Control of endothelial sprouting by a Tel-CtBP complex

ABSTRACT: Branching from conduits is a defining feature of the gas delivery systems of invertebrates (tracheae built from epithelial cells) and vertebrates (vasculature lined by endothelial cells). Here, we show that the vertebrate transcriptional repressor Tel plays an evolutionarily conserved role in angiogenesis: it is indispensable for sprouting of primary human endothelial cells and for the normal development of the Danio rerio embryo blood circulatory system. Tel controls endothelial sprouting via binding to the generic co-repressor C-terminal binding protein (CtBP). In endothelial cells, the Tel:CtBP complex temporally restricts a VEGF-mediated pulse of dll4 expression and consequently integrates VEGFR intracellular signaling and intercellular Notch-Dll4 signaling. It further refines branching by regulating expression of other factors that constrain angiogenesis such as sprouty family members and ve-cadherin. Thus, the Tel:CtBP complex moderates the balance between positive and antagonistic angiogenesis cues and thereby conditions endothelial cells for angiogenesis. Since the activity of CtBP is attuned to intracellular NADH levels, our results raise the possibility that Tel-mediated sprouting could be sensitized to the metabolic status of the tissue. Tel control of branching appears to be evolutionarily conserved since Yan, the invertebrate orthologue of Tel, is similarly required for branching morphogenesis of the invertebrate tracheae. Collectively, our work suggests that Tel is a central regulator of angiogenesis and highlights Tel and its associated networks as potential targets for the development of therapeutic strategies to inhibit pathological angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19335 | GEO | 2010/09/09

SECONDARY ACCESSION(S): PRJNA121703

REPOSITORIES: GEO