Vascular endothelial growth factor suppresses TNFSF15 production in endothelial cells by stimulating miR-31 and miR-20a expression via activation of Akt and Erk signals.
Vascular endothelial growth factor suppresses TNFSF15 production in endothelial cells by stimulating miR-31 and miR-20a expression via activation of Akt and Erk signals.
复制标题
血管内皮生长因子通过激活 Akt 和 Erk 信号刺激 miR-31 和 miR-20a 表达，抑制内皮细胞中 TNFSF15 的产生
DOI：
10.1002/2211-5463.12171
复制
发表时间：
2017-01
期刊：
影响因子：
2.6
通讯作者：
Li LY
中科院分区：
文献类型：
--
作者：
Deng HT;Liu HL;Zhai BB;Zhang K;Xu GC;Peng XM;Zhang QZ;Li LY
肿瘤坏死因子超家族-15（TNFSF 15; VEGI; TL 1A）是血管生成的负调节因子，用于血管稳态，由成熟血管系统中的内皮细胞产生。已知它被血管内皮生长因子（VEGF）下调，VEGF是新血管形成的主要调节因子，但这种相互作用的机制尚不清楚。在这里，我们报告了VEGF能够刺激两种microRNA的产生，miR-20 a和miR-31，它们直接靶向TNFSF 15的3′-UTR。此外，我们发现两种VEGF刺激的细胞生长信号Erk和Akt负责促进miR-20 a和miR-31的表达。用Akt抑制剂LY 294002处理人脐静脉内皮细胞（HUVEC）导致miR-20 a和miR-31的产生减少，而Erk抑制剂U 0126阻止了VEGF刺激的miR-20 a表达，但不能阻止miR-31的表达。此外，Erk或Akt信号的失活恢复TNFSF 15基因表达。在血管生成试验中，HUVEC中miR-20 a或miR-31水平升高导致体外毛细血管样小管形成增强，而miR-20 a和miR-31水平降低导致抑制。这些发现与miR-20 a和miR-31介导VEGF诱导的TNFSF 15下调的观点一致。因此，靶向这些microRNA分子可能提供抑制血管生成的有效方法。
Tumor necrosis factor superfamily‐15 (TNFSF15; VEGI; TL1A) is a negative modulator of angiogenesis for blood vessel homeostasis and is produced by endothelial cells in a mature vasculature. It is known to be downregulated by vascular endothelial growth factor (VEGF), a major regulator of neovascularization but the mechanism of this interaction is unclear. Here we report that VEGF is able to stimulate the production of two microRNAs, miR‐20a and miR‐31, which directly target the 3′‐UTR of TNFSF15. Additionally, we show that two VEGF‐stimulated cell growth signals, Erk and Akt, are responsible for promoting the expression of miR‐20a and miR‐31. Treatment of human umbilical vein endothelial cells (HUVECs) with Akt inhibitor LY294002 results in diminished miR‐20a and miR‐31 production, while Erk inhibitor U0126 prevented VEGF‐stimulated expression of miR‐20a but not that of miR‐31. Furthermore, inactivation of either Erk or Akt signals restores TNFSF15 gene expression. In an angiogenesis assay, elevated miR‐20a or miR‐31 levels in HUVECs leads to enhancement of capillary‐like tubule formation in vitro, whereas lowered miR‐20a and miR‐31 levels results in an inhibition. These findings are consistent with the view that miR‐20a and miR‐31 mediate VEGF‐induced downregulation of TNFSF15. Targeting these microRNA molecules may therefore provide an effective approach to inhibit angiogenesis.