VEGF function for upregulation of endogenous PlGF expression during FGF-2-mediated therapeutic angiogenesis.
Vascular endothelial growth factor (VEGF) is a major positive angiogenic factor. Using a murine hindlimb ischemia model, we previously showed that fibroblast growth factor-2 (FGF-2) enhances the expression of endogenous VEGF which highly contribute to the therapeutic effect of FGF-2 gene transfer. Recently, placental growth factor (PlGF) has been shown to play an important role in angiogenesis. However, the molecular mechanism of endogenous PlGF during FGF-2-mediated angiogenesis has not been elucidated. Severe hindlimb ischemia stimulated PlGF expression that was more strongly enhanced by FGF-2 gene transfer, and a blockade of PlGF activity diminished the recovery of blood flow by FGF-2-mediated angiogenesis. The PlGF expression in cultured endothelial cells was significantly enhanced by VEGF stimulation, but not by FGF-2. The upregulation of endogenous PlGF expression was significantly decreased by the inhibition of endogenous VEGF activity in vivo. Subsequent signal inhibition experiments revealed that the PKC, MEK, and possibly NF-kappaB-related pathways were essential in stimulating PlGF expression with VEGF, while p70S6K is the regulator for VEGF expression. These results indicate that the FGF-2-mediated enhancement of PlGF expression was dependent on VEGF function, and the FGF-2/VEGF axis participates in FGF-2-mediated angiogenesis indirectly via PlGF as well as directly.
Fujii
Takaaki
T
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. f-takaaki@cvc.pref.gunma.jp
Yonemitsu
Yoshikazu
Y
Onimaru
Mitsuho
M
Inoue
Makoto
M
Hasegawa
Mamoru
M
Kuwano
Hiroyuki
H
Sueishi
Katsuo
K
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply / Q000293:injuries; D006801:Humans; D007511:Ischemia; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; D000072483:Placenta Growth Factor