Inhibition of endothelial cell activation by bHLH protein E2-2 and its impairment of angiogenesis.
Inhibition of endothelial cell activation by bHLH protein E2-2 and its impairment of angiogenesis.
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DOI：
10.1182/blood-2009-05-223057
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发表时间：
2010-05
期刊：
影响因子：
20.3
通讯作者：
A. Tanaka;F. Itoh;Koichi Nishiyama;T. Takezawa;H. Kurihara;S. Itoh;Mitsuyasu Kato
中科院分区：
文献类型：
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作者：
A. Tanaka;F. Itoh;Koichi Nishiyama;T. Takezawa;H. Kurihara;S. Itoh;Mitsuyasu Kato
E2-2属于碱性螺旋-环-螺旋（bHLH）转录因子家族。E2-2与参与血管生成的DNA结合抑制剂（Id）1结合。在本文中，我们证明了E2-2与Id 1相互作用，并提供证据表明，这种相互作用增强血管生成。突变分析表明，HLH结构域的E2-2是必需的与Id 1的相互作用，反之亦然。此外，Id 1干扰E2-2介导的荧光素酶报告活性的影响。有趣的是，将表达E2-2的腺病毒注射到植入皮肤下的基质胶塞中阻断了体内血管生成。与此相反，注射Id 1表达腺病毒拯救E2-2介导的抑制体内血管生成反应。与基质胶塞试验结果一致，E2-2可抑制内皮细胞（EC）迁移、网络形成和增殖。另一方面，敲低EC中的E2-2增加EC迁移。外源性表达Id 1可解除E2-2对EC迁移的阻断作用。我们还证明E2-2可以通过抑制VEGFR 2启动子活性来干扰VEGFR 2表达。本研究表明，E2-2可以维持EC的静止，而Id 1可以对抗这种作用。
E2-2 belongs to the basic helix-loop-helix (bHLH) family of transcription factors. E2-2 associates with inhibitor of DNA binding (Id) 1, which is involved in angiogenesis. In this paper, we demonstrate that E2-2 interacts with Id1 and provide evidence that this interaction potentiates angiogenesis. Mutational analysis revealed that the HLH domain of E2-2 is required for the interaction with Id1 and vice versa. In addition, Id1 interfered with E2-2-mediated effects on luciferase reporter activities. Interestingly, injection of E2-2-expressing adenoviruses into Matrigel plugs implanted under the skin blocked in vivo angiogenesis. In contrast, the injection of Id1-expressing adenoviruses rescued E2-2-mediated inhibition of in vivo angiogenic reaction. Consistent with the results of the Matrigel plug assay, E2-2 could inhibit endothelial cell (EC) migration, network formation, and proliferation. On the other hand, knockdown of E2-2 in ECs increased EC migration. The blockade of EC migration by E2-2 was relieved by exogenous expression of Id1. We also demonstrated that E2-2 can perturb VEGFR2 expression via inhibition of VEGFR2 promoter activity. This study suggests that E2-2 can maintain EC quiescence and that Id1 can counter this effect.