Topography of Extracellular Matrix Mediates Vascular Morphogenesis and Migration Speeds in Angiogenesis

Abstract

The extracellular matrix plays a critical role in orchestrating the events necessary for wound healing, muscle repair, morphogenesis, new blood vessel growth, and cancer invasion. In this study, we investigate the influence of extracellular matrix topography on the coordination of multi-cellular interactions in the context of angiogenesis. To do this, we validate our spatio-temporal mathematical model of angiogenesis against empirical data, and within this framework, we vary the density of the matrix fibers to simulate different tissue environments and to explore the possibility of manipulating the extracellular matrix to achieve pro- and anti-angiogenic effects. The model predicts specific ranges of matrix fiber densities that maximize sprout extension speed, induce branching, or interrupt normal angiogenesis, which are independently confirmed by experiment. We then explore matrix fiber alignment as a key factor contributing to peak sprout velocities and in mediating cell shape and orientation. We also quantify the effects of proteolytic matrix degradation by the tip cell on sprout velocity and demonstrate that degradation promotes sprout growth at high matrix densities, but has an inhibitory effect at lower densities. Our results are discussed in the context of ECM targeted pro- and anti-angiogenic therapies that can be tested empirically.

Author Summary

A cell migrating in the extracellular matrix environment has to pull on the matrix fibers to move. When the matrix is too dense, the cell secretes enzymes to degrade the matrix proteins in order to get through. And when the matrix is too sparse, the cell produces matrix proteins to locally increase the “foothold”. How cells interact with the extracellular matrix is important in many processes from wound healing to cancer invasion. We use a computational model to investigate the topography of the matrix on cell migration and coordination in the context of tumor induced new blood vessel growth. The model shows that the density of the matrix fibers can have a strong effect on the extension speed and the morphology of a new blood vessel. Further results show that matrix degradation by the cells can enhance vessel sprout extension at high matrix density, but impede sprout extension at low matrix density. These results can potentially point to new targets for pro- and anti-angiogenesis therapies.