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dc.contributor.authorHarrington, LSen
dc.contributor.authorSainson, RCAen
dc.contributor.authorWilliams, CKen
dc.contributor.authorTaylor, JMen
dc.contributor.authorShi, Wen
dc.contributor.authorLi, J-Len
dc.contributor.authorHarris, ALen

The Notch ligand, Dll4, is essential for angiogenesis during embryonic vascular development and is involved in tumour angiogenesis. Several recent publications demonstrated that blockade of Dll4 signalling inhibits tumour growth, suggesting that it may constitute a good candidate for anti-cancer therapy. In order to understand the role of Dll4 at the cellular level, we performed an analysis of Dll4-regulated genes in HUVECs. The genes identified included several angiogenic signalling pathways, such as VEGF, FGF and HGF. In particular we identified downregulation (VEGFR2, placenta growth factor PlGF) of VEGF pathway components resulting in the overall effect of limiting the response of HUVEC to VEGF. However extensive upregulation of VEGFR1 was observed allowing continued response to its ligand PlGF but the soluble form of the VEGFR1, sVEGFR1 was also upregulated. PlGF enhanced tubulogenesis of HUVEC suggesting that downregulation of PlGF and upregulation of VEGFR1 including sVEGFR1 are important mechanisms by which Dll4 attenuates PlGF and VEGF signalling. Dll4-stimulated HUVECs had impaired ERK activation in response to VEGF and HGF indicating that Dll4 signalling negatively regulates these pathways. Dll4 expression reduced vessel sprout length in a 3D tubulogenesis assay confirming that Dll4 signalling inhibits angiogenesis. Altogether, our data suggest that Dll4 expression acts as a switch from the proliferative phase of angiogenesis to the maturation and stabilisation phase by blocking endothelial cell proliferation and allowing induction of a more mature, differentiated phenotype. The regulation of sVEGFR1 provides a novel mechanism for Dll4 signalling to regulate cells at distance, not just in adjacent cells.

dc.format.extent144 - 154en
dc.subjectBasic Helix-Loop-Helix Transcription Factorsen
dc.subjectCalcium-Binding Proteinsen
dc.subjectCell Differentiationen
dc.subjectCell Proliferationen
dc.subjectCells, Cultureden
dc.subjectCluster Analysisen
dc.subjectEndothelial Cellsen
dc.subjectEnzyme Activationen
dc.subjectExtracellular Signal-Regulated MAP Kinasesen
dc.subjectGene Expression Profilingen
dc.subjectGene Expression Regulationen
dc.subjectHepatocyte Growth Factoren
dc.subjectHomeodomain Proteinsen
dc.subjectIntercellular Signaling Peptides and Proteinsen
dc.subjectMembrane Proteinsen
dc.subjectNeovascularization, Physiologicen
dc.subjectOligonucleotide Array Sequence Analysisen
dc.subjectPlacenta Growth Factoren
dc.subjectPregnancy Proteinsen
dc.subjectProto-Oncogene Proteinsen
dc.subjectProto-Oncogene Proteins c-meten
dc.subjectRNA, Messengeren
dc.subjectReceptors, Growth Factoren
dc.subjectReceptors, Notchen
dc.subjectReproducibility of Resultsen
dc.subjectReverse Transcriptase Polymerase Chain Reactionen
dc.subjectSTAT1 Transcription Factoren
dc.subjectSerrate-Jagged Proteinsen
dc.subjectSignal Transductionen
dc.subjectSnail Family Transcription Factorsen
dc.subjectTranscription Factor HES-1en
dc.subjectTranscription Factorsen
dc.subjectTransduction, Geneticen
dc.subjectVascular Endothelial Growth Factor Aen
dc.subjectVascular Endothelial Growth Factor Receptor-1en
dc.titleRegulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells.en
dc.typeJournal Article
plymouth.journalMicrovasc Resen
plymouth.organisational-group/Plymouth/00 Groups by role
plymouth.organisational-group/Plymouth/00 Groups by role/Academics
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Biomedical Research Group
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Biomedical Research Group/RC Reporting Group BRG
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Collaboration for the Advancement of Medical Education Research Assessment
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
dc.publisher.placeUnited Statesen
dc.rights.embargoperiodNot knownen
rioxxterms.typeJournal Article/Reviewen

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