Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension.

Idiopathic pulmonary arterial hypertension (PAH) is characterized by proliferation of pulmonary vascular endothelial and smooth muscle cells causing increased vascular resistance and right heart failure. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) are believed to cause the familial form of the disease. Reduced expression of BMPR2 is also noted in secondary PAH. Recent advances in the therapy of PAH have improved quality of life and survival, but many patients continue to do poorly. The possibility of treating PAH via improving BMPR2 signaling is thus a rational consideration. Such an approach could be synergistic with or additive to current treatments. We developed adenoviral vectors containing the BMPR2 gene. Transfection of cells in vitro resulted in upregulation of SMAD signaling and reduced cell proliferation. Targeted delivery of vector to the pulmonary vascular endothelium of rats substantially reduced the pulmonary hypertensive response to chronic hypoxia, as reflected by reductions in pulmonary artery and right ventricular pressures, right ventricular hypertrophy, and muscularization of distal pulmonary arterioles. These data provide further evidence for a role for BMPR2 in PAH and provide a rationale for the development of therapies aimed at improving BMPR2 signaling.