Bmpr2 Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension

Background: Monoallelic mutations in the gene encoding bone morphogenetic protein receptor 2 (Bmpr2) are the main genetic risk factor for heritable pulmonary arterial hypertension (PAH) with incomplete penetrance. Several Bmpr2 transgenic mice have been reported to develop mild spontaneous PAH. In this study, we examined whether rats with the Bmpr2 mutation were susceptible to developing more severe PAH. Methods: The zinc finger nuclease method was used to establish rat lines with mutations in the Bmpr2 gene. These rats were then characterized at the hemodynamic, histological, electrophysiological, and molecular levels. Results: Rats with a monoallelic deletion of 71 bp in exon 1 (Δ71 rats) showed decreased BMPRII expression and phosphorylated SMAD1/5/9 levels. Δ71 Rats develop age-dependent spontaneous PAH with a low penetrance (16%–27%), similar to that in humans. Δ71 Rats were more susceptible to hypoxia-induced pulmonary hypertension than wild-type rats. Δ71 Rats exhibited progressive pulmonary vascul...