Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation
Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation
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DOI：
10.1161/01.res.0000120861.27064.09
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发表时间：
2004-04-02
影响因子：
20.1
通讯作者：
Dimmeler, S
中科院分区：
文献类型：
--
作者：
Bruhl, T;Urbich, C;Dimmeler, S
同源异型盒基因（Homeobox genes，Hox）编码的转录因子调节细胞增殖和迁移，在胚胎发育过程中对心血管系统的发育起重要作用。在这项研究中，我们研究了HoxA 9在体外内皮细胞迁移和血管生成中的作用，并确定了一种新的靶基因EphB 4受体。抑制HoxA 9的表达减少了内皮细胞管的形成，并抑制了内皮细胞迁移，表明HoxA 9调节血管生成。由于Eph受体酪氨酸激酶对血管生成有重要作用，我们研究了HoxA 9是否可以转录调节EphB 4的表达。HoxA 9的下调降低了EphB 4的表达。染色质免疫沉淀显示HoxA 9与EphB 4启动子相互作用，而不具有DNA结合基序的HoxA 9缺失构建体（Deltaaa 206-272）不结合。一致地，HoxA 9野生型过表达激活EphB 4启动子，如通过报告基因表达所确定的。HoxA 9与EphB 4启动子结合并刺激其表达，导致内皮细胞迁移和管形成活性增加。因此，EphB 4表达的调节可能有助于HoxA 9在内皮细胞中的促血管生成作用。
Homeobox genes (Hox) encode for transcription factors, which regulate cell proliferation and migration and play an important role in the development of the cardiovascular system during embryogenesis. In this study, we investigated the role of HoxA9 for endothelial cell migration and angiogenesis in vitro and identified a novel target gene, the EphB4 receptor. Inhibition of HoxA9 expression decreased endothelial cell tube formation and inhibited endothelial cell migration, suggesting that HoxA9 regulates angiogenesis. Because Eph receptor tyrosine kinases importantly contribute to angiogenesis, we examined whether HoxA9 may transcriptionally regulate the expression of EphB4. Downregulation of HoxA9 reduced the expression of EphB4. Chromatin-immunoprecipitation revealed that HoxA9 interacted with the EphB4 promoter, whereas a deletion construct of HoxA9 without DNA-binding motif (Deltaaa 206-272) did not bind. Consistently, HoxA9 wild-type overexpression activated the EphB4 promoter as determined by reporter gene expression. HoxA9 binds to the EphB4 promoter and stimulates its expression resulting in an increase of endothelial cell migration and tube forming activity. Thus, modulation of EphB4 expression may contribute to the proangiogenic effect of HoxA9 in endothelial cells.