Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells
Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells
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DOI：
10.1042/bc20080221
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发表时间：
2009-09-01
影响因子：
2.7
通讯作者：
Merkulova-Rainon, Tatyana
中科院分区：
文献类型：
--
作者：
Sulpice, Eric;Ding, Shunli;Merkulova-Rainon, Tatyana
背景资料。内皮细胞在血管生成中起着重要作用，血管生成是指新血管从原有的血管床中生成的过程。VEGF-A（血管内皮生长因子- a）是发育和成人血管生成的关键调节因子。HGF（肝细胞生长因子）是一种多用途细胞因子，可能促进vegf - a驱动的血管生成，尽管这种合作的信号机制尚不完全清楚。我们分析了VEGF- a和HGF结合对VEGFR-2 （VEGF受体-2）和c-met受体激活的影响，以及对内皮细胞下游信号通路的刺激。我们发现VEGFR-2和c-met在物理上不相互关联，也不相互转磷酸化，这表明合作涉及远高于受体激活的信号事件。我们证明了VEGF异构体VEGF- a（165）和HGF刺激类似的mapk（丝裂原活化蛋白激酶），尽管激活的动力学和强度取决于生长因子和途径。当VEGF-A（165）和HGF联合刺激内皮细胞时，观察到信号的激活增强。此外，VEGF-A和HGF的结合导致ERK1/2（细胞外信号调节激酶1/2）和p38激酶的协同活化具有统计学意义。我们证明了VEGF-A（165）和HGF以不同的动力学激活FAK（局灶黏附激酶），并刺激磷酸化的FAK募集到不同的局灶黏附亚群。VEGF-A（165）和HGF分别调控与Rho或Rac优先激活相关的细胞骨架重塑的不同形态发生方面，并在体外以Rho或Rac依赖的方式诱导结构上不同的血管样模式。在血管生成条件下，VEGF-A与HGF结合可通过增强细胞内信号传导促进新生血管形成，并允许对参与细胞骨架和细胞迁移及形态发生调节的信号分子进行更精细的调控。
Background information. Endothelial cells play a major role in angiogenesis, the process by which new blood vessels arise from a pre-existing vascular bed. VEGF-A (vascular endothelial growth factor-A) is a key regulator of angiogenesis during both development and in adults. HGF (hepatocyte growth factor) is a pleiotropic cytokine that may promote VEGF-A-driven angiogenesis, although the signalling mechanisms underlying this co-operation are not completely understood.Results. We analysed the effects of the combination of VEGF-A and HGF on the activation of VEGFR-2 (VEGF receptor-2) and c-met receptors, and on the stimulation of downstream signalling pathways in endothelial cells. We found that VEGFR-2 and c-met do not physically associate and do not transphosphorylate each other, suggesting that co-operation involves signalling events more distal from receptor activation. We demonstrate that the VEGF isoform VEGF-A(165) and HGF stimulate a similar set of MAPKs (mitogen-activated protein kinases), although the kinetics and strengths of the activation differ depending on the growth factor and pathway. An enhanced activation of the signalling was observed when endothelial cells were stimulated by the combination of VEGF-A(165) and HGF. Moreover, the combination of VEGF-A and HGF results in a statistically significant synergistic activation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 kinases. We demonstrated that VEGF-A(165) and HGF activate FAK (focal adhesion kinase) with different kinetics and stimulate the recruitment of phosphorylated FAK to different subsets of focal adhesions. VEGF-A(165) and HGF regulate distinct morphogenic aspects of the cytoskeletal remodelling that are associated with the preferential activation of Rho or Rac respectively, and induce structurally distinct vascular-like patterns in vitro in a Rho- or Rac-dependent manner.Conclusions. Under angiogenic conditions, combining VEGF-A with HGF can promote neovascularization by enhancing intracellular signalling and allowing more finely regulated control of the signalling molecules involved in the regulation of the cytoskeleton and cellular migration and morphogenesis.