3D hybrid modeling of vascular network formation

Abstract: We develop an agent-based model of vasculogenesis, the de novo formation of blood vessels. Endothelial cells in the vessel network are viewed as linearly elastic spheres and are of two types: vessel elements are contained within the network; tip cells are located at endpoints. Tip cells move in response to forces due to interactions with neighbouring vessel elements, the local tissue environment, chemotaxis and a persistence force modeling their tendency to continue moving in the same direction. Vessel elements experience similar forces but not chemotaxis. An angular persistence force representing local tissue interactions stabilises buckling instabilities due to proliferation. Vessel elements proliferate, at rates that depend on their degree of stretch: elongated elements proliferate more rapidly than compressed elements. Following division, new cells are more likely to form new sprouts if the parent vessel is highly compressed and to be incorporated into the parent vessel if it is stretched. Model simulations reproduce key features of vasculogenesis. Parameter sensitivity analyses reveal significant changes in network size and morphology on varying the chemotactic sensitivity of tip cells, and the sensitivities of the proliferation rate and sprouting probability to mechanical stretch. Varying chemotactic sensitivity also affects network directionality. Branching and network density are influenced by the sprouting probability. Glyphs depicting multiple network properties show how network quantities change over time and as model parameters vary. We also show how glyphs constructed from in vivo data could be used to discriminate between normal and tumour vasculature and, ultimately, for model validation. We conclude that our biomechanical hybrid model generates vascular networks similar to those generated from in vitro and in vivo experiments.