Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation.
Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation.
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DOI：
10.1074/jbc.m108069200
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发表时间：
2001-12-28
影响因子：
4.8
通讯作者：
Pumiglia, K
中科院分区：
文献类型：
--
作者：
Meadows, KN;Bryant, P;Pumiglia, K
我们研究了RAS在血管内皮生长因子(VEGF)介导的信号转导中的作用以及对原代内皮细胞血管生成变化的促进作用。我们发现，在三维培养中，血管内皮生长因子能有效地诱导RAS的激活，并且这一步骤对于血管生成相关的几种细胞变化的刺激是必不可少的，包括增殖、迁移和分支形态的形成。抑制RAS信号通路可引起肌动蛋白结构的细微变化，但对磷脂酰肌醇3-激酶(PI3K)或p38信号通路无影响。相反，ERK的激活在很大程度上依赖于RAS。尽管抑制ERK活性可完全抑制细胞增殖并部分阻断体外分化，但ERK和PI3K活性均不是血管内皮生长因子诱导迁移所必需的。这些数据首次直接证明抑制RAS信号转导是抗血管生成的。有趣的是，血管内皮生长因子信号转导通路在RAS的上游和下游都有分支，不同的HAS依赖信号控制内皮细胞的增殖和迁移，而内皮细胞增殖和迁移是血管生成反应的重要组成部分。
We investigated the role of Ras in vascular endothelial growth factor (VEGF)-mediated signal transduction and the promotion of angiogenic changes primary endothelial cells. We find that VEGF potently induces Ras activation and that this step is essential for the stimulation by VEGF of several cellular changes associated with angiogenesis, including proliferation, migration, and branching morphogenesis in three-dimensional culture. Inhibition of Ras signaling induced subtle changes in the actin architecture but had no effect on the phosphatidylinositol 3-kinase (PI3K) or p38 signaling pathways. In contrast, activation of ERK was largely dependent on Ras. Although inhibiting ERK activity completely suppressed cell proliferation and partially blocked in vitro differentiation, neither ERK nor PI3K activity was required for VEGF-induced migration. These data provide the first direct demonstration that inhibition of Ras signal transduction is anti-angiogenic. Interestingly, VEGF signal transduction bifurcates both upstream and downstream of Ras, with different Has-dependent signals controlling endothelial cell proliferation and migration, essential components of the angiogenic response.