New prospects in the roles of the C-terminal domains of VEGF-A and their cooperation for ligand binding, cellular signal
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ORIGINAL PAPER
New prospects in the roles of the C-terminal domains of VEGF-A and their cooperation for ligand binding, cellular signaling and vessels formation Romain Delcombel • Lauriane Janssen • Roger Vassy • Melissa Gammons • Oualid Haddad • Benjamin Richard • Didier Letourneur • David Bates • Ce´line Hendricks • Johannes Waltenberger • Anna Starzec • Nor Eddine Sounni Agne`s Noe¨l • Christophe Deroanne • Charles Lambert • Alain Colige
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Received: 2 July 2012 / Accepted: 26 October 2012 / Published online: 20 December 2012 Ó Springer Science+Business Media Dordrecht 2012
Abstract VEGF-A is a crucial growth factor for blood vessel homeostasis and pathological angiogenesis. Due to alternative splicing of its pre-mRNA, VEGF-A is produced under several isoforms characterized by the combination of their C-terminal domains, which determines their respective structure, availability and affinity for co-receptors. As controversies still exist about the specific roles of these exon-encoded domains, we systematically compared the Electronic supplementary material The online version of this article (doi:10.1007/s10456-012-9320-y) contains supplementary material, which is available to authorized users. R. Delcombel (&) L. Janssen C. Hendricks C. Deroanne C. Lambert A. Colige Laboratory of Connective Tissues Biology, GIGA-R, University of Lie`ge, Avenue de l’Hoˆpital 3, 4000 Lie`ge, Belgium e-mail: [email protected] R. Vassy A. Starzec EA4222, Universite´ Paris 13, Sorbonne Paris Cite´, 74 rue Marcel Cachin, 93000 Bobigny, France M. Gammons D. Bates Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Preclinical Veterinary Sciences Building, Southwell Street, Bristol BS2 8EJ, UK O. Haddad B. Richard D. Letourneur Inserm U698, Universite´ Paris 13, Sorbonne Paris Cite´, 74 rue Marcel Cachin, 93000 Bobigny, France J. Waltenberger Department of Cardiology and Angiology, University Hospital of Mu¨nster, Albert-Schweitzer-Campus 1, A1, 48149 Mu¨nster, Germany N. E. Sounni A. Noe¨l Laboratory of Tumour and Development Biology, GIGA-R, University of Lie`ge, Avenue de l’Hoˆpital 3, 4000 Lie`ge, Belgium
properties of eight natural and artificial variants containing the domains encoded by exons 1–4 and various combinations of the domains encoded by exons 5, 7 and 8a or 8b. All the variants (VEGF111a, VEGF111b, VEGF121a, VEGF121b, VEGF155a, VEGF155b, VEGF165a, VEGF165b) have a similar affinity for VEGF-R2, as determined by Surface plasmon resonance analyses. They strongly differ however in terms of binding to neuropilin-1 and heparin/ heparan sulfate proteoglycans. Data indicate that the 6 amino acids encoded by exon 8a must be present and cooperate with those of exons 5 or 7 for efficient binding, which was confirmed in cell culture models. We further showed that VEGF165b has inhibitory effects in vitro, as previously reported, but that the shortest VEGF variant possessing also the 6 amino acids encoded by exon 8b (VEGF111b) is remarkably proangiogenic, demonstr
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