Elongation, proliferation & migration differentiate endothelial cell phenotypes and determine capillary sprouting

We present a multiscale systems model that closely simulates the mechanisms underlying sprouting at the onset of angiogenesis. Designed by agent-based programming, the model uses logical rules to guide the behavior of individual endothelial cells and segments of cells. The activation, proliferation, and movement of these cells lead to capillary growth in three dimensions. By this means, a novel capillary network emerges out of combinatorially complex interactions of single cells. Rules and parameter ranges are based on literature data on endothelial cell behavior in vitro. The model is designed generally, and will subsequently be applied to represent species-specific, tissue-specific in vitro and in vivo conditions.Initial results predict tip cell activation, stalk cell development and sprout formation as a function of local vascular endothelial growth factor concentrations and the Delta-like 4 Notch ligand, as it might occur in a three-dimensional in vitro setting. Results demonstrate the differential effects of ligand concentrations, cell movement and proliferation on sprouting and directional persistence.This systems biology model offers a paradigm closely related to biological phenomena and highlights previously unexplored interactions of cell elongation, migration and proliferation as a function of ligand concentration, giving insight into key cellular mechanisms driving angiogenesis.As a new capillary grows from a blood vessel, a series of cellular processes occur. These vascularization events have been extensively studied experimentally, however the whole angiogenic sequence has yet to be characterized by any experiment or model, and numerous unknowns remain. What is known is that an endothelial cell from an existing vessel becomes activated. The activated cell starts to migrate into the extracellular matrix by degrading it; this unique, spindle-shaped cell is called the tip cell. Cells adjacent to the tip cell begin to proliferate, and follow the tip cell; t