miR-342-5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling.
miR-342-5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling.
复制标题
miR-342-5p 是 Notch 下游分子，调节多种血管生成途径，包括 Notch、血管内皮生长因子和转化生长因子 β 信号传导
DOI：
10.1161/jaha.115.003042
复制
发表时间：
2016-02-08
影响因子：
5.4
通讯作者：
Han H
中科院分区：
文献类型：
--
作者：
Yan XC;Cao J;Liang L;Wang L;Gao F;Yang ZY;Duan JL;Chang TF;Deng SM;Liu Y;Dou GR;Zhang J;Zheng QJ;Zhang P;Han H
血管内皮细胞通过血管生成形成血管，受血管内皮生长因子、Notch、转化生长因子β等信号的协调调控，但具体的分子机制尚不清楚。小分子RNA测序初步证实miR-342-5P是内皮细胞Notch信号的下游新分子。报告实验、定量逆转录聚合酶链式反应和Western印迹分析表明，miR-342-5p通过抑制内皮细胞Smad1/5的磷酸化，靶向endoglin并调控转化生长因子β信号转导。通过纤维蛋白微球发芽试验、小鼠主动脉环培养和玻璃体内注射miR-342-5p蛋白凝胶，在体外和体内实验中，miR-342-5p基因的转染抑制了EC的增殖和管腔的形成，并减少了血管生成。此外，miR-342-5P促进内皮细胞迁移，并伴有内皮细胞标志物的减少和间质标志物的增加，提示内皮-间质转化增加。Endoglin至少部分逆转了miR-342-5p诱导的内皮-间充质转化。转化生长因子β可上调miR-342-5p的表达，抑制miR-342-5p可减弱转化生长因子β对内皮细胞腔形成和发芽的抑制作用。此外，血管内皮细胞生长因子抑制miR-342-5p的表达，miR-342-5p的表达抑制血管内皮细胞VEGFR2和VEGFR3的表达，并诱导内皮细胞Akt的磷酸化。在激光诱导的小鼠脉络膜新生血管模型中，miR-342-5p抑制了血管生成，突出了其临床潜力。MIR-342-5P是一种多功能的血管生成抑制因子，介导血管生成途径之间的作用和相互作用。
Endothelial cells (ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor (VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear. Small RNA sequencing initially identified miR‐342‐5p as a novel downstream molecule of Notch signaling in ECs. Reporter assay, quantitative reverse transcription polymerase chain reaction and Western blot analysis indicated that miR‐342‐5p targeted endoglin and modulated transforming growth factor β signaling by repressing SMAD1/5 phosphorylation in ECs. Transfection of miR‐342‐5p inhibited EC proliferation and lumen formation and reduced angiogenesis in vitro and in vivo, as assayed by using a fibrin beads–based sprouting assay, mouse aortic ring culture, and intravitreal injection of miR‐342‐5p agomir in P3 pups. Moreover, miR‐342‐5p promoted the migration of ECs, accompanied by reduced endothelial markers and increased mesenchymal markers, indicative of increased endothelial–mesenchymal transition. Transfection of endoglin at least partially reversed endothelial–mesenchymal transition induced by miR‐342‐5p. The expression of miR‐342‐5p was upregulated by transforming growth factor β, and inhibition of miR‐342‐5p attenuated the inhibitory effects of transforming growth factor β on lumen formation and sprouting by ECs. In addition, VEGF repressed miR‐342‐5p expression, and transfection of miR‐342‐5p repressed VEGFR2 and VEGFR3 expression and VEGF‐triggered Akt phosphorylation in ECs. miR‐342‐5p repressed angiogenesis in a laser‐induced choroidal neovascularization model in mice, highlighting its clinical potential. miR‐342‐5p acts as a multifunctional angiogenic repressor mediating the effects and interaction among angiogenic pathways.