Elevated circulating BMP9 aggravates pulmonary angiogenesis in hepatopulmonary syndrome rats through ALK1‐Endoglin‐Smad1/5/9 signalling

Abstract

AbstractBackgroundBone morphogenetic protein 9 (BMP9) is a hepatokine that plays a pivotal role in the progression of liver diseases. Moreover, an increasing number of studies have shown that BMP9 is associated with hepatopulmonary syndrome (HPS), but its role in HPS is unclear. Here, we evaluated the influence of CBDL on BMP9 expression and investigated potential mechanisms of BMP9 signalling in HPS.MethodsWe profiled the circulating BMP9 levels in common bile duct ligation‐induced HPS rat model, and then investigated the effects and mechanisms of HPS rat serum on pulmonary vascular endothelial dysfunction in rat model, as well as in primarily cultured rat pulmonary microvascular endothelial cells.ResultsOur data revealed that circulating BMP9 levels were significantly increased in the HPS rats compared to control group. Besides, the elevated BMP9 in HPS rat serum was not only crucial for promoting endothelial cell proliferation and tube formation through the activin receptor‐like kinase1 (ALK1)‐Endoglin‐Smad1/5/9 pathway, but also important for accumulation of monocytes. Treatments with ALK1‐Fc or silencing ALK1 expression to inhibit the BMP9 signalling pathway effectively eliminated these effects. In agreement with these observations, increased circulating BMP9 was associated with an increase in lung vessel density and accumulation of pro‐angiogenic monocytes in the microvasculature in HPS rats.ConclusionsThis study provided evidence that elevated circulating BMP9, secreted from the liver, promote pulmonary angiogenesis in HPS rats via ALK1‐Endoglin‐Smad1/5/9 pathway. In addition, BMP9‐regulated pathways are also involved in accumulation of pro‐angiogenic monocytes in the pulmonary microvasculature in HPS rats.