尖端的力——模拟发芽血管生成中的张力与增殖

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

作者信息

Santos-Oliveira Patrícia, Correia António, Rodrigues Tiago, Ribeiro-Rodrigues Teresa M, Matafome Paulo, Rodríguez-Manzaneque Juan Carlos, Seiça Raquel, Girão Henrique, Travasso Rui D M

机构信息

CFisUC, Department of Physics, University of Coimbra, Coimbra, Portugal.

Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

出版信息

PLoS Comput Biol. 2015 Aug 6;11(8):e1004436. doi: 10.1371/journal.pcbi.1004436. eCollection 2015 Aug.

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.

摘要

出芽血管生成是指新血管从已有的血管生长而来,这是一个复杂的过程,其中生化和机械信号调节内皮细胞的增殖和运动。因此,出芽血管生成的数学描述必须考虑生物信号以及相关的物理过程,特别是相邻内皮细胞与细胞外微环境之间的机械相互作用。在这项工作中,我们引入了第一个能够预测芽形态作为组织弹性特性和细胞施加的牵引力函数的出芽血管生成相场连续模型。该模型非常简洁,仅由三个耦合的偏微分方程组成,并且具有参数数量减少的明显优势。这个模型使我们能够将芽的生长描述为细胞间粘附力和芽尖细胞施加的牵引力的函数。在没有增殖的情况下,我们观察到芽要么达到最大长度,要么在牵引力和粘附力非常大时断裂。内皮细胞增殖会显著改变芽的形态,我们探讨了不同类型的内皮细胞增殖调节如何能够决定生长芽的形状。当增殖由内皮细胞应变触发且其速率随血管生成因子浓度增加时,总能在参数空间中获得形成良好的长而直的芽的最大区域。我们得出结论,在这种情况下,尖端细胞具有在跟随其引导的细胞中产生张力的作用。在那些最初的茎细胞上,这种张力会产生应变和/或空隙,不可避免地触发细胞增殖。新细胞占据尖端后面的空间,张力降低,然后这个过程重新开始。我们的结果突出了数学模型提出关于力在出芽中作用的相关假设的能力,从而强调了建模与分子生物学技术之间必要的合作,以改进当前的技术水平。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5aa9/4527825/ca995ccf06c8/pcbi.1004436.g001.jpg

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