RT Journal Article
SR Electronic
T1 VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B–PDGFRβ signaling
JF Journal of Cell Science
JO J. Cell Sci.
FD The Company of Biologists Ltd
SP 3759
OP 3768
DO 10.1242/jcs.02483
VO 118
IS 16
A1 Kano, Mitsunobu R.
A1 Morishita, Yasuyuki
A1 Iwata, Caname
A1 Iwasaka, Shigeru
A1 Watabe, Tetsuro
A1 Ouchi, Yasuyoshi
A1 Miyazono, Kohei
A1 Miyazawa, Keiji
YR 2005
UL http://jcs.biologists.org/content/118/16/3759.abstract
AB 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.