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Angiogenesis involves the formation of new blood vessels by sprouting orsplitting of existing blood vessels. During sprouting, a highly motile type ofendothelial cell, called the tip cell, migrates from the blood vessels followedby stalk cells, an endothelial cell type that forms the body of the sprout. Toget more insight into how tip cells contribute to angiogenesis, we extended anexisting computational model of vascular network formation based on thecellular Potts model with tip and stalk differentiation, without making apriori assumptions about the differences between tip cells and stalk cells. Topredict potential differences, we looked for parameter values that make tipcells (a) move to the sprout tip, and (b) change the morphology of theangiogenic networks. The screening predicted that if tip cells respond lesseffectively to an endothelial chemoattractant than stalk cells, they move tothe tips of the sprouts, which impacts the morphology of the networks. Acomparison of this model prediction with genes expressed differentially in tipand stalk cells revealed that the endothelial chemoattractant Apelin and itsreceptor APJ may match the model prediction. To test the model prediction weinhibited Apelin signaling in our model and in an \emph{in vitro} model ofangiogenic sprouting, and found that in both cases inhibition of Apelin or ofits receptor APJ reduces sprouting. Based on the prediction of thecomputational model, we propose that the differential expression of Apelin andAPJ yields a "self-generated" gradient mechanisms that accelerates theextension of the sprout.

Computational Screening of Tip and Stalk Cell Behavior Proposes a Role for Apelin Signaling in Sprout Progression