Angiogenesis involves the formation of new blood vessels by sprouting or
splitting of existing blood vessels. During sprouting, a highly motile type of
endothelial cell, called the tip cell, migrates from the blood vessels followed
by stalk cells, an endothelial cell type that forms the body of the sprout. To
get more insight into how tip cells contribute to angiogenesis, we extended an
existing computational model of vascular network formation based on the
cellular Potts model with tip and stalk differentiation, without making a
priori assumptions about the differences between tip cells and stalk cells. To
predict potential differences, we looked for parameter values that make tip
cells (a) move to the sprout tip, and (b) change the morphology of the
angiogenic networks. The screening predicted that if tip cells respond less
effectively to an endothelial chemoattractant than stalk cells, they move to
the tips of the sprouts, which impacts the morphology of the networks. A
comparison of this model prediction with genes expressed differentially in tip
and stalk cells revealed that the endothelial chemoattractant Apelin and its
receptor APJ may match the model prediction. To test the model prediction we
inhibited Apelin signaling in our model and in an \emph{in vitro} model of
angiogenic sprouting, and found that in both cases inhibition of Apelin or of
its receptor APJ reduces sprouting. Based on the prediction of the
computational model, we propose that the differential expression of Apelin and
APJ yields a "self-generated" gradient mechanisms that accelerates the
extension of the sprout.Comment: 48 pages, 10 figures, 8 supplementary figures. Accepted for
publication in PLoS ON