Vascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity

J Cell Physiol. 1998 Dec;177(3):439-52. doi: 10.1002/(SICI)1097-4652(199812)177:3<439::AID-JCP7>3.0.CO;2-2.


Vascular endothelial growth factor-C (VEGF-C) is a recently characterized member of the VEGF family of angiogenic polypeptides. We demonstrate here that VEGF-C is angiogenic in vitro when added to bovine aortic or lymphatic endothelial (BAE and BLE) cells but has little or no effect on bovine microvascular endothelial (BME) cells. As reported previously for VEGF, VEGF-C and basic fibroblast growth factor (bFGF) induced a synergistic in vitro angiogenic response in all three cells lines. Unexpectedly, VEGF and VEGF-C also synergized in the in vitro angiogenic response when assessed on BAE cells. Characterization of VEGF receptor (VEGFR) expression revealed that BME, BAE, and BLE cell lines express VEGFR-1 and -2, whereas of the three cell lines assessed, only BAE cells express VEGFR-3. We also demonstrate that VEGF-C increases plasminogen activator (PA) activity in the three bovine endothelial cell lines and that this is accompanied by a concomitant increase in PA inhibitor-1. Addition of alpha2-antiplasmin to BME cells co-treated with bFGF and VEGF-C partially inhibited collagen gel invasion. These results demonstrate, first, that by acting in concert with bFGF or VEGF, VEGF-C has a potent synergistic effect on the induction of angiogenesis in vitro and, second, that like VEGF and bFGF, VEGF-C is capable of altering endothelial cell extracellular proteolytic activity. These observations also highlight the notion of context, i.e., that the activity of an angiogenesis-regulating cytokine depends on the presence and concentration of other cytokines in the pericellular environment of the responding endothelial cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cattle
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • Drug Synergism
  • Endothelial Growth Factors / pharmacology*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism*
  • Fibroblast Growth Factor 2 / pharmacology*
  • Lymphokines / pharmacology*
  • Molecular Sequence Data
  • Neovascularization, Physiologic* / physiology
  • Peptide Hydrolases / metabolism*
  • Plasminogen Activator Inhibitor 1 / biosynthesis
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Urokinase-Type Plasminogen Activator / biosynthesis
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3
  • Vascular Endothelial Growth Factors


  • DNA, Complementary
  • Endothelial Growth Factors
  • Lymphokines
  • Plasminogen Activator Inhibitor 1
  • Receptors, Cell Surface
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2
  • Receptor Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-3
  • Peptide Hydrolases
  • Urokinase-Type Plasminogen Activator

Associated data

  • GENBANK/AF030379