The transcription factor ERG mediates multiple endothelial signalling pathways required for angiogenesis
File(s)
Author(s)
Shah, Aarti Vinodrai
Type
Thesis
Abstract
ERG is a crucial regulator of endothelial gene expression and controls endothelial functions including cell survival and monolayer permeability. Previous studies indicate a role for ERG in angiogenesis and vascular development, however the pathways through which ERG controls angiogenesis are unclear. Transcriptome profiling comparing ERG-positive and ERG-deficient endothelial cells has previously shown that ERG controls a network of genes that are essential to angiogenesis. This analysis identified genes involved in the Wnt, Notch and Angiopoietin1/Tie2 signalling pathways as candidate ERG targets.
ERG has been shown to drive expression of the junction molecule vascular endothelial (VE)–cadherin, which binds β-catenin, a crucial mediator of Wnt signalling, at the cell membrane. Here, I show that ERG controls β-catenin stability, by driving expression of both VE-cadherin and the Wnt receptor Frizzled-4- the balance of which regulates β-catenin localisation and activity. ERG promotes angiogenesis via Wnt/β-catenin signalling, since activation of Wnt signalling with lithium chloride, which stabilises β-catenin, corrects the angiogenic defect in ERG-deficient endothelial cells.
The Notch signalling pathway is critical for promoting vascular quiescence and I demonstrate that ERG controls Notch signalling by regulating the levels of two Notch ligands, Delta like ligand (Dll)-4 and Jagged-1, with reported opposing roles in the vasculature. ERG simultaneously drives expression of pro-quiescent Dll4 and represses expression of pro-angiogenic Jagged-1, which has been shown to antagonize Dll4-mediated signalling.
The Angiopoietin1/Tie2 pathway, also connected to the Wnt and Notch pathways, is a regulatory growth factor system essential for vessel maturation and quiescence. The results from this thesis suggest that ERG mediates growth factor Angiopoietin-1-dependent signals and ERG is required for Angiopoietin-1-induced Notch and Wnt signalling.
Thus, ERG is able to integrate with three signalling pathways controlling vascular growth and stability - Wnt, Notch, Angiopoietin1/Tie2- which may function downstream of ERG to regulate blood vessel patterning during angiogenesis.
ERG has been shown to drive expression of the junction molecule vascular endothelial (VE)–cadherin, which binds β-catenin, a crucial mediator of Wnt signalling, at the cell membrane. Here, I show that ERG controls β-catenin stability, by driving expression of both VE-cadherin and the Wnt receptor Frizzled-4- the balance of which regulates β-catenin localisation and activity. ERG promotes angiogenesis via Wnt/β-catenin signalling, since activation of Wnt signalling with lithium chloride, which stabilises β-catenin, corrects the angiogenic defect in ERG-deficient endothelial cells.
The Notch signalling pathway is critical for promoting vascular quiescence and I demonstrate that ERG controls Notch signalling by regulating the levels of two Notch ligands, Delta like ligand (Dll)-4 and Jagged-1, with reported opposing roles in the vasculature. ERG simultaneously drives expression of pro-quiescent Dll4 and represses expression of pro-angiogenic Jagged-1, which has been shown to antagonize Dll4-mediated signalling.
The Angiopoietin1/Tie2 pathway, also connected to the Wnt and Notch pathways, is a regulatory growth factor system essential for vessel maturation and quiescence. The results from this thesis suggest that ERG mediates growth factor Angiopoietin-1-dependent signals and ERG is required for Angiopoietin-1-induced Notch and Wnt signalling.
Thus, ERG is able to integrate with three signalling pathways controlling vascular growth and stability - Wnt, Notch, Angiopoietin1/Tie2- which may function downstream of ERG to regulate blood vessel patterning during angiogenesis.
Version
Open Access
Date Issued
2015-01
Date Awarded
2015-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Randi, Anna
Sponsor
National Heart & Lung Institute
Publisher Department
Vascular Sciences- National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)