The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/β-catenin signaling

Graeme M Birdsey; Aarti V Shah; Neil Dufton; Louise E Reynolds; Lourdes Osuna Almagro; Youwen Yang; Irene M Aspalter; Samia T Khan; Justin C Mason; Elisabetta Dejana; Berthold Göttgens; Kairbaan Hodivala-Dilke; Holger Gerhardt; Ralf H Adams; Anna M Randi

doi:10.1016/j.devcel.2014.11.016

The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/β-catenin signaling

Dev Cell. 2015 Jan 12;32(1):82-96. doi: 10.1016/j.devcel.2014.11.016.

Authors

Affiliations

¹ National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
² 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.
³ Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK.
⁴ FIRC Institute of Molecular Oncology Foundation, IFOM, 20139 Milan, Italy.
⁵ Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
⁶ Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine and Faculty of Medicine, University of Münster, D-48149 Münster, Germany.
⁷ National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / genetics
Antigens, CD / metabolism
Blotting, Western
Cadherins / genetics
Cadherins / metabolism
Cells, Cultured
Chromatin Immunoprecipitation
Endothelium, Vascular / cytology*
Endothelium, Vascular / metabolism*
Female
Frizzled Receptors / metabolism
Human Umbilical Vein Endothelial Cells / cytology
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Integrases / metabolism
Lung / cytology
Lung / metabolism
Mice
Mice, Transgenic
Neovascularization, Physiologic*
Oncogene Proteins / physiology*
Pregnancy
Real-Time Polymerase Chain Reaction
Signal Transduction
Transcription Factors / physiology*
Transcriptional Regulator ERG
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism
Wnt Proteins / genetics
Wnt Proteins / metabolism*
beta Catenin / genetics
beta Catenin / metabolism*

Substances

Antigens, CD
Cadherins
ERG protein, mouse
Frizzled Receptors
Fzd4 protein, mouse
Oncogene Proteins
Transcription Factors
Transcriptional Regulator ERG
Vascular Endothelial Growth Factor A
Wnt Proteins
beta Catenin
cadherin 5
vascular endothelial growth factor A, mouse
Cre recombinase
Integrases

Abstract

Publication types

MeSH terms

Substances

Grants and funding