Bone marrow transplantation reduces susceptibility to pulmonary hypertension in BMPR2 deficient mice

Abstract

Background: Evidence suggests that patients with pulmonary arterial hypertension (PAH) have abnormalities in the bone marrow (BM). Around 40% of patients with PAH are reported to have evidence of myelodysplasia. Conversely, PAH is often found (13-48% in patients with myeloproliferative disease. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) is the commonest genetic cause of PAH; therefore, we questioned whether transplantation of wild type (WT) BM reduces the susceptibility to PAH in the BMPR2+/- mouse. Methods: WT mice were transplanted with BMPR2+/- BM and BMPR2+/- mice were transplanted with WT BM. 16 weeks post-transplant mice were exposed to low-dose chronic LPS (0.5mg/kg 3 times a week for 6 weeks). Mice underwent right heart catheterisation. Tissues were removed for histology. Results: We observed a significant increase in RVSP and pulmonary vascular remodelling when WT mice were transplanted with BMPR2+/- BM. Conversely, we found that when BMPR2+/- mice were transplanted with WT BM they were protected from developing PAH. There was an increase in spleen weight in WT mice with BMPR2+/- BM. BM histology demonstrated an increase in megakaryocytes and there was an increase in circulating platelets. Conclusions: The BM plays an important role in the development of PAH. We have shown that the susceptibility to PAH in the BMPR2+/- mouse can be conferred on a wild type animal by BM transplantation and that the BMPR2+/- mouse can be protected from the development of PAH by bone marrow transplantation with WT BM. Further elucidation of the role of the BM is required, but may point to a potential future therapeutic strategy in PAH.