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首页> 外文期刊>Molecular and Cellular Biology >Vascular Endothelial Growth Factor Activates Nuclear Factor of Activated T Cells in Human Endothelial Cells: a Role for Tissue Factor Gene Expression
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Vascular Endothelial Growth Factor Activates Nuclear Factor of Activated T Cells in Human Endothelial Cells: a Role for Tissue Factor Gene Expression

机译：血管内皮生长因子激活人类内皮细胞中激活的T细胞的核因子：组织因子基因表达的作用。

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Vascular endothelial growth factor (VEGF) is a potent angiogenic inducer that stimulates the expression of tissue factor (TF), the major cellular initiator of blood coagulation. Here we show that signaling triggered by VEGF induced DNA-binding and transcriptional activities of nuclear factor of activated T cells (NFAT) and AP-1 in human umbilical vein endothelial cells (HUVECs). VEGF also induced TF mRNA expression and gene promoter activation by a cyclosporin A (CsA)-sensitive mechanism. As in lymphoid cells, NFAT was dephosphorylated and translocated to the nucleus upon activation of HUVECs, and these processes were blocked by CsA. NFAT was involved in the VEGF-mediated TF promoter activation as evidenced by cotransfection experiments with a dominant negative version of NFAT and site-directed mutagenesis of a newly identified NFAT site within the TF promoter that overlaps with a previously identified κB-like site. Strikingly, this site bound exclusively NFAT not only from nuclear extracts of HUVECs activated by VEGF, a stimulus that failed to induce NF-κB-binding activity, but also from extracts of cells activated with phorbol esters and calcium ionophore, a combination of stimuli that triggered the simultaneous activation of NFAT and NF-κB. These results implicate NFAT in the regulation of endothelial genes by physiological means and shed light on the mechanisms that switch on the gene expression program induced by VEGF and those regulating TF gene expression.
机译：血管内皮生长因子（VEGF）是有效的血管生成诱导剂，可刺激组织因子（TF）的表达，后者是血液凝固的主要细胞引发剂。在这里，我们显示了由VEGF触发的信号传导在人脐静脉内皮细胞（HUVEC）中激活了T细胞（NFAT）和AP-1的核因子的DNA结合和转录活性。 VEGF还通过环孢菌素A（CsA）敏感机制诱导TF mRNA表达和基因启动子激活。就像在淋巴样细胞中一样，HUVEC激活后，NFAT被去磷酸化并转移到细胞核中，这些过程被CsA阻断。 NFAT参与了VEGF介导的TF启动子激活，这是通过与NFAT显性负型共转染实验和TF启动子中新发现的NFAT位点（与先前鉴定的κB样位点重叠）的定点诱变进行证明的。令人惊讶的是，该位点不仅与NGF结合，不仅受VEGF激活的HUVEC核提取物（一种不能诱导NF-κB结合活性的刺激物）结合，还与受佛波酯和钙离子载体激活的细胞提取物结合，触发了NFAT和NF-κB的同时激活。这些结果暗示了NFAT通过生理手段调节内皮基因，并阐明了开启由VEGF诱导的基因表达程序和调节TF基因表达的机制的机制。

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