{ "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.", "abstract_shown": true, "affiliations": [ "Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, Liaoning, P.R. China.", "School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, P.R. China." ], "article_type": "Research Article", "arxiv": null, "author_total": 6, "authors": [ { "affs": [ 0, 1 ], "name": "Yu-Yuan Zhang", "orcid": "0000-0002-3192-6581" }, { "affs": [ 0, 1 ], "name": "Yi-Teng Wang" }, { "affs": [ 0, 1 ], "name": "Yan Qiu" }, { "affs": [ 0, 1 ], "name": "Yong-Jiang Li" }, { "affs": [ 0 ], "name": "Dong Chen" }, { "affs": [ 0, 1 ], "name": "Kai-Rong Qin", "orcid": "0000-0001-6781-2941" } ], "bibtex": "https://research.draconitic.com/paper/etjv5qkkzmdgb.bib", "cited_by": 0, "doi": "10.1371/journal.pcbi.1014860", "fulltext_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014860", "id": "etjv5qkkzmdgb", "issns": [ "1553-7358", "1553-734X" ], "landing_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014860", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2737|Nitric Oxide and Endothelin Effects" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Epithelium/Epithelial cells/Endothelial cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Monocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Epithelial cells/Endothelial cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Oxidative stress" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Signaling cascades/Stress signaling cascade" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Epithelium/Epithelial cells/Endothelial cells" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Physical sciences/Physics/Classical mechanics/Mechanical stress/Shear stresses" ] ], "openalex": "W7223158986", "pdf_url": "https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1014860&type=printable", "pmcid": "PMC13705609", "pmid": "42905865", "published": "2026-10-21", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/etjv5qkkzmdgb.ris", "sources": [ { "first_seen": "2026-10-30T12:17:23Z", "native_id": "10.1371/journal.pcbi.1014860", "source": "plos", "url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014860" }, { "first_seen": "2026-10-30T12:19:53Z", "native_id": "MED:42905865", "source": "europepmc", "url": "https://europepmc.org/article/MED/42905865" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" } ], "title": "Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype", "title_text": "Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype", "type": "peer-reviewed", "updated_at": "2026-10-30T12:19:53Z", "url": "https://research.draconitic.com/paper/etjv5qkkzmdgb", "venue": "PLOS Computational Biology", "versions": [] }