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Notch 信号通路和趋化机制调控早期血管生成:一个数学和计算模型。

Notch signaling and taxis mechanisms regulate early stage angiogenesis: A mathematical and computational model.

机构信息

G. Millán Institute for Fluid Dynamics, Nanoscience & Industrial Mathematics, and Department of Materials Science & Engineering and Chemical Engineering, Universidad Carlos III de Madrid, Leganés, Spain.

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

出版信息

PLoS Comput Biol. 2020 Jan 27;16(1):e1006919. doi: 10.1371/journal.pcbi.1006919. eCollection 2020 Jan.

Abstract

During angiogenesis, new blood vessels sprout and grow from existing ones. This process plays a crucial role in organ development and repair, in wound healing and in numerous pathological processes such as cancer progression or diabetes. Here, we present a mathematical model of early stage angiogenesis that permits exploration of the relative importance of mechanical, chemical and cellular cues. Endothelial cells proliferate and move over an extracellular matrix by following external gradients of Vessel Endothelial Growth Factor, adhesion and stiffness, which are incorporated to a Cellular Potts model with a finite element description of elasticity. The dynamics of Notch signaling involving Delta-4 and Jagged-1 ligands determines tip cell selection and vessel branching. Through their production rates, competing Jagged-Notch and Delta-Notch dynamics determine the influence of lateral inhibition and lateral induction on the selection of cellular phenotypes, branching of blood vessels, anastomosis (fusion of blood vessels) and angiogenesis velocity. Anastomosis may be favored or impeded depending on the mechanical configuration of strain vectors in the ECM near tip cells. Numerical simulations demonstrate that increasing Jagged production results in pathological vasculatures with thinner and more abundant vessels, which can be compensated by augmenting the production of Delta ligands.

摘要

在血管生成过程中,新的血管从现有血管中发芽和生长。这个过程在器官发育和修复、伤口愈合以及许多病理过程中起着至关重要的作用,如癌症进展或糖尿病。在这里,我们提出了一个早期血管生成的数学模型,该模型允许探索机械、化学和细胞线索的相对重要性。内皮细胞通过跟随血管内皮生长因子、黏附和刚度的外部梯度在细胞外基质中增殖和迁移,这被纳入到具有弹性有限元描述的细胞 Potts 模型中。涉及 Delta-4 和 Jagged-1 配体的 Notch 信号转导动力学决定了尖端细胞的选择和血管分支。通过它们的产生率,竞争的 Jagged-Notch 和 Delta-Notch 动力学决定了侧向抑制和侧向诱导对细胞表型选择、血管分支、吻合(血管融合)和血管生成速度的影响。吻合的发生可能会受到促进或阻碍,这取决于尖端细胞附近细胞外基质中应变向量的机械构型。数值模拟表明,增加 Jagged 的产生会导致血管变细和更丰富,这可以通过增加 Delta 配体的产生来补偿。

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