Pulmonary fibrosis is often complicated by
pulmonary hypertension (PH), and previous studies have shown a potential link between
bone morphogenetic protein receptor II (BMPR2) and PH secondary to
pulmonary fibrosis. We exposed transgenic mice expressing mutant BMPR2 and control mice to repetitive
intraperitoneal injections of
bleomycin for 4 weeks. The duration of transgene activation was too short for mutant BMPR2 mice to develop spontaneous PH. Mutant BMPR2 mice had increased right ventricular systolic pressure compared to control mice, without differences in
pulmonary fibrosis. We found increased
hypoxia-inducible factor (HIF)1-α stabilization in lungs of mutant-BMPR2-expressing mice compared to controls following
bleomycin treatment. In addition, expression of the
hypoxia response element
protein connective tissue growth factor was increased in transgenic mice as well as in a human pulmonary microvascular endothelial cell line expressing mutant BMPR2. In mouse pulmonary vascular endothelial cells, mutant BMPR2 expression resulted in increased HIF1-α and
reactive oxygen species production following exposure to
hypoxia, both of which were attenuated with the
antioxidant TEMPOL. These data suggest that expression of mutant BMPR2 worsens secondary PH through increased HIF activity in vascular endothelium. This pathway could be therapeutically targeted in patients with PH secondary to
pulmonary fibrosis.