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Blood, 1 February 2006, Vol. 107, No. 3, pp. 931-939. Prepublished online as a Blood First Edition Paper on October 11, 2005; DOI 10.1182/blood-2005-03-1000. This Article Full Text (PDF) All Versions of this Article: 2005-03-1000v1 107/3/931    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Williams, C. K Articles by Tosato, G. Search for Related Content PubMed PubMed Citation Articles by Williams, C. K Articles by Tosato, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 11, 2005 Accepted August 2, 2005 Upregulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function Cassin K Williams, Ji-Liang Li, Matilde Murga, Adrian L Harris*, and Giovanna Tosato Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Molecular Oncology Laboratories, Cancer Research UK, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom Molecular Oncology Laboratories, Cancer Research UK, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA * Corresponding author; email: harrisa{at}cancer.org.uk. Delta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing and some tumor endothelium, and is induced by vascular endothelial growth factor (VEGF)-A and hypoxia. Gene targeting studies have shown that Dll4 is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are currently not defined. In this study, we generated primary human endothelial cells that overexpress Dll4 protein to study Dll4 function and mechanism of action. Human umbilical vein endothelial cells retrovirally transduced with Dll4 displayed reduced proliferative and migratory responses selectively to VEGF-A. Expression of VEGF receptor-2, the principal signaling receptor for VEGF-A in endothelial cells, and co-receptor neuropilin-1 was significantly decreased in Dll4-transduced endothelial cells. Consistent with Dll4 signaling through Notch, expression of HEY2, one of the transcription factors that mediates Notch function, was significantly induced in Dll4-overexpressing endothelial cells. The -secretase inhibitor L-685,458 significantly reconstituted endothelial cell proliferation inhibited by immobilized extracellular Dll4, and reconstituted VEGFR2 expression in Dll4-overerexpressing endothelial cells. These results identify the Notch ligand Dll4 as a selective inhibitor of VEGF-A biological activities downregulating two VEGF receptors expressed on endothelial cells, and raise the possibility that Dll4 may be exploited therapeutically to modulate angiogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M.-T. Huang, Y.-S. Dai, Y.-B. Chou, Y.-H. Juan, C.-C. Wang, and B.-L. Chiang Regulatory T Cells Negatively Regulate Neovasculature of Airway Remodeling via DLL4-Notch Signaling J. 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