Table 1.
Notch cardiovascular phenotypes in mouse models.
| Gene | Normal cardiovascular expression | Genetic mouse model and cardiovascular phenotype | Survival | Reference |
|---|---|---|---|---|
| Notch1 | Arterial endothelium Vascular smooth muscle |
Global null: collapsed aorta and cardinal vein, reduced sprouting angiogenesis, abnormal yolk sac vasculature, and vascular remodeling | Lethal at E9.0–9.5 | Krebs et al. (2000, 2010) |
| Endocardium Atrioventricular canal |
EC gain of function: enlarged heart and reduced vessel diameter, abnormal remodeling of yolk sac vasculature, hemorrhaging | Lethal at E9.5 | ||
| Notch2 | Cardiac neural crest-derived VSMC | Global null: reduced pulmonary artery and aortic VSMC proliferation, defects in eye vasculature | Lethal at E11.5 | Krebs et al. (2000), Varadkar et al. (2008) |
| Endothelium | ||||
| Notch3 | Vascular smooth muscle | VSMC null: decreased VSMC differentiation, dilated aorta, and disorganized elastic lamina | Viable | Ruchoux et al. (2003), Domenga et al. (2004) |
| Pericytes | R169C mutation: Notch3ECD domain aggregates and GOM deposits in brain vessels, reduced caliber of brain arteries, and cerebral blood flow | |||
| Notch4 | Endothelium Endocardium Atrioventricular canal |
Global null: mainly undetectable vascular malformations, with enhanced vascular abnormalities when to crossed with Notch1 null mice compared to Notch1 null alone | Viable | Krebs et al. (2000) |
| Jag-1 | Endothelium VSMC Heart |
Global null: reduced VSMC maturation, abnormal yolk sac and embryonic vascular remodeling, cranial hemorrhaging | Lethal at E11.5–12 | Xue et al. (1999) |
| Dll-1 | Arterial endothelium late in development VSMC, adult EC |
Global null: hemorrhaging, increased venous EC markers, reduced arterial EC markers, impaired recovery of blood flow after hindlimb ischemia | Lethal at E12 | Hrabe de Angelis et al. (1997), Limbourg et al. (2007) |
| Dll-4 | Endothelium | Global null: defective arterial branching, aortic atresia, arterial regression, large artery stenosis, abnormal yolk sac vasculature | Lethal at E9.5 | Gale et al. (2004), Krebs et al. (2004), Trindade et al. (2008) |
| Endocardium | EC gain of function: enlarged dorsal aorta, reduced vascular sprouting, proliferation, migration, and sensitivity to VEGF | Lethal at E10 |
Gene targeting mutations in the Jag-2 and Dll-3 genes lead to developmental abnormalities, but no cardiovascular phenotypes have been reported. EC, endothelial cell; VSMC, vascular smooth muscle cell.