Atheroprotective Communication Between Endothelial Cells and Smooth Muscle Cells Through miRNAs

Nat Cell Biol. 2012 Feb 12;14(3):249-56. doi: 10.1038/ncb2441.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Cells, Cultured
  • Coculture Techniques
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / transplantation
  • Exosomes / metabolism
  • Exosomes / transplantation
  • Exosomes / ultrastructure
  • Gene Expression Regulation / drug effects
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Lovastatin / analogs & derivatives
  • Lovastatin / pharmacology
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Microscopy, Confocal
  • Microscopy, Electron
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Stress, Mechanical
  • Transfection

Substances

  • Apolipoproteins E
  • KLF2 protein, human
  • Kruppel-Like Transcription Factors
  • MIRN143 microRNA, human
  • MIRN145 microRNA, human
  • MicroRNAs
  • mevastatin
  • Lovastatin