title: Intercellular transfer of miR-126-3p by endothelial microparticles reduces vascular smooth muscle cell proliferation and limits neointima formation by inhibiting LRP6.
abstract: Vascular smooth muscle cell (VSMC) proliferation is of importance in the pathogenesis of vascular diseases such as restenosis or atherosclerosis. Endothelial microparticles (EMPs) regulate function and phenotype of target endothelial cells (ECs), but their influence on VSMC biology is unknown. We aim to investigate the role of EMPs in the regulation of vascular smooth muscle cell (VSMC) proliferation and vascular remodeling.
  
  
  
  Systemic treatment of mice with EMPs after vascular injury reduced neointima formation in vivo. In vitro, EMP uptake in VSMCs diminished VSMC proliferation and migration, both pivotal steps in neointima formation. To explore the underlying mechanisms, Taqman microRNA-array was performed and miR-126-3p was identified as the predominantly expressed miR in EMPs. Confocal microscopy revealed an EMP-mediated miR-126 transfer into recipient VSMCs. Expression of miR-126 target protein LRP6, regulating VSMC proliferation, was reduced in VSMCs after EMP treatment. Importantly, genetic regulation of miR-126 in EMPs showed a miR-126-dependent inhibition of LRP6 expression, VSMC proliferation and neointima formation in vitro and in vivo, suggesting a crucial role of miR-126 in EMP-mediated neointima formation reduction. Finally, analysis of miR-126 expression in circulating MPs in 176 patients with coronary artery disease revealed a reduced PCI rate in patients with high miR-126 expression level, supporting a central role for MP-incorporated miR-126 in vascular remodelling.
  
  
  
  EMPs reduce VSMC proliferation, migration and subsequent neointima formation by delivering functional miR-126 into recipient VSMCs.
authors.affiliation: Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Jansen
authors.affiliation: Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Stumpf
authors.affiliation: Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Proebsting
authors.affiliation: Department of Innate Immunity, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Bernardo S
authors.initials: BS
authors.lastname: Franklin
authors.affiliation: Institute of Physiology I, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Pfeifer
authors.affiliation: Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Flender
authors.affiliation: Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Schmitz
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Institute of Physiology I, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Department of Internal Medicine II, Rheinische Friedrich-Wilhelms University, Bonn, Germany. Electronic address: nikos.werner@ukb.uni-bonn.de.
authors.forename: Nikos
authors.initials: N
authors.lastname: Werner
mesh_terms: D000368:Aged; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport; D049109:Cell Proliferation; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058426:Neointima / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference
chemical_list: D060488:Low Density Lipoprotein Receptor-Related Protein-6; C527111:MIRN126 microRNA, human; D035683:MicroRNAs
keywords: Endothelial microparticles; Microrna-126; Vascular remodelling