title: MicroRNA-18a improves human cerebral arteriovenous malformation endothelial cell function.
abstract: OBJECTIVE
  Cerebral arteriovenous malformation (AVM) is a vascular disease that disrupts normal blood flow and leads to serious neurological impairment or death. Aberrant functions of AVM-derived brain endothelial cells (AVM-BECs) are a disease hallmark. Our aim was to use microRNA-18a (miR-18a) as a therapeutic agent to improve AVM-BEC function.
  
  
  METHODS
  Human AVM-BECs were tested for growth factor production and proliferation under different shear flow conditions and evaluated for tubule formation. Thrombospondin-1, inhibitor of DNA-binding protein 1, and vascular endothelial growth factor (VEGF) isotype mRNA levels were quantified by quantitative real-time polymerase chain reaction. Thrombospondin-1, VEGF-A, and VEGF-D protein expression was measured using enzyme-linked immunosorbent assay. Proliferation and tubule formation were evaluated using bromodeoxyuridine incorporation and growth factor-reduced Matrigel assays, respectively.
  
  
  RESULTS
  miR-18a increased thrombospondin-1 production but decreased inhibitor of DNA-binding protein 1, a transcriptional repressor of thrombospondin-1. miR-18a reduced VEGF-A and VEGF-D levels, both overexpressed in untreated AVM-BECs. This is the first study reporting VEGF-D overexpression in AVM. These effects were most prominent under arterial shear flow conditions. miR-18a also reduced AVM-BEC proliferation, improved tubule formation, and was effectively internalized by AVM-BECs in the absence of extraneous transfection reagents.
  
  
  CONCLUSIONS
  We report VEGF-D overexpression in AVM and the capacity of miR-18a to induce AVM-BECs to function more normally. This highlights the clinical potential of microRNA as a treatment for AVM and other vascular diseases.
authors.affiliation: From the Department of Neurological Surgery (R.F., A.A., T.C.C., S.L.G., F.M.H.), Department of Pathology (T.S., T.C.C., F.M.H.), and Department of Molecular Microbiology and Immunology (S.M.T.), Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Raquel
authors.initials: R
authors.lastname: Ferreira
authors.forename: Tiago
authors.initials: T
authors.lastname: Santos
authors.forename: Arun
authors.initials: A
authors.lastname: Amar
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Tahara
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
authors.forename: Steven L
authors.initials: SL
authors.lastname: Giannotta
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
mesh_terms: D000792:Angiography; D000963:Antimetabolites; D001921:Brain / Q000166:cytology / Q000473:pathology; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D020785:Central Nervous System Vascular Malformations / Q000188:drug therapy* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D035683:MicroRNAs / Q000627:therapeutic use*; D008870:Microtubules / Q000187:drug effects; D019699:Thrombospondins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D051798:Inhibitor of Differentiation Protein 1; C522576:MIRN18A microRNA, human; D035683:MicroRNAs; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; D001973:Bromodeoxyuridine
keywords: arteriovenous malformations; endothelial cells; microRNAs; thrombospondin 1; vascular endothelial growth factor D