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

Author:

Scharpfenecker Marion1,van Dinther M.1,Liu Zhen1,van Bezooijen R.L.12,Zhao Qinghai34,Pukac Laurie34,Löwik Clemens W. G. M.2,ten Dijke P.1

Affiliation:

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

Abstract

Genetic studies in mice and humans have shown that the transforming growth factor-β (TGF-β) 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.

Publisher

The Company of Biologists

Subject

Cell Biology

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