Inverting angiogenesis with interstitial flow and chemokine matrix-binding affinity

The molecular signaling pathways that orchestrate angiogenesis have been widely studied, but the role of biophysical cues has received less attention. Interstitial flow is unavoidable in vivo, and has been shown to dramatically change the neovascular patterns, but the mechanisms by which flow regulates angiogenesis remain poorly understood. Here, we study the complex interactions between interstitial flow and the affinity for matrix binding of different chemokine isoforms. Using a computational model, we find that changing the matrix affinity of the chemokine isoform can invert the effect of interstitial flow on angiogenesis—from preferential growth in the direction of the flow when the chemokine is initially matrix-bound to preferential flow against the flow when it is unbound. Although fluid forces signal endothelial cells directly, our data suggests a mechanism for the inversion based on biotransport arguments only, and offers a potential explanation for experimental results in which interstitial flow produced preferential vessel growth with and against the flow. Our results point to a particularly intricate effect of interstitial flow on angiogenesis in the tumor microenvironment, where the vessel network geometry and the interstitial flow patterns are complex. ; © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the ...