In search of “hepatic factor:” Lack of evidence for ALK1 ligands BMP9 and BMP10

Abstract

In children with single ventricle physiology, the Glenn procedure is performed to redirect venous return from the superior vena cava directly to the pulmonary arteries and route venous return from the inferior vena cava exclusively to the systemic circulation. Although this surgery successfully palliates the hemodynamic stress experienced by the single ventricle, patients frequently develop pulmonary arteriovenous malformations (PAVMs). Interestingly, PAVMs may regress upon rerouting of hepatic venous effluent to the pulmonary vasculature, suggesting the presence of a circulating "hepatic factor" that is required to prevent PAVMs. Here, we test the hypothesis that hepatic factor is bone morphogenetic protein 9 (BMP9) and/or BMP10. These circulating ligands are produced by the liver and activate endothelial endoglin (ENG)/ALK1 signaling, and mutations in ENG and ALK1 cause hereditary hemorrhagic telangiectasia, a genetic disease associated with AVM development. However, we found no within-subject variation in BMP9, BMP10, or BMP9/10 plasma concentrations when sampled from five cardiovascular sites, failing to support the idea that the Glenn would limit access of these ligands to the lung vasculature. Unexpectedly, however, we found a significant decrease in all three ligand concentrations in Glenn cases versus controls. Our findings suggest that BMP9/BMP10/ENG/ALK1 signaling may be decreased in the Glenn vasculature but fail to implicate these ligands as hepatic factor.