Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting

Spatial regulation of angiogenesis is important for the generation of functionalengineered vasculature in regenerative medicine. The Notch ligands Jag1 andDll4 show distinct expression patterns in endothelial cells and, respectively, pro-mote and inhibit endothelial sprouting. Therefore, patterns of Notch ligands maybe utilized to spatially control sprouting, but their potential and the underlyingmechanisms of action are unclear. Here, we coupled in vitro and in silico modelsto analyze the ability of micropatterned Jag1 and Dll4 ligands to spatially controlendothelial sprouting. Dll4 patterns, but not Jag1 patterns, elicited spatial con-trol. Computational simulations of the underlying signaling dynamics suggestthat different timing of Notch activation by Jag1 and Dll4 underlie their distinctability to spatially control sprouting. Hence, Dll4 patterns efficiently direct thesprouts, whereas longer exposure to Jag1 patterns is required to achieve spatialcontrol. These insights in sprouting regulation offer therapeutic handles forspatial regulation of angiogenesis.</p