There are 32 possible combinations of experiments from manipulating the five Boolean values for initial vari ables. Boolean values indicate whether Tipifarnib price or not five processes are allowed. Initial total capillary length is 127 um, at 0 hrs, for all model runs. Experiment 5, where no process is permitted, indicates near base line values. in this case, the only growth or cellular addition is the initial formation of tip cells. Experiment 6, on the other hand, stands in for a positive control all processes are on, and maximum growth and proliferation of both tip and stalk cells are expected. Figure 5C shows how branching is related to elongation and proliferation. Inhibitors,Modulators,Libraries Without one or the other, there Inhibitors,Modulators,Libraries is no branching, significant branching occurs when only tip cell proliferation is turned off.

Persistence Representations of persistence were compared graphi cally. Figure Inhibitors,Modulators,Libraries 6 shows the calculations for persistence weighting and the effect on total vessel length over time. When VEGF levels are not uniform, using a search routine for a local gradient combined with intrinsic cell persistence, produces some random movement of cells. When the tip cells intrinsic persistence is replaced by a biased weight towards a particular grid location, the results are shown and compared to length changes in time where there is 20% intrinsic persistence. With uniform VEGF levels Inhibitors,Modulators,Libraries in the grid, entirely random tip cell motion limits the planar XY growth perpendi cular from the initial vessels, while also limiting the total length of capillary growth.

Without a biased directional preference by cells, the model predicts a tortuous vascular network, Inhibitors,Modulators,Libraries regardless of the number or vitamin d degree of activated cells. Other factors not yet explicitly modeled that could affect persistence include collagen fiber alignment, and the influence of contact guidance. Branching The effect of branching on total vessel length is shown in Figure 7. At the onset of angiogenesis, there is little branching. the model predicts it is not until 48 hrs in the default microenvironment, that branching has a signifi cant effect on the total vessel length changes. Branching predicted by the model correlates to results from available in vitro and in vivo experiments. In HUVECs cultured in 24 well plates with Matrigel at 10,000 cells well, the number of branch points at 24 hrs ranged from 5 for cells without growth factor to 80 for cells cultured with 100 ng ml soluble Dll4. Scaling these in vitro findings to the dimensions of 400 um 100 um 100 um, an estimate would be 0 2 branches in 24 hrs, which is what the model predicts at 10% branching for timesteps of 2 or 3 hrs. Dll4 Figure 8, and Movies 2, 3 and 4, show the effect of hypothetical haploinsuffi ciency of Dll4 during sprouting.