Modeling Endothelial Nitric Oxide Regulation Under Shear Stress Through a Systems Architecture Approach at King’s College London

King’s College London
King’s College London is a globally recognized research institution with strong expertise in cardiovascular biology, mechanobiology, and translational medicine. In collaboration with international academic partners, King’s College London researchers applied advanced computational systems biology approaches to investigate how biomechanical forces regulate endothelial function and vascular health.

Challenge

Nitric oxide (NO) production by vascular endothelial cells is a critical regulator of vasodilation and vascular homeostasis. NO synthesis is dynamically controlled by interconnected biochemical pathways that respond to fluid shear stress generated by blood flow. Traditional experimental and reductionist modeling approaches typically focus on isolated signaling mechanisms, limiting the ability to understand how calcium signaling, phosphorylation cascades, transcriptional regulation, and enzymatic activity interact over time. A systems-level, mechanistic framework was required to integrate these pathways and predict NO production dynamics under physiological shear stress conditions.

How CytoSolve Helped

CytoSolve provided the computational platform used by King’s College London collaborators to construct an integrative in silico systems architecture of shear-stress-induced nitric oxide production. Researchers conducted a systematic literature review to identify molecular mechanisms governing endothelial nitric oxide synthase (eNOS) activation and NO synthesis.

Four quantitatively defined molecular subsystems—calcium signaling, eNOS phosphorylation cascades, transcriptional regulation mediated by AP-1 and KLF2, and direct catalytic NO production—were converted into independently validated mathematical models. Using CytoSolve’s distributed integration framework, these subsystems were dynamically coupled, allowing real-time simulation of pathway interactions in response to shear stress. Time-dependent simulations were performed to quantify NO production and to analyze the relative contributions of each regulatory mechanism.

Key Benefits Realized

  • Unified systems architecture integrating multiple nitric oxide regulatory pathways
  • Quantitative, time-resolved simulation of endothelial responses to shear stress
  • Mechanistic insight into the interplay between calcium signaling, phosphorylation, and transcriptional control
  • Improved interpretability of complex mechanotransduction processes
  • Extensible modeling framework for testing genetic, mechanical, or pharmacological perturbations in silico

Outcome

The CytoSolve®-enabled systems architecture provided King’s College London researchers with an integrative, mechanistic framework for understanding endothelial nitric oxide regulation under fluid shear stress. The simulations reproduced experimentally observed NO production dynamics and clarified how distinct molecular pathways contribute over time to vascular responses. By preserving individual pathway identities while enabling dynamic coupling, the model demonstrated robustness and predictive value, offering a foundational tool for future investigations into vascular function, atherosclerosis, hypertension, and flow-mediated vascular remodeling.