VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling

J Cell Sci. 2005 Aug 15;118(Pt 16):3759-68. doi: 10.1242/jcs.02483.


Combined stimulation with VEGF-A, FGF-2, or PDGF-BB has emerged as a potent strategy for therapeutic angiogenesis, although the mechanisms underlying the synergism of these factors are not well understood. In the present study, we investigated the mechanism of synergism between VEGF-A and FGF-2 by using Matrigel plug assay in vivo and embryonic stem cell (ESC)-derived VEGF receptor 2 (VEGFR2)-positive cells in vitro. Experiments in vitro revealed that, in addition to having direct mitogenic effects, these molecules enhance intercellular PDGF-B signaling in a cell-type specific manner: VEGF-A enhances endothelial PDGF-B expression, whereas FGF-2 enhances mural PDGF receptor beta (PDGFRbeta) expression. Co-stimulation with VEGF-A and FGF-2 caused significant mural cell recruitment in vitro and formation of functional neovasculature in vivo, compared with single-agent stimulation. These effects were abrogated not only by anti-PDGFRbeta neutralizing antibody, but also by exogenous PDGF-BB, which could overwhelm the endogenous PDGF-BB distribution. These findings indicated the importance of preservation of the periendothelial PDGF-BB gradient. Thus, we demonstrated that the directional enhancement of endogenous PDGF-B-PDGFRbeta signaling is indispensable for the synergistic effect of VEGF-A and FGF-2 on neoangiogenesis in adults. The findings provide insights into the mechanisms underlying the effects of co-stimulation by growth factors, which could lead to rational design of therapeutic angiogenic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Blood Vessels / cytology
  • Blood Vessels / drug effects
  • Blood Vessels / metabolism*
  • Cell Communication / drug effects
  • Cell Communication / physiology
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Line
  • Drug Synergism
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Fibroblast Growth Factor 2 / metabolism*
  • Fibroblast Growth Factor 2 / pharmacology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology*
  • Proto-Oncogene Proteins c-sis / drug effects
  • Proto-Oncogene Proteins c-sis / metabolism*
  • Proto-Oncogene Proteins c-sis / pharmacology
  • Receptor, Platelet-Derived Growth Factor beta / drug effects
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology


  • Antibodies
  • Proto-Oncogene Proteins c-sis
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Fibroblast Growth Factor 2
  • Receptor, Platelet-Derived Growth Factor beta