Role of vascular smooth muscle cell phenotypic switching in plaque progression: A hybrid modeling study
Role of vascular smooth muscle cell phenotypic switching in plaque progression: A hybrid modeling study
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血管平滑肌细胞表型转换在斑块进展中的作用：混合模型研究
DOI：
10.1016/j.jtbi.2021.110794
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发表时间：
2021-06-11
影响因子：
2
通讯作者：
Li, Zhiyong
中科院分区：
文献类型：
--
作者：
Pan, Jichao;Cai, Yan;Li, Zhiyong
越来越多的遗传谱系作图实验明确表明，动脉粥样硬化斑块中的血管平滑肌细胞（VSMC）具有广泛的可塑性，并表明VSMC可以响应斑块微环境调节其表型。在这里，建立了一个多尺度混合离散-连续（HDC）建模系统，以研究动脉粥样硬化病变内VSMC表型转换的复杂作用。VSMCs和巨噬细胞的增殖、迁移、表型转化和坏死等细胞行为由离散模型中的元胞自动机（CA）规则决定。而斑块微环境因子如脂质、细胞外基质（ECM）和趋化因子的动力学在宏观上则由连续反应扩散方程描述。模拟结果表明，VSMC活动如何改变细胞外微环境，从而影响斑块的形态和稳定性。VSMC表型的调节不仅可以影响斑块形态（坏死核心大小和纤维帽厚度），而且还可以影响微环境因子（脂蛋白、ECM和趋化因子）的沉积和分布。此外，它被发现，可以通过阻断VSMC转分化为巨噬细胞样状态，并促进其肌纤维母细胞表型，这表明，针对VSMC表型转换可能是一个潜在的和有前途的治疗策略动脉粥样硬化斑块的脆弱性抑制。(C)2021爱思唯尔有限公司版权所有。
Growing genetic lineage mapping experiments have definitively shown a wide-ranging plasticity of vascular smooth muscle cells (VSMCs) in atherosclerotic plaque and suggested that VSMCs can modulate their phenotypes in response to plaque microenvironment. Here, a multiscale hybrid discrete-continuous (HDC) modeling system is established to investigate the complex role of VSMC phenotypic switching within atherosclerotic lesions. The cellular behaviors of VSMCs and macrophages, including proliferation, migration, phenotypic transformation and necrosis, are determined by cellular automata (CA) rules in discrete model. While the dynamics of plaque microenvironmental factors, such as lipid, extracellular matrix (ECM) and chemokines, are described by continuous reaction-diffusion equations in macroscopy. The simulation results demonstrate how the VSMC activities change the extracellular microenvironment and consequently affect the plaque morphology and stability. The regulation of VSMC phenotypes can affect not only the plaque morphology (necrotic core size and fibrous cap thickness) but also the deposition and distribution of microenvironmental factors (lipoprotein, ECM, and chemokines). In addition, it is found that plaque vulnerability can be inhibited by blocking VSMC transdifferentiation to a macrophage-like state and promoting it to a myofibroblastic phenotype, which suggests that targeting VSMC phenotypic switching could be a potential and promising therapeutic strategy for atherosclerosis. (C) 2021 Elsevier Ltd. All rights reserved.