Purchase this article with an account.
C. Mailhos; Analysis of the Notch ligand Delta–4 in developmental and pathological neovascularization . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4654.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: Delta–Notch signaling regulates cell–fate choices in tissues during metazoan development, including the cardiovasculature. Delta4 (Dl4) is a Notch ligand expressed primarily in arterial endothelium during early mouse embryogenesis. Subsequent expression is restricted to microvessels and levels are greatly reduced in adult tissues. However, Dl4 expression is re–activated in sites of active blood vessel growth in the adult mouse, such as the maturing follicles of the ovary, and during pathological neovascular situations. Our current aim is to better understand Dl4 function, and its potential as a vascular target in ocular neovascular disease. Methods: To analyze Dl4 function in embryonic development, we have generated null and conditional loss–of–function Dl4 mice. Null mutants were generated by deletion of the first exon and insertion of an IRES–ß–gal–neo cassette by homologous recombination. Endothelial–specific knockout mice were generated by insertion of lox sites flanking the first three exons of the Delta–4 gene and deletion of these segments by breeding to mice harboring Tie1Cre. Dl4 expression during retinal vascular development and pathological retinal neovascularization was characterized using in situ hybridization and qRT–PCR. Results:Analysis of Dl4 null mice revealed that recovery of heterozygote animals occurred at a lower frequency than expected (25–30%), suggesting a partially penetrant haplo–insufficiency. No homozygote embryos were found as early as embryonic day 7, before any vascular patterning occurs, suggesting an earlier role for Dl4 in mouse development. Deletion of Dl4 function specifically within the developing endothelium resulted in defective aorta formation, loss of arterial identity, impaired microvessel sprouting into the neural tube and abnormal yolk sac microvasculature. Lastly, a potential role for Dl4 in ocular angiogenesis is suggested by its restricted expression at the very front of growing microvessels as they extend peripherally during retinal development, and by its upregulation during pathological retinal neovascularization. Conclusion: Dl4’s vessel–specific expression, functional role in vessel morphogenesis and re–activation during pathological ocular neovascularization make it an attractive new target for anti–angiogenic therapy.
This PDF is available to Subscribers Only