The Endothelial Transcription Factor ERG Promotes Vascular Stability and Growth through Wnt/β-Catenin Signaling
| Autor: | Neil Dufton, Kairbaan Hodivala-Dilke, Louise E. Reynolds, Samia Taufiq Khan, Berthold Göttgens, Ralf H. Adams, Anna M. Randi, Aarti V. Shah, Holger Gerhardt, Irene M. Aspalter, Lourdes Osuna Almagro, Graeme M. Birdsey, Elisabetta Dejana, Justin C. Mason, Youwen Yang |
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| Přispěvatelé: | British Heart Foundation, Gottgens, Berthold [0000-0001-6302-5705], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Předmět: |
Vascular Endothelial Growth Factor A
Frizzled genetic structures Angiogenesis CELL DIFFERENTIATION PATHWAY ACTIVATION Mice 0302 clinical medicine Pregnancy Lung IN-VIVO Cells Cultured beta Catenin 11 Medical and Health Sciences Transcriptional Regulator ERG Oncogene Proteins 0303 health sciences biology Wnt signaling pathway Cadherins 3. Good health Vascular endothelial growth factor B Vascular endothelial growth factor A N-CADHERIN 030220 oncology & carcinogenesis Female Erg Life Sciences & Biomedicine Signal Transduction EXPRESSION Chromatin Immunoprecipitation Beta-catenin PATHOLOGICAL ANGIOGENESIS Blotting Western VE-CADHERIN Neovascularization Physiologic Mice Transgenic Real-Time Polymerase Chain Reaction Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Antigens CD Human Umbilical Vein Endothelial Cells Animals Humans Molecular Biology 030304 developmental biology Science & Technology Integrases Cell Biology 06 Biological Sciences GENE Frizzled Receptors eye diseases Wnt Proteins biology.protein Cancer research THERAPEUTIC ANGIOGENESIS Endothelium Vascular sense organs Developmental Biology Transcription Factors |
| Zdroj: | Developmental Cell |
| ISSN: | 1534-5807 |
| DOI: | 10.1016/j.devcel.2014.11.016 |
| Popis: | Summary 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 (ErgcEC-KO) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (ErgiEC-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 ErgcEC-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. Graphical Abstract Highlights • Inducible deletion of endothelial ERG in mice causes defective angiogenesis • ERG controls vascular stability through Wnt/β-catenin signaling • β-catenin activation rescues the angiogenic defect in vivo in ERG-deficient mice • Overexpression of ERG in vivo stabilizes VEGF-induced angiogenesis Birdsey, Shah et al. show that the endothelial ETS factor ERG controls Wnt/β-catenin signaling by promoting β-catenin stability, through pathways mediated by VE-cadherin and the Wnt receptor Frizzled-4. In vivo, ERG overexpression stabilizes VEGF-dependent angiogenesis. Thus, ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling. |
| Databáze: | OpenAIRE |
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