Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways
Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways
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DOI：
10.1152/ajpheart.00113.2006
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发表时间：
2006-12-01
影响因子：
4.8
通讯作者：
Kim, Young-Myeong
中科院分区：
文献类型：
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作者：
Lee, Seon-Jin;Namkoong, Seung;Kim, Young-Myeong
Fractalkine(FKN)参与了血管生成和血管炎症的调控，但其机制尚不清楚。我们研究了FKN调控血管生成的分子机制。我们发现，重组FKN在体外增加了人脐静脉内皮细胞的增殖、迁移和管状形成，并刺激了体内血管生成。FKN诱导的血管生成伴随着ERK、Akt和内皮型一氧化氮合酶(ENOS)的磷酸化，以及NO产生的增加。这些生化事件和血管生成完全被G蛋白偶联受体抑制剂百日咳毒素所抑制。Raf-1、MEK、磷脂酰肌醇3-激酶(PI3K)、内皮型一氧化氮合酶(ENOS)以及显性-阴性ERK和Akt的抑制剂均显著抑制FKN的血管生成活性。然而，Raf-1和MEK的抑制剂或显性阴性的ERK突变体可以阻断FKN诱导的ERK，但不能阻断Akt和eNOS的磷酸化。PI3K抑制剂和Akt显性负性突变体抑制Akt和eNOS的磷酸化，并抑制NO的产生。我们的结果表明，FKN通过G蛋白偶联受体CX3CR1激活Raf-1/MEK/ERK和PI3K/Akt/eNOS/NO信号通路来刺激血管生成，表明FKN的全面血管生成活性需要两条途径。本研究提示FKN可能在炎性血管生成的病理生理过程中发挥重要作用。
Fractalkine (FKN) has been implicated in modulation of angiogenesis and vascular inflammation, but the underlying mechanism has not been elucidated. We have investigated the molecular mechanism by which FKN regulates angiogenesis. We found that recombinant FKN increases in vitro proliferation, migration, and tube formation of human umbilical vein endothelial cells and stimulates in vivo angiogenesis. FKN-induced angiogenesis was accompanied by phosphorylation of ERK, Akt, and endothelial nitric oxide (NO) synthase (eNOS), as well as an increase in NO production. These biochemical events and angiogenesis were completely inhibited by the G protein-coupled receptor inhibitor pertussis toxin. Inhibitors of Raf-1, MEK, phosphatidylinositol 3-kinase (PI3K), and eNOS or transfection with dominant-negative forms of ERK and Akt significantly suppressed the angiogenic activity of FKN. However, inhibitors of Raf-1 and MEK or a dominant-negative ERK mutant blocked FKN-induced ERK, but not Akt and eNOS, phosphorylation. The PI3K inhibitor and a dominant-negative mutant of Akt suppressed Akt and eNOS phosphorylation and NO production. Our results demonstrated that FKN stimulated angiogenesis by activating the Raf-1/MEK/ERK and PI3K/Akt/eNOS/NO signal pathways via the G protein-coupled receptor CX3CR1, indicating that two pathways are required for full angiogenic activity of FKN. This study suggests that FKN may play an important role in the pathophysiological process of inflammatory angiogenesis.