title: BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis.
abstract: Genetic studies in mice and humans have shown that the transforming growth factor-beta (TGF-beta) type-I receptor activin receptor-like kinase 1 (ALK1) and its co-receptor endoglin play an important role in vascular development and angiogenesis. Here, we demonstrate that ALK1 is a signalling receptor for bone morphogenetic protein-9 (BMP-9) in endothelial cells (ECs). BMP-9 bound with high affinity to ALK1 and endoglin, and weakly to the type-I receptor ALK2 and to the BMP type-II receptor (BMPR-II) and activin type-II receptor (ActR-II) in transfected COS cells. Binding of BMP-9 to ALK2 was greatly facilitated when BMPR-II or ActR-II were co-expressed. Whereas BMP-9 predominantly bound to ALK1 and BMPR-II in ECs, it bound to ALK2 and BMPR-II in myoblasts. In addition, we observed binding of BMP-9 to ALK1 and endoglin in glioblastoma cells. BMP-9 activated Smad1 and/or Smad5, and induced ID1 protein and endoglin mRNA expression in ECs. Furthermore, BMP-9 was found to inhibit basic fibroblast growth factor (bFGF)-stimulated proliferation and migration of bovine aortic ECs (BAECs) and to block vascular endothelial growth factor (VEGF)-induced angiogenesis. Taken together, these results suggest that BMP-9 is a physiological ALK1 ligand that plays an important role in the regulation of angiogenesis.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: Scharpfenecker
authors.forename: Maarten
authors.initials: M
authors.lastname: van Dinther
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Rutger L
authors.initials: RL
authors.lastname: van Bezooijen
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhao
authors.forename: Laurie
authors.initials: L
authors.lastname: Pukac
authors.forename: Clemens W G M
authors.initials: CW
authors.lastname: Löwik
authors.forename: P
authors.initials: P
authors.lastname: ten Dijke
mesh_terms: D030201:Activin Receptors, Type I / Q000502:physiology; D030301:Activin Receptors, Type II / Q000502:physiology*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D019556:COS Cells; D002417:Cattle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D019485:Bone Morphogenetic Proteins; C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D007041:Hypoxanthine Phosphoribosyltransferase; C425423:ACVR1 protein, human; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II