title: The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/β-catenin signaling.
abstract: Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS transcription factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (Erg(cEC-KO)) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (Erg(iEC-KO)) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in Erg(cEC-KO) embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling.
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Birdsey
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Aarti V
authors.initials: AV
authors.lastname: Shah
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Dufton
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Reynolds
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Osuna Almagro
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Aspalter
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Samia T
authors.initials: ST
authors.lastname: Khan
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
authors.affiliation: FIRC Institute of Molecular Oncology Foundation, IFOM, 20139 Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Kairbaan
authors.initials: K
authors.lastname: Hodivala-Dilke
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine and Faculty of Medicine, University of Münster, D-48149 Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK. Electronic address: a.randi@imperial.ac.uk.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Randi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D051157:Frizzled Receptors / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D015513:Oncogene Proteins / Q000502:physiology*; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D000071230:Transcriptional Regulator ERG; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051157:Frizzled Receptors; D019426:Integrases; D015513:Oncogene Proteins; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D051176:beta Catenin; D000099152:Cadherin 5; C531115:ERG protein, mouse; C498581:Fzd4 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C045073:Cre recombinase