title: Endothelial microparticle-mediated transfer of MicroRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles.
abstract: BACKGROUND
  Repair of the endothelium after vascular injury is crucial for preserving endothelial integrity and preventing the development of vascular disease. The underlying mechanisms of endothelial cell repair are largely unknown. We sought to investigate whether endothelial microparticles (EMPs), released from apoptotic endothelial cells (ECs), influence EC repair.
  
  
  RESULTS
  Systemic treatment of mice with EMPs after electric denudation of the endothelium accelerated reendothelialization in vivo. In vitro experiments revealed that EMP uptake in ECs promotes EC migration and proliferation, both critical steps in endothelial repair. To dissect the underlying mechanisms, Taqman microRNA array was performed, and microRNA (miR)-126 was identified as the predominantly expressed miR in EMPs. The following experiments demonstrated that miR-126 was transported into recipient human coronary artery endothelial cells by EMPs and functionally regulated the target protein sprouty-related, EVH1 domain-containing protein 1 (SPRED1). Knockdown of miR-126 in EMPs abrogated EMP-mediated effects on human coronary artery endothelial cell migration and proliferation in vitro and reendothelialization in vivo. Interestingly, after simulating diabetic conditions, EMPs derived from glucose-treated ECs contained significantly lower amounts of miR-126 and showed reduced endothelial repair capacity in vitro and in vivo. Finally, expression analysis of miR-126 in circulating microparticles from 176 patients with stable coronary artery disease with and without diabetes mellitus revealed a significantly reduced miR-126 expression in circulating microparticles from diabetic patients.
  
  
  CONCLUSIONS
  Endothelial microparticles promote vascular endothelial repair by delivering functional miR-126 into recipient cells. In pathological hyperglycemic conditions, EMP-mediated miR-126-induced EC repair is altered.
authors.affiliation: Department of Internal Medicine II, University Hospital Bonn, Rheinische Friedrich-Wilhelms University, Bonn, Germany (F.J., M.H., A.C., T.S., S.P., G.N., N.W.); Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL (X.Y.); Institute of Physiology, University Hospital Bonn, Rheinische Friedrich-Wilhelms University, Bonn, Germany (D.W., S.V., B.K.F.); and Institute of Innate Immunity, Rheinische Friedrich-Wilhelms University, Bonn, Germany (B.S.F.).
authors.forename: Felix
authors.initials: F
authors.lastname: Jansen
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.forename: Marion
authors.initials: M
authors.lastname: Hoelscher
authors.forename: Arianna
authors.initials: A
authors.lastname: Cattelan
authors.forename: Theresa
authors.initials: T
authors.lastname: Schmitz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Proebsting
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.forename: Sarah
authors.initials: S
authors.lastname: Vosen
authors.forename: Bernardo S
authors.initials: BS
authors.lastname: Franklin
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Nikos
authors.initials: N
authors.lastname: Werner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D055252:Cell-Derived Microparticles / Q000473:pathology / Q000502:physiology*; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003331:Coronary Vessels / Q000293:injuries / Q000473:pathology / Q000502:physiology*; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology*; D005947:Glucose / Q000633:toxicity; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C527111:MIRN126 microRNA, human; C545201:MIRN126 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D012097:Repressor Proteins; C504812:SPRED1 protein, human; C433763:Spred1 protein, mouse; D005947:Glucose
keywords: SPRED1 protein, human; endothelium, vascular; microRNA-126, human; vascular diseases