The Force at the Tip - Modelling Tension and Proliferation in Sprouting Angiogenesis

Abstract

Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art.

Author Summary

Sprouting angiogenesis—a process by which new blood vessels grow from existing ones—is an ubiquitous phenomenon in health and disease of higher organisms, playing a crucial role in organogenesis, wound healing, inflammation, as well as on the onset and progression of over 50 different diseases such as cancer, rheumatoid arthritis and diabetes. Mathematical models have the ability to suggest relevant hypotheses with respect to the mechanisms of cell movement and rearrangement within growing vessel sprouts. The inclusion of both biochemical and mechanical processes in a mathematical model of sprouting angiogenesis permits to describe sprout extension as a function of the forces exerted by the cells in the tissue. It also allows to question the regulation of biochemical processes by mechanical forces and vice-versa. In this work we present a compact model of sprouting angiogenesis that includes the mechanical characteristics of the vessel and the tissue. We use this model to suggest the mechanism for the regulation of proliferation within sprout formation. We conclude that the tip cell has the role of creating a tension in the cells that follow its lead. On those first cells of the stalk, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. The modelling strategy used, deemed phase-field, permits to describe the evolution of the shape of different domains in complex systems. It is focused on the movement of the interfaces between the domains, and not on an exhaustive description of the transport properties within each domain. For this reason, it requires a reduced number of parameters, and has been used extensively in modelling other biological phenomena such as tumor growth. The coupling of mechanical and biochemical processes in a compact mathematical model of angiogenesis will enable the study of lumen formation and aneurisms in the near future. Also, this framework will allow the study of the action of flow in vessel remodelling, since local forces can readily be coupled with cell movement to obtain the final vessel morphology.