VEGF function for upregulation of endogenous PlGF expression during FGF-2-mediated therapeutic angiogenesis
VEGF function for upregulation of endogenous PlGF expression during FGF-2-mediated therapeutic angiogenesis
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DOI：
10.1016/j.atherosclerosis.2007.12.012
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发表时间：
2008-09-01
期刊：
影响因子：
5.3
通讯作者：
Sueishi, Katsuo
中科院分区：
文献类型：
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作者：
Fujii, Takaaki;Yonemitsu, Yoshikazu;Sueishi, Katsuo
血管内皮生长因子（VEGF）是一种主要的正性血管生成因子。使用小鼠后肢缺血模型，我们先前表明，成纤维细胞生长因子-2（FGF-2）增强内源性VEGF的表达，这高度有助于FGF-2基因转移的治疗效果。最近，胎盘生长因子（PlGF）已被证明在血管生成中发挥重要作用。然而，内源性PlGF在FGF-2介导的血管生成过程中的分子机制尚未阐明。严重的后肢缺血刺激PlGF的表达，更强烈地增强了FGF-2基因转移，和PlGF活性的封锁减少了FGF-2介导的血管生成的血流恢复。培养的内皮细胞中的PlGF表达通过VEGF刺激显著增强，但不通过FGF-2。内源性PlGF表达的上调通过抑制体内内源性VEGF活性而显著降低。随后的信号抑制实验表明，PKC，MEK，和可能的NF-κ B相关的途径是必不可少的刺激PlGF表达与VEGF，而p70 S6 K是VEGF表达的调节剂。这些结果表明，FGF-2介导的PlGF表达的增强依赖于VEGF功能，并且FGF-2/VEGF轴通过PlGF间接地以及直接地参与FGF-2介导的血管生成。(C)2007爱思唯尔爱尔兰有限公司保留所有权利。
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-kappa B-related pathways were essential in stimulating PlGF expression with VEGF, while p70S6K is the regulator for VEGF expression. These results indicate that the FGF2-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. (C) 2007 Elsevier Ireland Ltd. All rights reserved.