Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs.
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.
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe-University Hospital, 60590 Frankfurt, Germany.
Eduard
E
Hergenreider
Susanne
S
Heydt
Karine
K
Tréguer
Thomas
T
Boettger
Anton J G
AJ
Horrevoets
Andreas M
AM
Zeiher
Margot P
MP
Scheffer
Achilleas S
AS
Frangakis
Xiaoke
X
Yin
Manuel
M
Mayr
Thomas
T
Braun
Carmen
C
Urbich
Reinier A
RA
Boon
Stefanie
S
Dimmeler
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D055354:Exosomes / Q000378:metabolism / Q000637:transplantation / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013314:Stress, Mechanical; D014162:Transfection
D001057:Apolipoproteins E; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; C012258:mevastatin; D008148:Lovastatin