TY - JOUR
T1 - VEGF function for upregulation of endogenous PlGF expression during FGF-2-mediated therapeutic angiogenesis
AU - Fujii, Takaaki
AU - Yonemitsu, Yoshikazu
AU - Onimaru, Mitsuho
AU - Inoue, Makoto
AU - Hasegawa, Mamoru
AU - Kuwano, Hiroyuki
AU - Sueishi, Katsuo
N1 - Funding Information:
This work was supported in part by Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (Y.Y. and K.S.), and by a Grant of Promotion of Basic Science Research in Medical Frontiers of the Organization for Pharmaceutical Safety and Research (Y.Y., M.H., and K.S., project No. MF-21).
PY - 2008/9
Y1 - 2008/9
N2 - 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-κB-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.
AB - 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-κB-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.
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U2 - 10.1016/j.atherosclerosis.2007.12.012
DO - 10.1016/j.atherosclerosis.2007.12.012
M3 - Article
C2 - 18258238
AN - SCOPUS:49749102835
SN - 0021-9150
VL - 200
SP - 51
EP - 57
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -