Interrogation of the Cellular Pathogenesis of Pulmonary Hypertension

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DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PH), a progressive disease defined by an elevation in the mean pulmonary artery pressure above 25 mm Hg, leads to right heart failure and a significant risk of death. Genetic alterations in two members of the TGF ¿ superfamily pathways, bone morphogenetic protein receptor II (BMPR II) and the TGF-¿ receptor I, ALK1, have been implicated in the pathogenesis of PH. Despite the genetic and functional significance of the TGF pathway, it is unclear how dysregulation of TGF signaling results in PAH. We hypothesize that the development of PAH results from an imbalance in TGF signaling within endothelial cells. Specifically, enhanced TGF signaling in endothelial cells promotes a phenotypic change that allows the cells to undergo endothelial-mesenchymal transition and contribute to the smooth muscle or myofibroblast cell population. This project addresses one of the fundamental questions in pulmonary hypertension, the mechanism by which altered TGF ¿ signaling contributes to the pathogenesis of PH. The complexity of this question is amplified by the myriad of cellular processes in which TGF ¿ participates and the multiple cell types (endothelial, smooth muscle, and adventitial fibroblasts) it is capable of affecting and which may influence the development of pulmonary hypertension. In order to begin addressing the molecular pathway, this project proposes to study the role of TGF ¿ signaling in endothelial cells. We will rely on an endothelial cell inducible deletion of TGF ¿ receptor II and the well-established hypoxic model of PH to demonstrate the role of endothelial cell TGF ¿ signaling in the development of PH. Endothelial-mesenchymal transition will be characterized by genetically tagging endothelial cells and following their fate after exposure to chronic hypoxia. Finally, we will demonstrate that TGF ¿ signaling is required for endothelial-mesenchymal transition and test a novel inhibitor of TGF ¿ mediated transition. Understanding the molecular mechanism by which this occurs can provide insight into the initiation of human PAH and the development of novel therapeutic targets.