New prospects in the roles of the C-terminal domains of VEGF-A and their cooperation for ligand binding, cellular signaling and vessels formation

作者：Delcombel Romain^*; Janssen Lauriane; Vassy Roger; Gammons Melissa; Haddad Oualid; Richard Benjamin; Letourneur Didier; Bates David; Hendricks Celine; Waltenberger Johannes; Starzec Anna; Sounni Nor Eddine; Noel Agnes; Deroanne Christophe; Lambert Charles; Colige Alain

来源：Angiogenesis, 2013, 16(2): 353-371.

DOI：10.1007/s10456-012-9320-y

• VEGF isoforms
• Angiogenesis
• Neuropilin-1
• VEGF receptor
• Alternative splicing

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 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 (VEGF(111)a, VEGF(111)b, VEGF(121)a, VEGF(121)b, VEGF(155)a, VEGF(155)b, VEGF(165)a, VEGF(165)b) 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 VEGF(165)b has inhibitory effects in vitro, as previously reported, but that the shortest VEGF variant possessing also the 6 amino acids encoded by exon 8b (VEGF(111)b) is remarkably proangiogenic, demonstrating the critical importance of domain interactions for defining the VEGF properties. The number, size and localization of newly formed blood vessels in a model of tumour angiogenesis strongly depend also on the C-terminal domain composition, suggesting that association of several VEGF isoforms may be more efficient for treating ischemic diseases than the use of any single variant.

• 出版日期2013-4