VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B—PDGFRβ signaling.
In: Journal of Cell Science, Jg. 118 (2005-08-15), Heft 16, S. 3759-3768
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Zugriff:
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. Costimulation 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 costimulation by growth factors, which could lead to rational design of therapeutic angiogenic strategies. [ABSTRACT FROM AUTHOR]
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VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B—PDGFRβ signaling.
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Autor/in / Beteiligte Person: | Kano, Mitsunobu R. ; Morishita, Yasuyuki ; Iwata, Caname ; Iwasaka, Shigeru ; Watabe, Tetsuro ; Ouchi, Yasuyoshi ; Miyazono, Kohei ; Miyazawa, Keiji |
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Zeitschrift: | Journal of Cell Science, Jg. 118 (2005-08-15), Heft 16, S. 3759-3768 |
Veröffentlichung: | 2005 |
Medientyp: | academicJournal |
ISSN: | 0021-9533 (print) |
DOI: | 10.1242/jcs.02483 |
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