Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells

Authors

  • Eric Sulpice,

    1. Institut des Vaisseaux et du Sang, INSERM U965, Université Paris 7, Hôpital Lariboisiére, 8 rue Guy Patin, 75475 Paris, Cedex 10, France
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Shunli Ding,

    1. Institut des Vaisseaux et du Sang, INSERM U965, Université Paris 7, Hôpital Lariboisiére, 8 rue Guy Patin, 75475 Paris, Cedex 10, France
    Search for more papers by this author
    • These authors contributed equally to this work.

    • Wisconsin University Medical School, Madison, WI 53706, U.S.A.

  • Béatrice Muscatelli-Groux,

    1. Institut des Vaisseaux et du Sang, INSERM U965, Université Paris 7, Hôpital Lariboisiére, 8 rue Guy Patin, 75475 Paris, Cedex 10, France
    Search for more papers by this author
  • Mathieu Bergé,

    1. Institut des Vaisseaux et du Sang, INSERM U965, Université Paris 7, Hôpital Lariboisiére, 8 rue Guy Patin, 75475 Paris, Cedex 10, France
    Search for more papers by this author
  • Zhong Chao Han,

    1. State Key Laboratory of Experimental Hematology, Institute of Hematology, 288 Nanjing Road, 300020 Tianjin, People's Republic of China
    Search for more papers by this author
  • Jean Plouet,

    1. Institut des Vaisseaux et du Sang, INSERM U965, Université Paris 7, Hôpital Lariboisiére, 8 rue Guy Patin, 75475 Paris, Cedex 10, France
    Search for more papers by this author
  • Gérard Tobelem,

    1. Institut des Vaisseaux et du Sang, INSERM U965, Université Paris 7, Hôpital Lariboisiére, 8 rue Guy Patin, 75475 Paris, Cedex 10, France
    Search for more papers by this author
  • Tatyana Merkulova-Rainon

    Corresponding author
    1. Institut des Vaisseaux et du Sang, INSERM U965, Université Paris 7, Hôpital Lariboisiére, 8 rue Guy Patin, 75475 Paris, Cedex 10, France
    Search for more papers by this author

(email tatiana.merkoulova@inserm.fr).

Abstract

Background information. 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-A165 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-A165 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-A165 and HGF activate FAK (focal adhesion kinase) with different kinetics and stimulate the recruitment of phosphorylated FAK to different subsets of focal adhesions. VEGF-A165 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.

Ancillary