VEGF function for upregulation of endogenous PlGF expression during FGF-2-mediated therapeutic angiogenesis

Takaaki Fujii, Yoshikazu Yonemitsu, Mitsuho Onimaru, Makoto Inoue, Mamoru Hasegawa, Hiroyuki Kuwano, Katsuo Sueishi

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)51-57
Number of pages7
Issue number1
Publication statusPublished - Sept 2008

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine


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