Background Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2) underlie the majority (>70%) of cases of heritable pulmonary arterial hypertension (hPAH) and a variable proportion of idiopathic PAH (15%–40%). There are also reports of PAH in patients with mutations in the downstream Smad signalling proteins. However, to date there is no mouse model that mimics the genetic mutations in human disease.
Methods We developed a knock-in mouse harbouring a heterozygous (±) human disease causing mutation in BMPR-II: a nonsense mutation in the cytoplasmic tail (R899X) to determine the in vivo physiologic consequences of this BMPR2 mutation. In addition, we crossed this animal with Smad1± knockout mice to determine the effect of additional loss of signalling via this pathway. Haemodynamic, and morphometric data were collected at 3 months and 6 months of age.
Results At 3 months of age pulmonary haemodynamics and vascular morphometry of R899X± and Smad1± mice were similar to wild-type littermate controls. In contrast, at 6 months of age R899X± and Smad1± mice developed mild pulmonary hypertension with pulmonary vascular remodelling compared with wild-types. Pulmonary artery smooth muscle cells from R899X± mice were hyperproliferative in serum and exhibited defects in Smad signalling in response to BMPs. When R899X± mice were crossed with Smad1± animals, double heterozygous mice had significantly higher right ventricular systolic pressures than single heterozygous mice.
Conclusion These findings demonstrate that knockin of a human disease causing BMPR-II mutation causes age-related pulmonary hypertension in mice. In addition, we show that the accumulation of defects in the BMP/Smad signalling pathway increases the susceptibility to pulmonary hypertension, highlighting the central role of this pathway in disease.