Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Woodstock Road, Oxford OX2 6GG, United Kingdom.
Phys Rev E. 2017 Jan;95(1-1):012410. doi: 10.1103/PhysRevE.95.012410. Epub 2017 Jan 25.
Angiogenesis is the process by which new blood vessels develop from existing vasculature. During angiogenesis, endothelial tip cells migrate via diffusion and chemotaxis, loops form via tip-to-tip and tip-to-sprout anastomosis, new tip cells are produced via branching, and a vessel network forms as endothelial cells follow the paths of tip cells. The latter process is known as the snail trail. We use a mean-field approximation to systematically derive a continuum model from a two-dimensional lattice-based cellular automaton model of angiogenesis in the corneal assay, based on the snail-trail process. From the two-dimensional continuum model, we derive a one-dimensional model which represents angiogenesis in two dimensions. By comparing the discrete and one-dimensional continuum models, we determine how individual cell behavior manifests at the macroscale. In contrast to the phenomenological continuum models in the literature, we find that endothelial cell creation due to tip cell movement (vessel formation via the snail trail) manifests as a source term of tip cells on the macroscale. Further, we find that phenomenological continuum models, which assume that endothelial cell creation is proportional to the flux of tip cells in the direction of increasing chemoattractant concentration, qualitatively capture vessel formation in two dimensions, but must be modified to accurately represent vessel formation. Additionally, we find that anastomosis imposes restrictions on cell density, which, if violated, leads to ill-posedness in our continuum model. We also deduce that self-loops should be excluded when tip-to-sprout anastomosis is active in the discrete model to ensure propagation of the vascular front.
血管生成是指新血管从现有脉管系统中发育的过程。在血管生成过程中,内皮细胞尖端通过扩散和趋化性迁移,通过尖端到尖端和尖端到萌芽吻合形成环,通过分支产生新的尖端细胞,内皮细胞沿着尖端细胞的路径形成血管网络。后一过程称为蜗牛迹。我们使用平均场近似法,基于蜗牛迹过程,从角膜测定中的二维基于格子的血管生成细胞自动机模型系统地推导出一个连续体模型。从二维连续体模型中,我们推导出一个一维模型,它代表二维的血管生成。通过比较离散和一维连续体模型,我们确定了个体细胞行为在宏观尺度上的表现方式。与文献中的现象连续体模型不同,我们发现由于尖端细胞运动导致的内皮细胞生成(通过蜗牛迹形成血管)在宏观尺度上表现为尖端细胞的源项。此外,我们发现现象连续体模型假设内皮细胞生成与沿着趋化剂浓度增加方向的尖端细胞通量成正比,定性地捕捉了二维中的血管形成,但必须进行修改以准确地表示血管形成。此外,我们发现吻合对细胞密度施加限制,如果违反该限制,则会导致我们的连续体模型不适定。我们还推断,在离散模型中,当尖端到萌芽吻合活跃时,应排除自环,以确保血管前沿的传播。