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.
Original language | English |
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Pages (from-to) | 249-256 |
Number of pages | 8 |
Journal | Nature cell biology |
Volume | 14 |
Issue number | 3 |
DOIs | |
Publication status | Published - 12 Feb 2012 |
Keywords
- Animals
- Aorta/metabolism
- Apolipoproteins E/deficiency
- Atherosclerosis/genetics
- Cells, Cultured
- Coculture Techniques
- Endothelial Cells/cytology
- Exosomes/metabolism
- Gene Expression Regulation/drug effects
- Human Umbilical Vein Endothelial Cells/cytology
- Humans
- Kruppel-Like Transcription Factors/genetics
- Lovastatin/analogs & derivatives
- Mice
- Mice, Knockout
- MicroRNAs/genetics
- Microscopy, Confocal
- Microscopy, Electron
- Myocytes, Smooth Muscle/cytology
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/genetics
- Stress, Mechanical
- Transfection