Cardiovascular Research Center (CSIC-ICCC), Hospital de Sant Pau (UAB), IIB-Sant Pau. CiberOBN, Instituto de Salut Carlos III, C/ Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.
Angiogenesis. 2012 Dec;15(4):657-69. doi: 10.1007/s10456-012-9293-x. Epub 2012 Aug 7.
Tissue factor (TF) has well-recognized roles as initiator of blood coagulation as well as an intracellular signaling receptor. TF signaling regulates gene transcription and protein translation. Recently, we have shown that TF-induced mature neovessel formation is ultimately driven by CCL2 expression. However, the signaling process induced by TF to promote microvessel formation remains to be determined. This study was designed with the objective to investigate the mechanisms involved in TF-induced neovessel formation. Here, we have identified that Ets-1 expression is a downstream effector of TF signaling. TF-siRNA induced a highly significant reduction in Ets-1 expression levels and in Ets-1/DNA binding while inducing abrogation of microvessel formation. Activation of Ets-1 rescued the effect of TF inhibition and restored microvessel formation confirming the critical role of Ets-1 in TF-induced angiogenesis. VE-cadherin expression, a key regulator of endothelial intercellular junctions, and an Ets-1 target molecule was dependent of TF-inhibition. We show that TF signals through ERK1/2 to activate Ets-1 and induce CCL2 gene expression by binding to its promoter region. We conclude that endothelial cell TF signals through ERK1/2 and Ets-1 to trigger microvessel formation.
组织因子（TF）作为血液凝固的启动因子以及细胞内信号受体具有公认的作用。TF 信号转导调节基因转录和蛋白质翻译。最近，我们已经表明，TF 诱导的成熟新血管形成最终是由 CCL2 表达驱动的。然而，TF 促进微血管形成所诱导的信号转导过程仍有待确定。本研究旨在探讨 TF 诱导新血管形成中涉及的机制。在这里，我们已经确定 Ets-1 表达是 TF 信号的下游效应物。TF-siRNA 诱导 Ets-1 表达水平和 Ets-1/DNA 结合的显著降低，同时诱导微血管形成的中断。Ets-1 的激活挽救了 TF 抑制的作用，并恢复了微血管形成，证实了 Ets-1 在 TF 诱导的血管生成中的关键作用。VE-钙粘蛋白表达是内皮细胞细胞间连接的关键调节剂，也是 Ets-1 的靶分子，依赖于 TF 抑制。我们表明，TF 通过 ERK1/2 信号转导激活 Ets-1，并通过结合其启动子区域诱导 CCL2 基因表达。我们得出结论，内皮细胞 TF 通过 ERK1/2 和 Ets-1 信号触发微血管形成。
