Vascular patterning defects associated with expression of activated Notch4in embryonic endothelium

Notch proteins function as receptors for membrane-bound ligands (Jagged and Delta-like) to regulate cell-fate determination. We have investigated the role of Notch signaling in embryonic endothelium of the mouse by expressing an activated form of the Notch4 protein in vasculature under the regulatio n of the Flk1 (VEGFR) locus. Expression of activated Notch4 results in a gr owth and developmental delay and embryonic lethality at about 10 days postc oitum. The extent of the developing vasculature in mutant embryos was restr icted, fewer small vessels were seen, and vascular networks were disorganiz ed. The brain periphery of mutant embryos contained large dilated vessels w ith evidence of compromised vessel-wall integrity and large areas of necros is; yolk-sac vasculature was abnormal. Expression of an activated form of N otch4 in embryonic vasculature leads to abnormal vessel structure and patte rning, implicating the Notch pathway in phases of vascular development asso ciated with vessel patterning and remodeling.