Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe-University Hospital, 60590 Frankfurt, Germany.
Nat Cell Biol. 2012 Feb 12;14(3):249-56. doi: 10.1038/ncb2441.
The shear-responsive transcription factor Krüppel-like factor 2 (KLF2) is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow. As microRNAs (miRNAs) post-transcriptionally control gene expression in many pathogenic and physiological processes, we investigated the regulation of miRNAs by KLF2 in endothelial cells. KLF2 binds to the promoter and induces a significant upregulation of the miR-143/145 cluster. Interestingly, miR-143/145 has been shown to control smooth muscle cell (SMC) phenotypes; therefore, we investigated the possibility of transport of these miRNAs between endothelial cells and SMCs. Indeed, extracellular vesicles secreted by KLF2-transduced or shear-stress-stimulated HUVECs are enriched in miR-143/145 and control target gene expression in co-cultured SMCs. Extracellular vesicles derived from KLF2-expressing endothelial cells also reduced atherosclerotic lesion formation in the aorta of ApoE(-/-) mice. Combined, our results show that atheroprotective stimuli induce communication between endothelial cells and SMCs through an miRNA- and extracellular-vesicle-mediated mechanism and that this may comprise a promising strategy to combat atherosclerosis.
剪切响应转录因子 Krüppel 样因子 2（KLF2）是一种关键的内皮基因表达模式调节因子，可被保护性血流诱导。由于 microRNAs（miRNAs）在后转录水平上控制许多致病和生理过程中的基因表达，我们研究了 KLF2 在血管内皮细胞中对 miRNAs 的调节作用。KLF2 结合到启动子上，并显著上调 miR-143/145 簇。有趣的是，miR-143/145 已被证明可以控制平滑肌细胞（SMC）表型；因此，我们研究了这些 miRNA 在血管内皮细胞和 SMC 之间运输的可能性。事实上，由 KLF2 转导或切应力刺激的 HUVECs 分泌的细胞外囊泡富含 miR-143/145，并控制共培养的 SMC 中的靶基因表达。来自表达 KLF2 的内皮细胞的细胞外囊泡也减少了 ApoE(-/-) 小鼠主动脉中的动脉粥样硬化病变形成。综合来看，我们的研究结果表明，保护性刺激通过 miRNA 和细胞外囊泡介导的机制在血管内皮细胞和 SMC 之间诱导通讯，这可能是一种有前途的抗动脉粥样硬化策略。
