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Evidence of a role of Notch components in the formation and stabilization of blood vessels is provided by in vivo studies modulating the expression of the Notch receptor or ligand during development. The primary vascular plexus in mice begins remodeling at approximately embryonic day (E)9.5–11.5, leading to the establishment of arteries and veins. During early mouse embryogenesis, Dll4 is the first Notch ligand to be expressed in a robust manner, followed by Jagged1. Dll4 is expressed in the heart as well as in the endothelium of blood vessels . Haploinsufficiency for Dll4 in mice led to embryonic death at E10.5 due to vascular defects and disrupted basement membrane around the aorta . Dll4--null mice displayed more severe embryonic vascular defects, and embryonic death was observed at E9.5 . Excessive nonproductive angiogenesis with increased num-bers of tip cells has also been reported in zebrafish and mice retina models following loss of Dll4 expression.
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