BMPR2 and the Pathogenesis of Pulmonary Hypertension

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DESCRIPTION (provided by applicant): Primary pulmonary hypertension (PPH) is a disease characterized by elevated pulmonary artery blood pressure, remodeling of the lung vasculature, and progressive right ventricular hypertrophy. Despite recent therapeutic advances, nearly 40% of PPH patients die within three years of diagnosis. The familial form of PPH is inherited as an autosomal dominant trait with incomplete penetrance and has been associated with mutations in the gene encoding the type II bone morphogenetic protein receptor (BMPR2). Moreover, about 25% of patients with sporadic PPH also have BMPR2 mutations. The principal investigator has assembled a multidisciplinary team of scientists with the objective of elucidating the role of BMPR2 in the pathogenesis of PPH. The investigators have already developed a series of genetically modified mice with mutations in the BMPR2 gene, as well as mice with a conditional BMPR2 mutation. BMPR2 mice were found to be normal at baseline but develop greater pulmonary hypertension than wild type mice after prolonged hypoxia. The proposed research is divided into four aims. First, the pulmonary vascular remodeling response to environmental and pharmacologic stimuli associated with the development of pulmonary hypertension in animal models will be compared in wild type and BMPR2 mice. Second, pulmonary vascular endothelial and smooth muscle cells will be isolated from genetically modified mice, and the ability of BMP to modulate cell proliferation, migration, and apoptosis will be assessed. Third, pulmonary vascular structure and function will be evaluated in mice with BMPR2 mutations that retain kinase activity. Finally, mice with a conditional BMPR2 mutation will be used to investigate the contribution of endothelial and smooth muscle cells to the pathogenesis of pulmonary hypertension. The results of the proposed studies will likely provide important insights into the pathogenesis of PPH including why only some patients with BMPR2 mutations develop the disease. Moreover, these studies may validate BMPR2 mice as a valuable model with which to screen new and old drugs with the goal of identifying agents that may cause PPH in individuals predisposed to the disease.