title: Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells.
abstract: BACKGROUND
  Endothelial cells play a major role in angiogenesis, the process by which new blood vessels arise from a pre-existing vascular bed. VEGF-A (vascular endothelial growth factor-A) is a key regulator of angiogenesis during both development and in adults. HGF (hepatocyte growth factor) is a pleiotropic cytokine that may promote VEGF-A-driven angiogenesis, although the signalling mechanisms underlying this co-operation are not completely understood.
  
  
  RESULTS
  We analysed the effects of the combination of VEGF-A and HGF on the activation of VEGFR-2 (VEGF receptor-2) and c-met receptors, and on the stimulation of downstream signalling pathways in endothelial cells. We found that VEGFR-2 and c-met do not physically associate and do not transphosphorylate each other, suggesting that co-operation involves signalling events more distal from receptor activation. We demonstrate that the VEGF isoform VEGF-A(165) and HGF stimulate a similar set of MAPKs (mitogen-activated protein kinases), although the kinetics and strengths of the activation differ depending on the growth factor and pathway. An enhanced activation of the signalling was observed when endothelial cells were stimulated by the combination of VEGF-A(165) and HGF. Moreover, the combination of VEGF-A and HGF results in a statistically significant synergistic activation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 kinases. We demonstrated that VEGF-A(165) and HGF activate FAK (focal adhesion kinase) with different kinetics and stimulate the recruitment of phosphorylated FAK to different subsets of focal adhesions. VEGF-A(165) and HGF regulate distinct morphogenic aspects of the cytoskeletal remodelling that are associated with the preferential activation of Rho or Rac respectively, and induce structurally distinct vascular-like patterns in vitro in a Rho- or Rac-dependent manner.
  
  
  CONCLUSIONS
  Under angiogenic conditions, combining VEGF-A with HGF can promote neovascularization by enhancing intracellular signalling and allowing more finely regulated control of the signalling molecules involved in the regulation of the cytoskeleton and cellular migration and morphogenesis.
authors.affiliation: Institut des Vaisseaux et du Sang, INSERM U965, Université Paris 7, Hôpital Lariboisiére, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Sulpice
authors.forename: Shunli
authors.initials: S
authors.lastname: Ding
authors.forename: Béatrice
authors.initials: B
authors.lastname: Muscatelli-Groux
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bergé
authors.forename: Zhong Chao
authors.initials: ZC
authors.lastname: Han
authors.forename: Jean
authors.initials: J
authors.lastname: Plouet
authors.forename: Gérard
authors.initials: G
authors.lastname: Tobelem
authors.forename: Tatyana
authors.initials: T
authors.lastname: Merkulova-Rainon
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases