Pulmonary arterial hypertension (PAH) is a disease of the pulmonary arterial vasculature and its remodeling, in which patient mortality is significantly associated with impaired RV function. The prognosis of patients with PAH is very poor with five-year survival <50%, and there are no available therapies to prevent right heart failure in PAH. Recent studies by the applicant?s group in animal models of PAH and clinical studies have shown that altered RV diastolic stiffness to be an important feature of PAH pathogenesis. Here we propose to investigate the structural mechanisms by which remodeling of RV extracellular matrix (ECM) alters their mechanical properties and the cellular mechanisms by which changes in RV mechanical loading and material properties in turn regulate the phenotype and pro-fibrotic signaling of cardiac fibroblasts. Using a comprehensive time-course in a well-established animal model of PAH progression, we will conduct detailed in-vivo physiological studies and biaxial tissue biomechanical testing of intact and decellularized RV samples together with microstructural mathematical modeling to determine how ECM remodeling alters RV myocardial mechanic and diastolic function. We will then recapitulate these alterations in RV ECM structure and mechanics in a novel in-vitro model to investigate how altered ECM structure and loading conditions in PAH regulate RV cardiac fibroblasts (CFB) differentiation, activation, and pro-fibrotic ECM expression. Finally, we will use these new in-vitro measurements to extend and validate a mathematical model of mechano- regulated CBF cell signaling.
The specific aims of this proposal will determine the time course of changes in RV geometry, contractility and diastolic material properties that compensate for altered hemodynamic loads during PAH and determine how these mechanisms become maladaptive (Aim 1); the changes in RV myocardial structure and mechanics during adaptive and maladaptive RV ECM remodeling, and identify the biomechanical stimuli driving these changes in PAH (Aim 2); and the mechanobiological mechanisms regulating adaptive and maladaptive RV ECM remodeling during PAH (Aim 3). The overall outcome of the proposed research will be the discovery of quantitative biological principles of the RV extracellular matrix (ECM) remodeling that contribute to the changes in diastolic function that occur during the progression of PAH and the transition to decompensated RV dysfunction.
Pulmonary arterial hypertension (PAH) is involved in 200,000 hospitalizations per year in the United States with has high mortality rates due to impaired right ventricular (RV) function. The prognosis is very poor with five-year survival <50%, and there are no available therapies to prevent right heart failure. The goal of this research is to investigate the tissue mechanisms by which remodeling of the collagen extracellular matrix in PAH alters RV myocardium stiffness initially to compensate and how in the progression of the disease this stiffening reverse leading to RV dilation in a well-established rat model.