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Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs

Nature Cell Biology volume 14, pages 249–256 (2012)Cite this article

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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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References

  1. Davies, P. F., Polacek, D. C., Handen, J. S., Helmke, B. P. & DePaola, N. A spatial approach to transcriptional profiling: mechanotransduction and the focal origin of atherosclerosis. Trends Biotechnol. 17, 347–351 (1999).

    Article  CAS  Google Scholar 

  2. Boon, R. A. & Horrevoets, A. J. Key transcriptional regulators of the vasoprotective effects of shear stress. Hamostaseologie 29, 39–40; 41–33 (2009).

    Article  Google Scholar 

  3. Kuo, C. T. et al. The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes Dev. 11, 2996–3006 (1997).

    Article  CAS  Google Scholar 

  4. Lee, J. S. et al. Klf2 is an essential regulator of vascular hemodynamic forces in vivo. Dev. Cell 11, 845–857 (2006).

    Article  CAS  Google Scholar 

  5. Wu, J., Bohanan, C. S., Neumann, J. C. & Lingrel, J. B. KLF2 transcription factor modulates blood vessel maturation through smooth muscle cell migration. J. Biol. Chem. 283, 3942–3950 (2008).

    Article  CAS  Google Scholar 

  6. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  Google Scholar 

  7. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    Article  CAS  Google Scholar 

  8. Montgomery, R. L. & van Rooij, E. MicroRNA regulation as a therapeutic strategy for cardiovascular disease. Curr. Drug Targets 11, 936–942 (2010).

    Article  CAS  Google Scholar 

  9. Small, E. M. & Olson, E. N. Pervasive roles of microRNAs in cardiovascular biology. Nature 469, 336–342 (2011).

    Article  CAS  Google Scholar 

  10. Zernecke, A. et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal 2, ra81 (2009).

    Article  Google Scholar 

  11. Nicoli, S. et al. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature 464, 1196–1200 (2010).

    Article  CAS  Google Scholar 

  12. Qin, X. et al. MicroRNA-19a mediates the suppressive effect of laminar flow on cyclin D1 expression in human umbilical vein endothelial cells. Proc. Natl Acad. Sci. USA 107, 3240–3244 (2010).

    Article  CAS  Google Scholar 

  13. Fang, Y., Shi, C., Manduchi, E., Civelek, M. & Davies, P. F. MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc. Natl Acad. Sci. USA 107, 13450–13455 (2010).

    Article  CAS  Google Scholar 

  14. Cordes, K. R. et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460, 705–710 (2009).

    Article  CAS  Google Scholar 

  15. Elia, L. et al. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ. 16, 1590–1598 (2009).

    Article  CAS  Google Scholar 

  16. Boettger, T. et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J. Clin. Invest. 119, 2634–2647 (2009).

    Article  CAS  Google Scholar 

  17. Dekker, R. J. et al. KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood 107, 4354–4363 (2006).

    Article  CAS  Google Scholar 

  18. Wang, K. C. et al. Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth. Proc. Natl Acad. Sci. USA 107, 3234–3239 (2010).

    Article  CAS  Google Scholar 

  19. Fasanaro, P. et al. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J. Biol. Chem. 283, 15878–15883 (2008).

    Article  CAS  Google Scholar 

  20. Kazenwadel, J., Michael, M. Z. & Harvey, N. L. Prox1 expression is negatively regulated by miR-181 in endothelial cells. Blood 116, 2395–2401 (2010).

    Article  CAS  Google Scholar 

  21. Zhang, Y. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39, 133–144 (2010).

    Article  CAS  Google Scholar 

  22. Chan, L. S., Yue, P. Y., Mak, N. K. & Wong, R. N. Role of microRNA-214 in ginsenoside-Rg1-induced angiogenesis. Eur. J. Pharm. Sci. 38, 370–377 (2009).

    Article  CAS  Google Scholar 

  23. SenBanerjee, S. et al. KLF2 is a novel transcriptional regulator of endothelial proinflammatory activation. J. Exp. Med. 199, 1305–1315 (2004).

    Article  CAS  Google Scholar 

  24. Li, L., Chen, X. P. & Li, Y. J. MicroRNA-146a and human disease. Scand. J. Immunol. 71, 227–231 (2010).

    Article  CAS  Google Scholar 

  25. Zhu, N. et al. Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis 215, 286–293 (2011).

    Article  CAS  Google Scholar 

  26. Jain, M. K. & Ridker, P. M. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat. Rev. Drug Discov. 4, 977–987 (2005).

    Article  CAS  Google Scholar 

  27. Zhang, C. X., Cheng, Y. H., Liu, X. J. & Yang, J. MicroRNA-145 in vascular smooth muscle cell biology and vascular disease. Circulation 120, S584 (2009).

    Article  Google Scholar 

  28. Cheng, Y. H. et al. MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ. Res. 105, 158-U113 (2009).

    Article  Google Scholar 

  29. Loots, G. G. & Ovcharenko, I. rVISTA 2.0: evolutionary analysis of transcription factor binding sites. Nucleic Acids Res. 32, W217–W221 (2004).

    Article  CAS  Google Scholar 

  30. Camussi, G., Deregibus, M. C., Bruno, S., Cantaluppi, V. & Biancone, L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 78, 838–848 (2010).

    Article  CAS  Google Scholar 

  31. Collino, F. et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One 5, e11803 (2010).

    Article  Google Scholar 

  32. Gyorgy, B. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol. Life Sci. 68, 2667–2688 (2011).

    Article  CAS  Google Scholar 

  33. Cocucci, E., Racchetti, G. & Meldolesi, J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 19, 43–51 (2009).

    Article  CAS  Google Scholar 

  34. Simpson, R. J., Jensen, S. S. & Lim, J. W. Proteomic profiling of exosomes: current perspectives. Proteomics 8, 4083–4099 (2008).

    Article  CAS  Google Scholar 

  35. Kosaka, N. et al. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 285, 17442–17452 (2010).

    Article  CAS  Google Scholar 

  36. Xin, M. et al. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Gene Dev. 23, 2166–2178 (2009).

    Article  CAS  Google Scholar 

  37. Parmar, K. M. et al. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J. Clin. Invest. 116, 49–58 (2006).

    Article  CAS  Google Scholar 

  38. Aliotta, J. M. et al. Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Exp. Hematol. 38, 233–245 (2010).

    Article  CAS  Google Scholar 

  39. Yuan, A. et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One 4, e4722 (2009).

    Article  Google Scholar 

  40. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  Google Scholar 

  41. Boettger, T. et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J. Clin. Invest. 119, 2634–2647 (2009).

    Article  CAS  Google Scholar 

  42. Kuehbacher, A., Urbich, C., Zeiher, A. M. & Dimmeler, S. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ. Res. 101, 59–68 (2007).

    Article  CAS  Google Scholar 

  43. Dekker, R. J. et al. KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood 107, 4354–4363 (2006).

    Article  CAS  Google Scholar 

  44. Prokopi, M. et al. Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures. Blood 114, 723–732 (2009).

    Article  CAS  Google Scholar 

  45. Mastronarde, D. N. Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 152, 36–51 (2005).

    Article  Google Scholar 

  46. Mayr, M. et al. Proteomics, metabolomics, and immunomics on microparticles derived from human atherosclerotic plaques. Circ. Cardiovasc. Genet. 2, 379–388 (2009).

    Article  CAS  Google Scholar 

Download references

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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Author notes

  1. Reinier A. Boon and Stefanie Dimmeler: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe-University Hospital, 60590 Frankfurt, Germany

    Eduard Hergenreider, Susanne Heydt, Karine Tréguer, Carmen Urbich, Reinier A. Boon & Stefanie Dimmeler

  2. Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany

    Thomas Boettger & Thomas Braun

  3. Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands

    Anton J. G. Horrevoets

  4. Department of Internal Medicine III, Cardiology, Goethe-University Hospital, 60590 Frankfurt, Germany

    Andreas M. Zeiher

  5. Institute for Biophysics, Goethe-University, 60438 Frankfurt, Germany

    Margot P. Scheffer & Achilleas S. Frangakis

  6. Cardiovascular Division, King’s College London, London SE5 9NU, UK

    Xiaoke Yin & Manuel Mayr

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  1. Eduard Hergenreider
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Contributions

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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