title: Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth.
abstract: BACKGROUND
  The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long noncoding RNAs in the vasculature are largely unknown.
  
  
  OBJECTIVE
  Here, we characterized the expression of long noncoding RNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1).
  
  
  RESULTS
  Endothelial cells of different origin express relative high levels of the conserved long noncoding RNAs MALAT1, taurine upregulated gene 1 (TUG1), maternally expressed 3 (MEG3), linc00657, and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by small interfering RNAs or GapmeRs induced a promigratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by vascular endothelial growth factor, MALAT1 small interfering RNAs induced discontinuous sprouts indicative of defective proliferation of stalk cells. In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularization. Pharmacological inhibition of MALAT1 by GapmeRs reduced blood flow recovery and capillary density after hindlimb ischemia. Gene expression profiling followed by confirmatory quantitative reverse transcriptase-polymerase chain reaction demonstrated that silencing of MALAT1 impaired the expression of various cell cycle regulators.
  
  
  CONCLUSIONS
  Silencing of MALAT1 tips the balance from a proliferative to a migratory endothelial cell phenotype in vitro, and its genetic deletion or pharmacological inhibition reduces vascular growth in vivo.
authors.affiliation: From the Institute of Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (K.M.M., Y.M., A.D., D.J., Y.P., S.U., R.A.B., S.D.); Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin-Buch, Germany (X.Y., W.C.); Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Tumor Therapy, Frankfurt, Germany (M.Z.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.); and German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany (T.B., S.U., S.D.).
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Michalik
authors.forename: Xintian
authors.initials: X
authors.lastname: You
authors.forename: Yosif
authors.initials: Y
authors.lastname: Manavski
authors.forename: Anuradha
authors.initials: A
authors.lastname: Doddaballapur
authors.forename: Martin
authors.initials: M
authors.lastname: Zörnig
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: David
authors.initials: D
authors.lastname: John
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Ponomareva
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Shizuka
authors.initials: S
authors.lastname: Uchida
authors.forename: Reinier A
authors.initials: RA
authors.lastname: Boon
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; C557041:MALAT1 long non-coding RNA, human; C557040:Malat1 long non-coding RNA, mouse; D009841:Oligonucleotides; D062085:RNA, Long Noncoding
keywords: RNA, long noncoding; angiogenesis effect; endothelium; ischemia; neovascularization inhibitors