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

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• 作者：Romain Delcombel (1)
  Lauriane Janssen (1)
  Roger Vassy (2)
  Melissa Gammons (3)
  Oualid Haddad (4)
  Benjamin Richard (4)
  Didier Letourneur (4)
  David Bates (3)
  Céline Hendricks (1)
  Johannes Waltenberger (5)
  Anna Starzec (2)
  Nor Eddine Sounni (6)
  Agnès No?l (6)
  Christophe Deroanne (1)
  Charles Lambert (1)
  Alain Colige (1)
  
• 关键词：VEGF isoforms ; Angiogenesis ; Neuropilin ; 1 ; VEGF receptor ; Alternative splicing
• 刊名：Angiogenesis
• 出版年：2013
• 出版时间：April 2013
• 年：2013
• 卷：16
• 期：2
• 页码：353-371
• 全文大小：2202KB
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• 作者单位：Romain Delcombel (1)
  Lauriane Janssen (1)
  Roger Vassy (2)
  Melissa Gammons (3)
  Oualid Haddad (4)
  Benjamin Richard (4)
  Didier Letourneur (4)
  David Bates (3)
  Céline Hendricks (1)
  Johannes Waltenberger (5)
  Anna Starzec (2)
  Nor Eddine Sounni (6)
  Agnès No?l (6)
  Christophe Deroanne (1)
  Charles Lambert (1)
  Alain Colige (1)
  
  1. Laboratory of Connective Tissues Biology, GIGA-R, University of Liège, Avenue de l’H?pital 3, 4000, Liège, Belgium
  2. EA4222, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93000, Bobigny, France
  3. Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Preclinical Veterinary Sciences Building, Southwell Street, Bristol, BS2 8EJ, UK
  4. Inserm U698, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93000, Bobigny, France
  5. Department of Cardiology and Angiology, University Hospital of Münster, Albert-Schweitzer-Campus 1, A1, 48149, Münster, Germany
  6. Laboratory of Tumour and Development Biology, GIGA-R, University of Liège, Avenue de l’H?pital 3, 4000, Liège, Belgium
  
• ISSN：1573-7209

文摘

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- 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, 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.