There is increasing evidence of a link between abnormalities in the myeloid cell lineage and pulmonary arterial hypertension (PAH). Heterozygous mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) are the most common genetic cause of PAH. We sought to characterise the impact of the genetic loss of BMPR2 in the myeloid lineage in mice and humans.
Mx1-cre mice were crossed with bmpr2flox/floxmice. At approximately 8 weeks old cre-recombinase was induced with polyinosinic-polycytidylic acid (Poly I:C). Control mice were induced. Approximately 16 weeks post-induction mice underwent right-heart catheterisation, exsanguination and tissue was removed for analysis. Mouse data are presented as mean ±SEM. In a large cohort of PAH patients with (n=160) and without (n=831) BMPR2 mutations blood count indices were analysed. Data presented as median [IQR].
16 weeks post-induction of Mx1-cre/bmpr2flox/floxmice we observed an increase (p<0.05) in red blood cells (x106/mm3) (12.7±0 vs. 12.1±0.2), haematocrit (%) (64.8±0.7 vs.62.6±1) and haemoglobin (g/dl) (16±0.9 vs. 15.4±0.2) compared with bmpr2flox/floxmice. An increase in circulating monocytes (x103/mm3) was also observed (p<0.05) (0.4±0.05 vs. 0.3±0.05). There was an increase (p<0.05) in megakaryocytes in the femurs (80±10 vs. 17±5) and an increase (p<0.01) in the ratio of spleen/body weight (0.003±0.0001 vs. 0.002±0.0001) in Mx1-cre/bmpr2flox/flox mice. Right ventricular systolic pressures were similar in both groups. In PAH patients differences (p<0.05) were seen in haemoglobin (BMPR2 mutation: 162g/L [151.75 – 173]) vs. no mutation: 150g/L [135 – 163]), haematocrit (0.48 [0.45 - 0.52] vs. 0.44 [0.41 - 0.48]) and white blood cells (8.8 [7.3 - 10.4] vs. 8.11 [6.77 - 9.61]).
We have identified a role for bmpr2 in the differentiation of the mouse myeloid lineage, which was also confirmed in patients with BMPR2 mutations and PAH. BMPR2 appears particularly important in the differentiation of megakaryocyte-erythrocyte lineage.