Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs

E Hergenreider, S Heydt, K Tréguer, T Boettger… - Nature cell …, 2012 - nature.com
E Hergenreider, S Heydt, K Tréguer, T Boettger, AJG Horrevoets, AM Zeiher, MP Scheffer…
Nature cell biology, 2012nature.com
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) …
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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