title: Development of Long Noncoding RNA-Based Strategies to Modulate Tissue Vascularization.
abstract: BACKGROUND
  Long noncoding ribonucleic acids (lncRNAs) are a subclass of regulatory noncoding ribonucleic acids for which expression and function in human endothelial cells and angiogenic processes is not well studied.
  
  
  OBJECTIVE
  The authors discovered hypoxia-sensitive human lncRNAs via next-generation ribonucleic acid sequencing and microarray approaches. To address their functional importance in angiogenic processes, several endothelial lncRNAs were characterized for their angiogenic characteristics in vitro and ex vivo.
  
  
  METHODS
  Ribonucleic acid sequencing and microarray-derived data showed specific endothelial lncRNA expression changes after hypoxia. Validation experiments confirmed strong hypoxia-dependent activation of 2 intergenic lncRNAs: LINC00323 and MIR503HG.
  
  
  RESULTS
  Silencing of these lncRNA transcripts led to angiogenic defects, including repression of growth factor signaling and/or the key endothelial transcription factor GATA2. Endothelial loss of these hypoxia-driven lncRNAs impaired cell-cycle control and inhibited capillary formation. The potential clinical importance of these endothelial lncRNAs to vascular structural integrity was demonstrated in an ex vivo model of human induced pluripotent stem cell-based engineered heart tissue.
  
  
  CONCLUSIONS
  The authors report an expression atlas of human hypoxia-sensitive lncRNAs and identified 2 lncRNAs with important functions to sustain endothelial cell biology. LncRNAs hold great promise to serve as important future therapeutic targets of cardiovascular disease.
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Fiedler
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg, Eppendorf, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
authors.forename: Kaja
authors.initials: K
authors.lastname: Breckwoldt
authors.affiliation: Department of Bioinformatics, University of Würzburg, Würzburg, Germany.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Remmele
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Hartmann
authors.affiliation: Department of Bioinformatics, University of Würzburg, Würzburg, Germany; Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Pfanne
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Just
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
authors.forename: Ke
authors.initials: K
authors.lastname: Xiao
authors.affiliation: Department of Bioinformatics, University of Würzburg, Würzburg, Germany.
authors.forename: Meik
authors.initials: M
authors.lastname: Kunz
authors.affiliation: Department of Bioinformatics, University of Würzburg, Würzburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg, Eppendorf, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Hansen
authors.affiliation: Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Department of Bioinformatics, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg, Eppendorf, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany; National Heart and Lung Institute, Imperial College London, London, United Kingdom; REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany. Electronic address: thum.thomas@mh-hannover.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics*; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D023822:Tissue Engineering / Q000379:methods
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D062085:RNA, Long Noncoding; C000610378:long non-coding RNA MIR503HG, human
keywords: angiogenesis; endothelial cell biology; hypoxia; lncRNA