AN ANTISENSE OLIGONUCLEOTIDE TO THE NOTCH LIGAND JAGGED ENHANCES FIBROBLAST GROWTH FACTOR-INDUCED ANGIOGENESIS IN-VITRO

Angiogenesis, or the formation of new blood vessels, plays a central r ole in a number of physiologic and pathologic conditions, including wo und healing, dia betic retinopathy, and solid tumor growth, and endoth elial cells can be induced to mimic this process in vitro. Using a mod ification of the differential display method (Zimrin, A. B., Villepont eau, B., and Maciag, T. (1995) Biochem, Biophys, Res. Commun. 213, 630 -638), we isolated the human homolog of the Jagged ligand for the Notc h receptor from human endothelial cells exposed to fibrin and demonstr ate that the Jagged transcript, but not the Notch 1 or Notch 2 transcr ipts, are up-regulated by fibrin, Interestingly, the addition of an an tisense Jagged oligomer to bovine microvascular endothelial cells grow n on a collagen gel resulted in a marked increase in invasion and tube formation in the underlying gel in response to fibroblast growth fact or. In contrast, no effect was observed on vascular endothelial growth factor-induced angiogenesis under identical conditions, These data su ggest that Jagged-Notch signaling is able to regulate fibroblast growt h factor-induced endothelial cell migration in vitro, an early event d uring angiogenesis in vivo.