On the role of mechanical signals on sprouting angiogenesis through computer modeling approaches.

Sprouting angiogenesis, the formation of new vessels from preexisting vasculature, is an essential process in the regeneration of new tissues as well as in the development of some diseases like cancer. Although early studies identified chemical signaling as the main driver of this process, many recent studies have shown a strong role of mechanical signals in the formation of new capillaries. Different types of mechanical signals (e.g., external forces, cell traction forces, and blood flow-induced shear forces) have been shown to play distinct roles in the process; however, their interplay remains still largely unknown. During the last decades, mathematical and computational modeling approaches have been developed to investigate and better understand the mechanisms behind mechanically driven angiogenesis. In this manuscript, we review computational models of angiogenesis with a focus on models investigating the role of mechanics on the process. Our aim is not to provide a detailed review on model methodology but to describe what we have learnt from these models. We classify models according to the mechanical signals being investigated and describe how models have looked into their role on the angiogenic process. We show that a better understanding of the mechanobiology of the angiogenic process will require the development of computer models that incorporate the interactions between the multiple mechanical signals and their effect on cellular responses, since they all seem to play a key in sprout patterning. In the end, we describe some of the remaining challenges of computational modeling of angiogenesis and discuss potential avenues for future research.