title: Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells.
abstract: Signaling between endothelial cells, endothelial progenitor cells, and stromal cells is crucial for the establishment and maintenance of vascular integrity and involves exosomes, among other signaling pathways. Exosomes are important mediators of intercellular communication in immune signaling, tumor survival, stress responses, and angiogenesis. The ability of exosomes to incorporate and transfer messenger RNAs (mRNAs) encoding for "acquired" proteins or micro RNAs (miRNAs) repressing "resident" mRNA translation suggests that they can influence the physiological behavior of recipient cells. We demonstrate that miR-214, an miRNA that controls endothelial cell function and angiogenesis, plays a dominant role in exosome-mediated signaling between endothelial cells. Endothelial cell-derived exosomes stimulated migration and angiogenesis in recipient cells, whereas exosomes from miR-214-depleted endothelial cells failed to stimulate these processes. Exosomes containing miR-214 repressed the expression of ataxia telangiectasia mutated in recipient cells, thereby preventing senescence and allowing blood vessel formation. Concordantly, specific reduction of miR-214 content in exosome-producing endothelial cells abolishes the angiogenesis stimulatory function of the resulting exosomes. Collectively, our data indicate that endothelial cells release miR-214-containing exosomes to stimulate angiogenesis through the silencing of ataxia telangiectasia mutated in neighboring target cells.
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands. b.w.m.vanbalkom@umcutrecht.nl
authors.forename: Bas W M
authors.initials: BW
authors.lastname: van Balkom
authors.forename: Olivier G
authors.initials: OG
authors.lastname: de Jong
authors.forename: Michiel
authors.initials: M
authors.lastname: Smits
authors.forename: Jolanda
authors.initials: J
authors.lastname: Brummelman
authors.forename: Krista
authors.initials: K
authors.lastname: den Ouden
authors.forename: Petra M
authors.initials: PM
authors.lastname: de Bree
authors.forename: Monique A J
authors.initials: MA
authors.lastname: van Eijndhoven
authors.forename: D Michiel
authors.initials: DM
authors.lastname: Pegtel
authors.forename: Willem
authors.initials: W
authors.lastname: Stoorvogel
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism* / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D055571:Secretory Pathway / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases