Introduction: Hepatopulmonary syndrome (HPS) is characterized by impaired gas exchange caused by intrapulmonary vascular dilatations (IPVDs). Accumulating evidence supports that bone morphogenetic protein (BMP)-9, a circulating factor mainly produced by the liver, plays an essential role in the maintenance of pulmonary vascular integrity.

Aims: In the present study, we aimed to evaluate the role of BMP-9 and its signaling in the development of HPS.

Methods: To validate common bile duct ligation (CBDL) and partial portal vein ligation (PPVL) in rats as two experimental HPS models, gas exchange impairment and the presence of IPVDs were assessed. Then, we determined BMP-9 activity in the serum of control, CBDL and PPVL rats and analyzed the phosphorylation status of Smad1/5/8 in lungs. Gas exchange impairment and the presence of IPVDs were also studied in BMP-9 knock out rats. Finally, curative effect of low doses of the BMP activator FK506 was studied in the two models.

Results: CBDL and PPVL rats had lower hepatic expression of BMP-9 and displayed hypoxemia with IPVDs at 4 and 10 weeks, respectively. BMP-9 activity in the serum was lower in CBDL and PPVL rats relative to sham. Furthermore, CBDL and PPVL rats exhibited a reduction in the pSmad1/5/8 levels in the pulmonary endothelium. Consistent with a detrimental role played by BMP-9 in HPS, we also found that Bmp9-/- rats exhibited IPVDs and mild hypoxemia. Finally, curative treatment of CBDL and PPVL rats with low doses of FK506 restored the phosphorylated Smad1/5/8 levels and attenuated IPVDs and gas exchange impairment.

Conclusion: Loss of BMP-9 signaling induced by portal hypertension is involved in the development of experimental HPS.