the initial funding period (2008-2012), we focused on the vascular impact of the mechanically important protein collagen on proximal arterial stiffening, pulmonary hemodynamics and subsequent changes in RV function with hypoxia-induced pulmonary hypertension (HPH). Here we extend the work in three important ways. First, we employ novel methods to generate not only RV dysfunction but also RV failure, which has been a limitation of mouse PH models until recently. Second, we designed a novel experimental approach to uncouple and therefore distinguish the effects of proximal PA stiffening from distal PA narrowing, which are tightly coupled clinically but may impair RV function through independent mechanisms. Third, we investigate the role of RV collagen content and cross-linking in RV dysfunction and the transition to failure. Our aims are: Aim 1. To demonstrate the dependence of adaptive RV hypertrophy (thickened but not failing RV) on distal PA narrowing and independence from proximal PA stiffening in mild/moderate PAH, because we hypothesize that increases in mean pulmonary arterial pressure due to distal PA narrowing are necessary and sufficient to cause adaptive RV hypertrophy in mild to moderate PAH. Aim 2. To demonstrate the dependence of maladaptive RV remodeling (failing RV) on the combination of distal PA narrowing and proximal PA stiffening in severe PAH, because we hypothesize that increases in mean pulmonary arterial pressure are necessary but not sufficient to cause maladaptive RV remodeling in severe PAH; we hypothesize that increases in pulse pressure induced by proximal PA stiffening are also necessary. Aim 3. To investigate the relationship between RV function and RV fibrosis because we hypothesize that a more fibrotic RV is more impaired by distal PA narrowing and proximal PA stiffening than a less fibrotic RV. The clinical and scientific communities investigating PAH were recently charged with improving our understanding of the dependence of RV function on pulmonary vascular changes. Our goals are to investigate critical mechanobiological changes in proximal and distal PAs as well as the RV itself that drive the transition from a hypertrophied, functional RV to a failing RV during PAH progression, with a particular emphasis on the role of collagen, which in the future may impact treatment options for this rapidly fatal disease.