Introduction Increasing evidence suggests that patients with pulmonary arterial hypertension (PAH) have abnormalities in the bone marrow (BM). Approximately 40% of patients with PAH are reported to have evidence of myelodysplasia. Conversely PAH is often found (13–48%) in patients with myeloproliferative disease. In a bone marrow transplant (BMT) model it has been shown that mice transplanted with CD133+ cells from PAH patients developed pulmonary vascular remodelling and right ventricular hypertrophy; whereas, CD133+ cells from controls did not. CD133+ cells from PAH patients also showed greater myeloid commitment. Since mutation in the bone morphogenetic protein receptor type 2 (BMPR2) is the commonest genetic cause of PAH we questioned whether bone marrow transplantation of wild type bone marrow reduces the susceptibility to PAH in the BMPR2 heterozygous mouse.
Methods WT mice were transplanted with BMPR2 ± BM and BMPR2 ± mice were transplanted with WT BM. Sixteen weeks post-transplant mice were exposed to low-dose chronic LPS (0.5 mg/kg 3 times a week for 6 weeks), which we recently showed is a potent stimulus for the development of PAH in the BMPR2 heterozygous mouse. Mice underwent right heart catheterisation. Tissues were removed for histology.
Results We observed a significant increase in RVSP when WT mice were transplanted with BMPR2 ± bone marrow after chronic LPS dosing. There was an increase in spleen weight and circulating platelets in WT mice with BMPR2 ± bone marrow and a converse reduction in spleen weight and platelets in BMPR2 ± mice with WT BM. Bone marrow histology demonstrated reduced myeloid cells and megakaryocytes, iron deposition and fibrosis related to LPS administration. In preventative studies BMPR2 ± mice transplanted with WT bone marrow did not develop significant pulmonary hypertension after chronic LPS exposure.
Conclusions The susceptibility to PAH in the BMPR2 heterozygous mouse can be conferred on a wild type animal by bone marrow transplantation of BMPR2 deficient bone marrow. Transplanting WT BM into BMPR2 ± mice prevented PAH. The role of bone marrow derived cells in the pathobiology of PAH requires further elucidation, but may point to a potential future treatment