School of Mechanical Engineering, Purdue University, West Lafayette, IN, USA.
Department of Mechanical and Civil Engineering, California Institute of Technology, Pasadena, CA, USA.
Sci Rep. 2022 Mar 10;12(1):4237. doi: 10.1038/s41598-022-08186-0.
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.
尽管分子信号通路在血管生成中起着重要作用，但生物物理线索的作用却较少受到关注。间质流在体内是不可避免的，并且已经表明它可以极大地改变新血管的模式，但目前对流动如何调节血管生成的机制还了解甚少。在这里，我们研究了间质流与不同趋化因子同工型与基质结合亲和力之间的复杂相互作用。使用计算模型，我们发现改变趋化因子同工型的基质亲和力可以反转间质流对血管生成的影响——从趋化因子最初与基质结合时沿流动方向的优先生长转变为无结合时的优先逆流生长。尽管流体力直接作用于内皮细胞，但我们的数据表明，这种反转是基于生物传输论点的机制，并为实验结果提供了一种潜在的解释，即在这些实验结果中，间质流产生了沿流和逆流的优先血管生长。我们的结果表明，间质流对肿瘤微环境中的血管生成有特别复杂的影响，其中血管网络几何形状和间质流模式都很复杂。
