Journal
DEVELOPMENTAL CELL
Volume 32, Issue 1, Pages 82-96Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2014.11.016
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Funding
- British Heart Foundation [PG/09/096, RG/11/17/29256]
- National Lung and Heart Institute Foundation Studentship
- DOC-fFORTE fellowship of the Austrian Academy of Sciences at the London Research Institute
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
- Biotechnology and Biological Sciences Research Council [BB/I00050X/1] Funding Source: researchfish
- British Heart Foundation [PG/10/94/28651, RG/11/17/29256] Funding Source: researchfish
- Cancer Research UK [12007, 12765, 18673] Funding Source: researchfish
- Medical Research Council [MC_PC_12009, G0901609, 1365527] Funding Source: researchfish
- Worldwide Cancer Research [12-1068] Funding Source: researchfish
- BBSRC [BB/I00050X/1] Funding Source: UKRI
- MRC [G0901609] Funding Source: UKRI
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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/beta-catenin pathway by promoting beta-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 beta-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.
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