Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype.

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.