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Bulletin of mathematical biology
Feb 19, 2025;87 (4): 46.

Unveiling the Negative Synergistic Effect of Wall Shear Stress and Insulin on Endothelial NO Dynamics by Mathematical Modeling.

Yu-Yuan Zhang, Yong-Jiang Li, Xu-Qu Hu, Chun-Dong Xue, Shen Li, Zheng-Nan Gao, Kai-Rong Qin
Author Information
  1. Yu-Yuan Zhang: Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China.
  2. Yong-Jiang Li: Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China. yongjiangli@dlut.edu.cn.
  3. Xu-Qu Hu: Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China.
  4. Chun-Dong Xue: Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China.
  5. Shen Li: Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China.
  6. Zheng-Nan Gao: Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China.
  7. Kai-Rong Qin: Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China. krqin@dlut.edu.cn. ORCID
PMID: 39969626 DOI: 10.1007/s11538-025-01424-2

Abstract

Diabetic vascular complications (DVCs) are diabetes-induced vascular dysfunction and pathologies, leading to the major causes of morbidity and mortality in millions of diabetic patients worldwide. DVCs are provoked by endothelial dysfunction which is closely coordinated with two important hallmarks: one is the insufficient insulin secretion or insulin resistance, and another is the decrease in intracellular nitric oxide (NO) influenced by dynamic wall shear stress (WSS). Although the intracellular NO dynamics in endothelial cells (ECs) is crucial for endothelial function, the regulation of NO production by dynamic WSS and insulin is still poorly understood. In this study, we have proposed a mathematical model of intracellular NO production in ECs under the stimulation of dynamic WSS combined with insulin. The model integrates simultaneously the biochemical signaling pathways of insulin and the mechanotransduction pathways induced by dynamic WSS. The accuracy and reliability of the model to quantitatively describe NO production in ECs were compared and validated with reported experimental data. According to the validated model, inhibition of protein kinase B (AKT) phosphorylation and Ca influx by dynamic oscillatory WSS disrupts the dual nature of endothelial nitric oxide synthase (eNOS) enzyme activation. This disruption leads to the decrease in NO production and the bimodal disappearance of NO waveforms. Moreover, the results reveal that dynamic WSS combined with insulin promote endothelial NO production through negative synergistic effects, which is resulted from the temporal differences in mechanical and biochemical signaling. In brief, the proposed model elucidates the mechanism of NO generation activated by dynamic WSS combined with insulin, providing a potential target and theoretical framework for future treatment of DVCs.

Keywords

Dynamic WSS Endothelial cells Insulin Negative synergistic effect Nitric oxide

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Grants

  1. 12372304/National Natural Science Foundation of China

MeSH Term

Insulin
Nitric Oxide
Nitric Oxide Synthase Type III
Humans
Stress, Mechanical
Mathematical Concepts
Mechanotransduction, Cellular
Models, Cardiovascular
Endothelial Cells
Proto-Oncogene Proteins c-akt
Endothelium, Vascular
Computer Simulation
Phosphorylation
Animals

Chemicals

Insulin
Nitric Oxide
Nitric Oxide Synthase Type III
Proto-Oncogene Proteins c-akt
Journal Article
Article has an altmetric score of 2

Word Cloud

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