The Notch signaling pathway is an important contributor to the development and 
homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch 
receptors and ligands have been linked to a variety of hereditary diseases that 
impact both the heart and the vasculature. In particular, mutations in the gene 
encoding the human Notch ligand jagged 1 result in a multisystem autosomal 
dominant disorder called Alagille syndrome, which includes tetralogy of Fallot 
among its more severe cardiac pathologies. Jagged 1 is expressed throughout the 
developing embryo, particularly in endothelial cells. Here, we demonstrate that 
endothelial-specific deletion of Jag1 leads to cardiovascular defects in both 
embryonic and adult mice that are reminiscent of those in Alagille syndrome. 
Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular 
septal defects, coronary vessel abnormalities and valve defects. Examination of 
mid-gestational embryos revealed that the loss of Jag1, similar to the loss of 
Notch1, disrupts endothelial-to-mesenchymal transition during endocardial 
cushion formation. Furthermore, adult mutant mice exhibit cardiac valve 
calcifications associated with abnormal matrix remodeling and induction of bone 
morphogenesis. This work shows that the endothelium is responsible for the wide 
spectrum of cardiac phenotypes displayed in Alagille Syndrome and it 
demonstrates a crucial role for Jag1 in valve morphogenesis.