A Novel Mechanism of Vascular Remodeling in Interstitial Lung Disease Associated Pulmonary Hypertension

About This Grant

Pulmonary hypertension (PH) clinically defined by an increase in pulmonary arterial pressure and pulmonary vascular resistance, inevitably leading to right ventricular hypertrophy, right ventricle failure and death. The pathologic pulmonary vascular narrowing and remodeling that is a hallmark of PH and the cause of increased pulmonary vascular resistance involves multiple events coordinated by different cell types that encompass the pulmonary arterial wall. Although therapies targeting abnormalities in the vasocontractile pathways have been developed over the last two decades, mortality rates remain high and lung transplantation is still the only option in severe PH patients. Among the five major clinical groups of PH, PH due to associated interstitial lung disease (PH-ILD) and is a confounding complication of chronic lung pathology. A significant contributor to PH-ILD mortality is the ineffectiveness of current oral vasodilator therapies and the fact that no treatment is available to specifically target and reverse the pathologic pulmonary vascular remodeling seen in ILD-PH. Bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) is a secreted regulator of BMP signaling pathway and is highly expressed in lung endothelial cells. The role of BMPER in the development of pulmonary vascular remodeling in PH, particularly ILD-PH has never been studied. We have shown that BMPER is expressed in the lung vascular cells of patients with ILD-PH and that genetic BMPER deletion in a pre-clinical model of ILD prevents the development of PH. In this study, we will study the molecular mechanisms of how BMPER promotes pulmonary vascular remodeling. First, we will evaluate the protective effect of BMPER depletion and pulmonary cellular landscape associated with BMPER over-expression in a preclinical model. Next, we will delineate the molecular action of BMPER in pulmonary smooth muscle proliferative pathways in a pre-clinical model. Last, we will validate our results in ILD-PH patients by evaluating BMPER expression and its mechanistic role in pulmonary vasculopathy in veterans with ILD.