The Endothelial Transcription Factor ERG Promotes Vascular Stability and Growth through Wnt/β-Catenin Signaling

Abstract

SummaryBlood 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.

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

“…Deletion of Erg resulted in embryonic lethality by embryonic day (E) 11.5-E12.5, similar to previous reports (Birdsey et al, 2015;Vijayaraj et al, 2012) (Fig. S7A-F).…”

“…Crucially, mutation of S215 to alanine, an amino acid refractory to phosphorylation (a so-called 'phospho mutant'), abolishes ERG function in prostate cancer cells (Selvaraj et al, 2015). Although several studies have implicated ERG as a mediator of EC survival, proliferation, motility and vascular integrity (Birdsey et al, 2008(Birdsey et al, , 2012(Birdsey et al, , 2015Liu and Patient, 2008;Yuan et al, 2011), whether ERG acts as a hub, integrating signals downstream of VEGF to control these diverse EC behaviors is not known.…”

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

“…Proangiogenic effects of lithium were demonstrated in our endothelial cell culture and also in previous studies in embryonic vessels in vivo and in endothelial cells in vitro. 63,64 Our data suggest that lithium's vascular effects were likely mediated primarily through activation of the Wnt signaling pathway, by inhibiting the secondary Wnt signaling complex containing GSK3b, thus stabilizing the downstream factor b-catenin to eventually promote vascular formation. However, it is not clear whether potential Wnt/GSK3-independent effects of lithium may also be at work, including those through inositol depletion, 65 bone morphogenetic protein (BMP)-2 signaling, 66 transcription factor 7-like 2 gene RNA splicing, 67 or mitogenactivated protein (MAP) extracellular signal-related kinase (ERK) kinase (MEK)-ERK pathway.…”

Development and plasticity of alveolar type 1 cells

“…6B,C). This was accompanied by a simplified vascular network, as determined using the endothelial marker ICAM2, which labels both cell junctions and cell surface (Halai et al, 2014), and a lower, albeit variable, density of endothelial cells as determined using the endothelial nuclear marker ERG (Birdsey et al, 2015) (three mice in each group; Fig. 6C).…”