Thus, from the model, it would be predicted, that where there is no VEGF gradient and cells are activated, total vessel length increases CC-5013 significantly from 24 72 hrs, though largely indepen dent of the concentration of VEGF beyond 1 ng ml. this is in good qualitative agreement with Inhibitors,Modulators,Libraries the trend lines for VEGF dependence from experiments using a bovine aortic endothelial cell radial array assay, which showed saturation in vessel length changes with increasing. Furthermore, the model predicts that increasing overall uniform VEGF concentration increases the variability in the length changes. In qualitatively comparing the Inhibitors,Modulators,Libraries model predictions to experimental measurements of sprout increase as a function of VEGF and time in HUVEC spheroid models seeded in a collagen gel, two things are of note.

One, the variability in results from one experiment to another is high, while two, the sprout length changes are generally less than that predicted by the model at 48 and 72 hrs. This latter observation may reflect that the current model has no boundary restrictions. In vivo, the sprouting capillaries would be restricted by tissue and other vasculature, and in vitro, Inhibitors,Modulators,Libraries the extracellular matrix could affect growth differently than modeled, as could the limited viability of the cells in culture. In the current simulation, there is no mechanical limitation on their growth and only several initial capillaries present in the model. moreover, cell apoptosis and vessel pruning has yet to be considered. In further renditions of the model, it will be important to test the effect of larger capillary networks.

the presence of other cells and tissues. and the effect of apoptosis and vessel pruning. While independent rules for migration and Inhibitors,Modulators,Libraries proliferation are a function of absolute VEGF concentration, the driving force for angiogenesis predicted by the model is VEGF gradient. The structure of the vasculature in the simulation changes over time, and this is caused by VEGF gradients stimulating a directed growth with the described push pull phenomenon associated Inhibitors,Modulators,Libraries with tip and stalk cells. The VEGF gradient provides a chemical cue that promotes the motion of the tip cell. Increases in VEGF concentration alone do not have this effect, but rather increases speed and random motility of cells, in the model. this has also been supported experimentally.

Once the leading node of the etc tip cell moves, the adjacent stalk cell elongates or grows to maintain contact and vessel integrity. Beyond what has been modeled and discussed so far, there are a number of other factors that influence VEGF gradients and a cells response to them. Endothelial cells themselves may secrete VEGF as they form a sprout. Outside the primary source of VEGF stimuli, cells such as pericytes, endothelial cell precursors and smooth muscle cells may influence VEGF levels by secretion or physical position.