  During angiogenesis, endothelial cells compete for the tip position during
angiogenesis: a phenomenon named tip cell overtaking. It is still unclear to
what extent tip cell overtaking is a side effect of sprouting or to what extent
a biological function. To address this question, we studied tip cell overtaking
in two existing cellular Potts models of angiogenic sprouting. In these models
angiogenic sprouting-like behavior emerges from a small set of plausible cell
behaviors and the endothelial cells spontaneously migrate forwards and
backwards within sprouts, suggesting that tip cell overtaking might occur as a
side effect of sprouting. In accordance with experimental observations, in our
simulations the cells' tendency to occupy the tip position can be regulated
when two cell lines with different levels of Vegfr2 expression are contributing
to sprouting (mosaic sprouting assay), where cell behavior is regulated by a
simple VEGF-Dll4-Notch signaling network. Our modeling results suggest that tip
cell overtaking occurs spontaneously due to the stochastic motion of cells
during sprouting. Thus, tip cell overtaking and sprouting dynamics may be
interdependent and should be studied and interpreted in combination.
VEGF-Dll4-Notch can regulate the ability of cells to occupy the tip cell
position, but only when cells in the simulation strongly differ in their levels
of Vegfr2. We propose that VEGF-Dll4-Notch signaling might not regulate which
cell ends up at the tip, but assures that the cell that randomly ends up at the
tip position acquires the tip cell phenotype.
