VEGF-Induced Expression of miR-17-92 Cluster in Endothelial Cells Is Mediated by ERK/ELK1 Activation and Regulates Angiogenesis.
VEGF-Induced Expression of miR-17-92 Cluster in Endothelial Cells Is Mediated by ERK/ELK1 Activation and Regulates Angiogenesis.
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DOI：
10.1161/circresaha.115.307408
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发表时间：
2016-01-08
影响因子：
20.1
通讯作者：
Suárez Y
中科院分区：
文献类型：
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作者：
Chamorro-Jorganes A;Lee MY;Araldi E;Landskroner-Eiger S;Fernández-Fuertes M;Sahraei M;Quiles Del Rey M;van Solingen C;Yu J;Fernández-Hernando C;Sessa WC;Suárez Y
补充数字内容可在文本中找到。一些证据表明，不同刺激对microRNA（miRNA）水平的调节可能有助于调节刺激诱导的反应。miR-17-92簇与肿瘤发生和血管生成有关，但其在血管内皮生长因子诱导的内皮细胞（EC）功能中的作用尚不清楚，其调控也未知。本研究的目的是阐明VEGF调节内皮细胞中miR-17-92簇表达的机制，并确定其在体外和体内调节内皮血管生成功能中的作用。这是通过分析内皮中miR-17-92簇的出生后失活（miR-17-92 iEC-KO小鼠）对发育性视网膜血管生成、VEGF诱导的耳血管生成和肿瘤血管生成的影响来完成的。在这里，我们表明，Erk/Elk 1激活对内皮细胞的VEGF刺激是负责Elk-1介导的转录激活（染色质免疫沉淀分析）的miR-17-92集群。此外，我们证明了VEGF介导的miR-17-92簇在体外的上调是EC增殖和血管生成发芽所必需的。最后，我们提供了遗传学证据，证明miR-17-92 iEC-KO小鼠在发育过程中减弱了生理性视网膜血管生成，并减少了VEGF诱导的耳血管生成和肿瘤血管生成。计算分析和拯救实验显示，PTEN（磷酸酶和张力蛋白同源物）是miR-17-92簇的靶标，并且是miR-17-92诱导的EC增殖的关键介质。然而，当miR-17-92被抑制时，血管生成转录程序减少。综上所述，我们的结果表明，VEGF诱导的miR-17-92簇表达有助于EC的血管生成开关，并参与血管生成的调节。
Supplemental Digital Content is available in the text. Several lines of evidence indicate that the regulation of microRNA (miRNA) levels by different stimuli may contribute to the modulation of stimulus-induced responses. The miR-17–92 cluster has been linked to tumor development and angiogenesis, but its role in vascular endothelial growth factor–induced endothelial cell (EC) functions is unclear and its regulation is unknown. The purpose of this study was to elucidate the mechanism by which VEGF regulates the expression of miR-17–92 cluster in ECs and determine its contribution to the regulation of endothelial angiogenic functions, both in vitro and in vivo. This was done by analyzing the effect of postnatal inactivation of miR-17–92 cluster in the endothelium (miR-17–92 iEC-KO mice) on developmental retinal angiogenesis, VEGF-induced ear angiogenesis, and tumor angiogenesis. Here, we show that Erk/Elk1 activation on VEGF stimulation of ECs is responsible for Elk-1-mediated transcription activation (chromatin immunoprecipitation analysis) of the miR-17–92 cluster. Furthermore, we demonstrate that VEGF-mediated upregulation of the miR-17–92 cluster in vitro is necessary for EC proliferation and angiogenic sprouting. Finally, we provide genetic evidence that miR-17–92 iEC-KO mice have blunted physiological retinal angiogenesis during development and diminished VEGF-induced ear angiogenesis and tumor angiogenesis. Computational analysis and rescue experiments show that PTEN (phosphatase and tensin homolog) is a target of the miR-17–92 cluster and is a crucial mediator of miR-17-92–induced EC proliferation. However, the angiogenic transcriptional program is reduced when miR-17–92 is inhibited. Taken together, our results indicate that VEGF-induced miR-17–92 cluster expression contributes to the angiogenic switch of ECs and participates in the regulation of angiogenesis.