多尺度建模揭示剪切应力诱导内皮表型中 AKT 介导的 NO-ROS 串扰非线性动力学
Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype
多尺度模型揭示，剪切应力下内皮功能障碍源于 NO 生成与 ROS 消耗的空间错配，而非整体缺失。该框架整合血流动力学刺激、细胞行为与非线性 AKT/NO/ROS 生化动力学，并耦合内皮表型转变。系统性模拟识别出一个"黄金窗口"：第 1 天干预并适度激活 AKT 可有效恢复内皮细胞并使氧化还原状态正常化，而过度激活则导致超生理性过度抑制。结果表明修复取决于氧化还原稳态与免疫动力学的紧密耦合，干预时机与剂量是精准血管治疗的关键因素。
来源：PLOS Computational Biology · journals.plos.org
by Yu-yuan Zhang, Yi-Teng Wang, Yan Qiu, Yong-Jiang Li, Dong Chen, Kai-Rong Qin
Endothelial dysfunction is a critical initiating event in atherosclerosis. The regulatory role of the AKT signaling pathway in the transition between injury and repair remains unclear. This study developed a multiscale model to elucidate how AKT signaling modulates endothelial repair under shear stress. The framework integrates hemodynamic stimuli, cellular behaviors, and nonlinear AKT/NO/ROS biochemical kinetics coupled with endothelial phenotypic transitions. Results demonstrate that endothelial dysfunction is driven by a spatial mismatch between NO production and ROS consumption rather than global deficiency. Phenotypic restoration is governed by the nonlinear interactions within the NO-ROS network. Systematic simulations identified a golden window, where Day 1 intervention and moderate AKT activation effectively restored endothelial cells and normalized redox status. Conversely, excessive activation caused supra-physiological over-suppression. These findings suggest that repair is determined by the tight coupling of redox homeostasis and immune dynamics, highlighting intervention timing and dosage as critical factors for precision vascular therapy.