Expression of Mutant Bone Morphogenetic Protein Receptor II Worsens Pulmonary Hypertension Secondary to Pulmonary Fibrosis

Abstract

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.

BMPR2 and HIF1-α overexpression in resected osteosarcoma correlates with distant metastasis and patient survival

“…For example, HIF1-α mediates TGF-β1-induced Snail and TWIST1 expression in breast cancer cells (26). Qian et al (27) reported that TGF-β1 affects the nuclear translocation activity of HIF1-α in NiONPs-induced pulmonary fibrosis. Similarly, mutant BMPR2 expression resulted in an increase of HIF1-α in mouse pulmonary vascular endothelial cells (28).…”

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

“…Vascular permeability in the lungs was quantitated using an AngioSense 750EX Fluorescent Imaging Agent (PerkinElmer) with spectroscopic imaging in a LI-COR Pearl Impulse Small Animal Imager (97). Elevated pulmonary artery pressure was documented indirectly by the measurement of RVSP and microvascular morphometry (98).…”

Vascular Endothelial Cell-Specific Connective Tissue Growth Factor (CTGF) Is Necessary for Development of Chronic Hypoxia-Induced Pulmonary Hypertension

“…At the completion of the chronic hypoxia protocol, mice underwent harvest for histology and hemodynamic measurement (Bryant et al, 2016 ). In indicated experiments, a separate group of mice underwent intraperitoneal injection with 0.018 U/g bleomycin (Thermo Fisher Scientific) or vehicle twice weekly for 28 days (Baran et al, 2007 ; Bryant et al, 2015 ). A group of vehicle- or bleomycin-treated mice were concomitantly dosed with 100 μL intraperitoneal liposomal clodronate (CL 2 MDP) 1 week prior to either bleomycin or chronic hypoxia exposure, and every 3 days thereafter, in order to induce lung macrophage apoptosis.…”

“…To this end, the tissue response to low oxygen mediated by hypoxia-inducible factor (HIF)—a tightly conserved and regulated transcription factor across species—is known to be integral in the development of PH (Yu et al, 1999 ; Brusselmans et al, 2003 ). Building on these data, our group has recently uncovered a necessary role for tissue-specific—vascular endothelium derived—HIF in several models of PH (Bryant et al, 2015 , 2016 ). Specifically, we found that deletion of endothelial HIF leads to improved vascular barrier integrity in response to injury, and is associated with protection against pulmonary vessel “leakiness” leading to PH.…”