Toward a Multi-Scale Computational Model of Arterial Adaptation in Hypertension: Verification of a Multi-Cell Agent Based Model

摘要

Agent-based models (ABMs) represent a novel approach to study and simulate complex mechano chemo-biological responses at the cellular level. Such models have been used to simulate a variety of emergent responses in the vasculature, including angiogenesis and vasculogenesis. Although not used previously to study large vessel adaptations, we submit that ABMs will prove equally useful in such studies when combined with well-established continuum models to form multi-scale models of tissue-level phenomena. In order to couple agent-based and continuum models, however, there is a need to ensure that each model faithfully represents the best data available at the relevant scale and that there is consistency between models under baseline conditions. Toward this end, we describe the development and verification of an ABM of endothelial and smooth muscle cell responses to mechanical stimuli in a large artery. A refined rule-set is proposed based on a broad literature search, a new scoring system for assigning confidence in the rules, and a parameter sensitivity study. To illustrate the utility of these new methods for rule selection, as well as the consistency achieved with continuum-level models, we simulate the behavior of a mouse aorta during homeostasis and in response to both transient and sustained increases in pressure. The simulated responses depend on the altered cellular production of seven key mitogenic, synthetic, and proteolytic biomolecules, which in turn control the turnover of intramural cells and extracellular matrix. These events are responsible for gross changes in vessel wall morphology. This new ABM is shown to be appropriately stable under homeostatic conditions, insensitive to transient elevations in blood pressure, and responsive to increased intramural wall stress in hypertension.