Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs

• Published in: Nature cell biology Vol. 14; no. 3; pp. 249 - 256
• Main Authors: Hergenreider, Eduard, Heydt, Susanne, Tréguer, Karine, Boettger, Thomas, Horrevoets, Anton J. G., Zeiher, Andreas M., Scheffer, Margot P., Frangakis, Achilleas S., Yin, Xiaoke, Mayr, Manuel, Braun, Thomas, Urbich, Carmen, Boon, Reinier A., Dimmeler, Stefanie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2012; Nature Publishing Group
• Subjects: 631/208/200; 631/337/384/331; 631/80/86; 692/699/75/593/2100; Animals; Aorta - metabolism; Aorta - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biology; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cells, Cultured; Coculture Techniques; Communication; Developmental Biology; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelial Cells - transplantation; Exosomes - metabolism; Exosomes - transplantation; Exosomes - ultrastructure; Extracellular vesicles; Gene expression; Gene Expression Regulation - drug effects; Genetic aspects; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Lesions; Life Sciences; Lovastatin - analogs & derivatives; Lovastatin - pharmacology; Mice; Mice, Knockout; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Microscopy, Confocal; Microscopy, Electron; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; Physiological aspects; Physiology; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Shear stress; Signal Transduction - genetics; Smooth muscle; Stem Cells; Stress, Mechanical; Transcription factors; Transfection; United Kingdom; Netherlands; Germany
• ISSN: 1465-7392; 1476-4679
• 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. Dimmeler and colleagues show that the atheroprotective transcription factor KLF2 activates expression of the microRNAs miR-143/145 in endothelial cells. miR-143/145 are subsequently enriched in secreted microvesicles and taken up by smooth muscle cells to elicit anti-atherogenic responses.