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Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs

Abstract

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.

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Figure 1: KLF2 regulates endothelial miRNA expression.
Figure 2: Shear stress and statins induce endothelial miR-143/145 expression through KLF2.
Figure 3: KLF2 and shear stress induce miR-143 and miR-145 content of extracellular vesicles.
Figure 4: Endothelial cells transmit RNAs to SMCs in vitro.
Figure 5: Endothelial cells transmit functional miR-143 and miR-145 to SMCs.

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Acknowledgements

We thank M. Muhly-Reinholz, A. Fischer and N. Reinfeld for technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (SFB834 and SFB902), the Excellence Cluster Cardiopulmonary System (Exc 147-1) and the European Research Council (Advanced grant ‘Angiomirs’).

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E.H. designed and carried out experiments, analysed data and wrote the manuscript. S.H. and K.T. carried out experiments and analysed data. X.Y. and M.M. carried out the proteomic analysis. M.P.S. and A.S.F. carried out electron microscopy. T. Braun, T. Boettger and A.J.G.H. provided essential materials. C.U. and A.M.Z. provided conceptual advice. R.A.B. and S.D. designed experiments, analysed data and wrote the manuscript. All authors have proofread the manuscript.

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Correspondence to Stefanie Dimmeler.

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E.H., R.A.B. and S.D. applied for a patent

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Hergenreider, E., Heydt, S., Tréguer, K. et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 14, 249–256 (2012). https://doi.org/10.1038/ncb2441

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