Résumé
Bone morphogenetic protein 9 (BMP9) and BMP10 are thetwo high-affinity ligands for the endothelial receptor activinreceptor-like kinase 1 (ALK1) and are key regulators of vascularremodeling. They are both present in the blood, buttheir respective biological activities are still a matter ofdebate. The aim of the present work was to characterize theircirculating forms to better understand how their activitiesare regulated in vivo. First, by cotransfecting BMP9 andBMP10, we found that both can form a disulfide-bonded heterodimerin vitro and that this heterodimer is functional onendothelial cells via ALK1. Next, we developed an ELISA thatcould specifically recognize the BMP9–BMP10 heterodimerand which indicated its presence in both human and mouseplasma. In addition to using available Bmp9-KO mice,we generated a conditional Bmp10-KO mouse strain. Theplasma from Bmp10-KO mice, similarly to that of Bmp9-KOmice, completely lacked the ability to activate ALK1-transfected3T3 cells or phospho-Smad1–5 on endothelial cells,indicating that the circulating BMP activity is mostly due tothe BMP9–BMP10 heterodimeric form. This result was confirmedin human plasma that had undergone affinity chromatographyto remove BMP9 homodimer. Finally, we provideevidence that hepatic stellate cells in the liver could be thesource of the BMP9–BMP10 heterodimer. Together, ourfindings demonstrate that BMP9 and BMP10 can heterodimerizeand that this heterodimer is responsible for mostof the biological BMP activity found in plasma.