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First published online 20 February 2007
doi: 10.1242/jcs.002949

Journal of Cell Science 120, 964-972 (2007)
Published by The Company of Biologists 2007
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Research Article

BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis

Marion Scharpfenecker1, M. van Dinther1, Zhen Liu1, R.L. van Bezooijen1,2, Qinghai Zhao3,4, Laurie Pukac3,4, Clemens W. G. M. Löwik2 and P. ten Dijke1,*

1 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
2 Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
3 Human Genome Sciences, Inc., Rockville, MD 20850, USA
4 CoGenesys, Rockville, MD 20850, USA

* Author for correspondence (e-mail: p.ten_dijke{at}lumc.nl)

Accepted 21 December 2006

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.

Key words: ALK1, Angiogenesis, bFGF, BMP, Endoglin, Signalling, Smad, VEGF




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