Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin
Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin
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DOI：
10.1182/blood-2007-08-105346
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发表时间：
2008-04-01
期刊：
影响因子：
20.3
通讯作者：
Randi, Anna M.
中科院分区：
文献类型：
--
作者：
Birdsey, Graeme M.;Dryden, Nicola H.;Randi, Anna M.
在血管生成过程中，细胞凋亡和存活之间的平衡受到严格调控。ETS转录因子Erg是体外内皮管形成所必需的。利用反义寡核颗粒抑制人脐静脉内皮细胞（HUVECs）中Erg的表达，导致细胞-细胞接触脱离和细胞死亡增加。在HUVECs中，通过反义抑制Erg的表达也降低了粘附分子血管内皮(VE)-钙粘蛋白的表达，而VE -钙粘蛋白是内皮细胞间连接和存活的关键调节因子。通过染色质免疫沉淀，我们发现Erg与ve -钙粘蛋白启动子结合。此外，在转激活实验中发现Erg可以增强ve -钙粘蛋白启动子的活性。过度表达VE-cadherin- gfp可部分挽救Erg抑制诱导的细胞凋亡，提示VE-cadherin参与了Erg依赖的存活信号。为了证明Erg在体内血管生成中的作用，我们在基质-凝胶塞模型中使用siRNA对抗Erg。Erg抑制导致血管化明显减少，caspase阳性内皮细胞（ECs）增加。这些结果确定了通过转录因子Erg和粘附分子VE-cadherin调节血管生成和内皮细胞存活的新途径。
Tight regulation of the balance between apoptosis and survival is essential in angiogenesis. The ETS transcription factor Erg is required for endothelial tube formation in vitro. Inhibition of Erg expression in human umbilical vein endothelial cells (HUVECs), using antisense oligonucleoticles, resulted in detachment of cell-cell contacts and increased cell death. Inhibition of Erg expression by antisense in HUVECs also lowered expression of the adhesion molecule vascular endothelial (VE)-cadherin, a key regulator of endothelial intercellular junctions and survival. Using chromatin immunoprecipitation, we showed that Erg binds to the VE-cadherin promoter. Furthermore, Erg was found to enhance VE-cadherin promoter activity in a transactivation assay. Apoptosis induced by inhibition of Erg was partly rescued by overexpression of VE-cadherin-GFP, suggesting that VE-cadherin is involved in the Erg-dependent survival signals. To show the role of Erg in angiogenesis in vivo, we used siRNA against Erg in a Matri-gel plug model. Erg inhibition resulted in a significant decrease in vascularization, with increase in caspase-positive endothelial cells (ECs). These results identify a new pathway regulating angiogenesis and endothelial survival, via the transcription factor Erg and the adhesion molecule VE-cadherin.