BMPR2 Preserves Mitochondrial Function and DNA during Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension

Mitochondrial dysfunction, inflammation, and mutant bone morphogenetic protein receptor 2 (BMPR2) are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels, and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1α and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1α, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1α, TFAM, mitochondrial membrane potential, ATP production, and glycolysis, and induces mitochondrial fission and a pro-inflammatory state. These features are recapitulated in PAECs from PAH patients with mutant BMPR2. [Display omitted] •Hypoxic pulmonary hypertension persists in mice with Bmpr2 deleted in endothelium•Impaired pulmonary artery regeneration is linked to mitochondrial DNA deletion•Hypoxia-reoxygenation reduces p53, PGC1α, ATP, and mitochondrial membrane potential•Reduced BMPR2 in normoxia causes hyperpolarized mitochondria and inflammation Human mutations in bone morphogenetic protein receptor 2 (BMPR2) have been linked to endothelial cell dysfunction in pulmonary arterial hypertension. Diebold et al. show that disrupted BMPR2 signaling results in aberrant mitochondrial metabolism, mtDNA damage, and apoptosis of pulmonary arterial endothelial cells.