Computational models of sprouting angiogenesis and cell migration: towards multiscale mechanochemical models of angiogenesis

Angiogenesis, the formation of new bloods vessels from the existing vasculature, is a process that is essential during development and regeneration of tissues, and that plays a major role in diseases like cancer. Computational models have been designed to obtain a better under- standing of the mechanisms behind angiogenesis. In this paper we review computational models of sprouting angiogenesis. These models can be subdivided into three categories: models that mainly focus on tip cell migration, models that make a distinction between the role of tip cells and stalk cells, and models that consider cell shape dynamics. Many models combine discrete modeling of individual cells with continuous modeling of the extracellular matrix (ECM) and diffusing solutes, in this way resulting in a hybrid model. We discuss their merits in unraveling the role of certain factors for vascular network formation, such as the role of (chemotactic, haptotactic, contact) guid- ance cues in the dynamics and morphology of vascular network formation, and the role of cell-cell interactions that govern tip cell selection and phenotypic changes in general. At the same time, we identify a need for the inclusion of cell mechanical principles in models of angiogenesis, in partic- ular for the description of cell migration, cell-matrix and cell-cell interaction, as the generation of cellular forces is key to cell migration. To further underline this we review models of single cell migration that incorporate such principles, which could be the starting point for formulating novel models of angiogenesis that respect the fundamental laws of classical mechanics at the cell level. As the generation of cellular forces is strongly mediated by pro-angiogenic signals, such models must couple cell mechanical principles to molecular signaling into multiscale mechanochemical models of angiogenesis. Finally, a tight coupling between models and experiments will be re- quired to facilitate model improvements and the generation of novel insights on the regulation of angiogenesis.