A hybrid model of the role of VEGF binding in endothelial cell migration and capillary formation.

Vascular endothelial growth factor (VEGF) is the most studied family of soluble, secreted mediators of endothelial cell migration, survival, and proliferation. VEGF exerts its function by binding to specific tyrosine kinase receptors on the cell surface and transducing the effect through downstream signaling. In order to study the influence of VEGF binding on endothelial cell motion, we develop a hybrid model of VEGF-induced angiogenesis, based on the theory of reinforced random walks. The model includes the chemotactic response of endothelial cells to angiogenic factors bound to cell-surface receptors, rather than approximating this as a function of extracellular chemical concentrations. This allows us to capture biologically observed phenomena such as activation and polarization of endothelial cells in response to VEGF gradients across their lengths, as opposed to extracellular gradients throughout the tissue. We also propose a novel and more biologically reasonable functional form for the chemotactic sensitivity of endothelial cells, which is also governed by activated cell-surface receptors. This model is able to predict the threshold level of VEGF required to activate a cell to move in a directed fashion as well as an optimal VEGF concentration for motion. Model validation is achieved by comparison of simulation results directly with experimental data.