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During angiogenesis, new blood vessels headed by a migrating endothelial tipcell sprout from pre-existing ones. This process is known to be regulated bytwo signaling pathways concurrently, vascular endothelial growth factor A(VEGFA) and Notch-Delta. Extracellular VEGFA activates the intracellularNotch-Delta pathway in nearby endothelial cells which results in endothelial(stalk, tip) differentiation. Retinal astrocytes appear to play a crucial rolein polarizing new sprouts by secreting VEGFA. \emph{In vivo} retinalangiogenesis experiments in neonatal mouse generated quantitative data on dailycell counts and morphological data of vascular network expanding overfibronectin-rich matrix. Based on this set of data and other existing ones, wedeveloped a cell-based, multiscale mathematical model using the cellular Pottsmodel framework to investigate the sprout evolution by integrating the VEGFAand Notch-Delta signaling pathways. The model incorporates three levels ofdescription: intracellular, intercellular, and extracellular. Starting with asingle astrocyte embedded in a fibronectin-rich matrix, we use the model toassess different scenarios regarding VEGFA levels and its interaction withmatrix proteins. Simulation results suggest that astrocyte-derived VEGFAgradients along with heterogeneous ECM reproduces sprouting morphology, and theextension speed is in agreement with experimental data in 7 days postnatalmouse retina. Results also reproduce empirical observations in sproutingangiogenesis, including anastomosis, dynamic tip cell competition, and sproutregression as a result of Notch blockade.

Integrative modeling of sprout formation in angiogenesis: coupling the VEGFA-Notch signaling in a dynamic stalk-tip cell selection