The DOI matches its Crossref record; 66 of the 66 references it cites were found in a registry or an index.
Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function
Open accessAbstract
Delta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing endothelium and in some tumor endothelium, and it 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 coreceptor 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 γ-secretase inhibitor L-685458 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 biologic activities down-regulating 2 VEGF receptors expressed on endothelial cells and raise the possibility that Dll4 may be exploited therapeutically to modulate angiogenesis.
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Cites
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Cited by
Goel, H. L., & Mercurio, A. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3627 · Cited by 1,253
Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis
Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R. J., Callahan, C., Kasman, I., et al. (2006) · Nature · doi:10.1038/nature05313 · Cited by 986
Angiogenesis: A Team Effort Coordinated by Notch
Phng, L.-K., & Gerhardt, H. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.01.015 · Cited by 832
Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries
Siekmann, A. F., & Lawson, N. D. (2007) · Nature · doi:10.1038/nature05577 · Cited by 687
VEGF and Notch in Tip and Stalk Cell Selection
Blanco, R., & Gerhardt, H. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006569 · Cited by 620
Metadata
- Authors
- Williams, C. K., Li, J.-L., Murga, M., Harris, A. L., & Tosato, G.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-02-01
- Volume
- 107
- Issue
- 3
- Pages
- 931-939
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2073465941
- Cited by
- 360
- References
- 66
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- green
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