CCL2 regulates angiogenesis via activation of Ets-1 transcription factor
CCL2 regulates angiogenesis via activation of Ets-1 transcription factor
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DOI：
10.4049/jimmunol.177.4.2651
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发表时间：
2006-08-15
影响因子：
4.4
通讯作者：
Andjelkovic, Anuska V.
中科院分区：
文献类型：
--
作者：
Stamatovic, Svetlana M.;Keep, Richard F.;Andjelkovic, Anuska V.
尽管最近的研究表明CC趋化因子CCL2可能直接影响血管生成，但参与这种调节的信号传导事件仍有待确定。本研究调查了 CCL2 诱导的血管生成中涉及的潜在信号机制。我们的体外和体内（血管生成的血管瘤模型）实验证实了早期的发现，即CCL2可以直接诱导血管生成。通过基因阵列分析，发现 CCL2 可诱导脑内皮细胞中多种血管生成因子的表达。其中最突出的是 Ets-1 转录因子的上调。 CCL2 诱导 Ets-1 mRNA 和蛋白质表达以及 Ets-1 DNA 结合活性显着增加。重要的是，Ets-1反义寡核苷酸在体外显着消除CCL2诱导的血管生成，表明Ets-1在这一过程中发挥着重要作用。 CCL2 激活 Ets-1 进一步调节一些 Ets-1 靶分子，包括 β(3) 整联蛋白。 CCL2 诱导 6, mRNA 和蛋白质表达显着上调，而 CCL2 的这种作用可被 Ets-1 反义寡核苷酸阻止。 CCL2 对 Ets-1 活性的功能调节依赖于 ERK-1/2 级联。 PD98509 对 ERK1/2 活性的抑制可阻止 CCL2 诱导的 Ets-1 DNA 结合活性和 Ets-1 mRNA 表达的增加。基于这些发现，我们认为 Ets-1 转录因子在 CCL2 对脑内皮细胞的作用和 CCL2 诱导的血管生成中发挥着关键作用。
Although recent studies have suggested that CC chemokine CCL2 may directly affect the angiogenesis, the signaling events involved in such regulation remain to be determined. This study investigated a potential signal mechanism involved in CCL2-induced angiogenesis. Our in vitro and in vivo (hemangioma model of angiogenesis) experiments confirmed earlier findings that CCL2 can induce angiogenesis directly. Using a gene array analysis, CCL2 was found to induce expression of several angiogenic factors in brain endothelial cells. Among the most prominent was an up-regulation in Ets-1 transcription factor. CCL2 induced a significant increase in Ets-1 mRNA and protein expression as well as Ets-1 DNA-binding activity. Importantly, Ets-1 antisense oligonucleotide markedly abrogated in vitro CCL2-induced angiogenesis, suggesting that Ets-1 is critically involved in this process. Activation of Ets-1 by CCL2 further regulated some of Ets-1 target molecules including beta(3) integrins. CCL2 induced significant up-regulation of 6, mRNA and protein expression, and this effect of CCL2 was prevented by the Ets-1 antisense oligonucleotide. The functional regulation of Ets-1 activity by CCL2 was dependent on ERK-1/2 cascade. Inhibition of ERK1/2 activity by PD98509 prevented CCL2-induced increases in Ets-1 DNA-binding activity and Ets-1 mRNA expression. Based on these findings, we suggest that Ets-1 transcription factor plays a critical role in CCL2 actions on brain endothelial cells and CCL2-induced angiogenesis.