title: Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury.
abstract: OBJECTIVE
  MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice.
  
  
  RESULTS
  MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin α5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin α5 and sirtuin1.
  
  
  CONCLUSIONS
  Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover D-30625, Germany Department of Cardiology, University Hospital Giessen & Marburg, Giessen, Germany.
authors.forename: Jan-Marcus
authors.initials: JM
authors.lastname: Daniel
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Penzkofer
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover D-30625, Germany Department of Cardiology, University Hospital Giessen & Marburg, Giessen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Teske
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover D-30625, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Dutzmann
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover D-30625, Germany Department of Cardiology, University Hospital Giessen & Marburg, Giessen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover D-30625, Germany Department of Cardiology, University Hospital Giessen & Marburg, Giessen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Bielenberg
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Bonauer
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Reinier A
authors.initials: RA
authors.lastname: Boon
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Ariane
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover D-30625, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover D-30625, Germany Department of Cardiology, University Hospital Giessen & Marburg, Giessen, Germany sedding.daniel@mh-hannover.de.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Sedding
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D058426:Neointima / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology; D057772:Vascular System Injuries / Q000235:genetics*
chemical_list: C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C541873:Mirn92 microRNA, mouse
keywords: Endothelial cells; MicroRNAs; Neointimal formation; Re-endothelialization