Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype
- 1Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, Liaoning, P.R. China.
- 2School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, P.R. China.
Abstract
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. Author summary: Atherosclerosis, the underlying cause of many dangerous cardiovascular diseases, typically initiates with blood vessel lining damage, known as endothelial dysfunction. While the mechanical friction from flowing blood, particularly continuous disturbances, is a major driver of this injury, how cellular self-repair processes are guided by internal chemical signals remains a puzzle. To address this, we developed a comprehensive computer simulation model that connects the physical forces of blood flow with the intricate chemical interactions inside and around cells. Crucially, our model demonstrates that vessel damage is not caused by a simple lack of protective molecules like nitric oxide, but rather by a spatial mismatch where these protective signals are overwhelmed by localized bursts of destructive oxidative molecules. By simulating therapeutic interventions, we discovered a golden window for healing: turning on a key healing pathway both early and in moderation optimal for guiding damaged cells back to health. Conversely, waiting too long or over-activating the pathway could disrupt the delicate immune and chemical balance. These simulation-derived insights provide a distinct blueprint for designing smarter, precisely timed, and properly dosed therapies to repair injured blood vessels before full-scale disease develops.
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BibTeX
@article{zhang2026multiscale,
title = {{Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype}},
author = {Yu-Yuan Zhang and Yi-Teng Wang and Yan Qiu and Yong-Jiang Li and Dong Chen and Kai-Rong Qin},
journal = {PLOS Computational Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pcbi.1014860},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014860},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype
AU - Yu-Yuan Zhang
AU - Yi-Teng Wang
AU - Yan Qiu
AU - Yong-Jiang Li
AU - Dong Chen
AU - Kai-Rong Qin
PY - 2026
DA - 2026/10/21
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014860
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014860
AB - 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. Author summary: Atherosclerosis, the underlying cause of many dangerous cardiovascular diseases, typically initiates with blood vessel lining damage, known as endothelial dysfunction. While the mechanical friction from flowing blood, particularly continuous disturbances, is a major driver of this injury, how cellular self-repair processes are guided by internal chemical signals remains a puzzle. To address this, we developed a comprehensive computer simulation model that connects the physical forces of blood flow with the intricate chemical interactions inside and around cells. Crucially, our model demonstrates that vessel damage is not caused by a simple lack of protective molecules like nitric oxide, but rather by a spatial mismatch where these protective signals are overwhelmed by localized bursts of destructive oxidative molecules. By simulating therapeutic interventions, we discovered a golden window for healing: turning on a key healing pathway both early and in moderation optimal for guiding damaged cells back to health. Conversely, waiting too long or over-activating the pathway could disrupt the delicate immune and chemical balance. These simulation-derived insights provide a distinct blueprint for designing smarter, precisely timed, and properly dosed therapies to repair injured blood vessels before full-scale disease develops.
SN - 1553-7358
SN - 1553-734X
ER -