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

Mitsunobu Kano, Yasuyuki Morishita, Caname Iwata, Shigeru Iwasaka, Tetsuro Watabe, Yasuyoshi Ouchi, Kohei Miyazono, Keiji Miyazawa

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Abstract

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 β (PDGFRβ) 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-PDGFRβ 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-PDGFRβ 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.

Original languageEnglish
Pages (from-to)3759-3768
Number of pages10
JournalJournal of Cell Science
Volume118
Issue number16
DOIs
Publication statusPublished - Aug 15 2005
Externally publishedYes

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Keywords

  • Angiogenesis
  • Endothelial cell
  • FGF
  • Mural cell
  • PDGF
  • VEGF

ASJC Scopus subject areas

  • Cell Biology

Cite this

Kano, M., Morishita, Y., Iwata, C., Iwasaka, S., Watabe, T., Ouchi, Y., Miyazono, K., & Miyazawa, K. (2005). VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRβ signaling. Journal of Cell Science, 118(16), 3759-3768. https://doi.org/10.1242/jcs.02483