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

Research output: Contribution to journalArticle

195 Citations (Scopus)

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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Platelet-Derived Growth Factor Receptors
Fibroblast Growth Factor 2
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor
Embryonic Stem Cells
Neutralizing Antibodies
Intercellular Signaling Peptides and Proteins
platelet-derived growth factor BB
Therapeutics
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

  • Cell Biology

Cite this

VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRβ signaling. / Kano, Mitsunobu; Morishita, Yasuyuki; Iwata, Caname; Iwasaka, Shigeru; Watabe, Tetsuro; Ouchi, Yasuyoshi; Miyazono, Kohei; Miyazawa, Keiji.

In: Journal of Cell Science, Vol. 118, No. 16, 15.08.2005, p. 3759-3768.

Research output: Contribution to journalArticle

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, vol. 118, no. 16, pp. 3759-3768. https://doi.org/10.1242/jcs.02483
Kano, Mitsunobu ; Morishita, Yasuyuki ; Iwata, Caname ; Iwasaka, Shigeru ; Watabe, Tetsuro ; Ouchi, Yasuyoshi ; Miyazono, Kohei ; Miyazawa, Keiji. / VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRβ signaling. In: Journal of Cell Science. 2005 ; Vol. 118, No. 16. pp. 3759-3768.
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