Mechanobiological model of arterial growth and remodeling

Abstract

A coupled agent-based model (ABM) and finite element analysis (FEA) computational framework is developed to study the interplay of bio-chemo-mechanical factors in blood vessels and their role in maintaining homeostasis. The agent-based model implements the power of REPAST Simphony libraries and adapts its environment for biological simulations. Coupling a continuum-level model (FEA) to a cellular-level model (ABM) has enabled this computational framework to capture the response of blood vessels to increased or decreased levels of growth factors, proteases and other signaling molecules (on the micro scale) as well as altered blood pressure. Performance of the model is assessed by simulating porcine left anterior descending artery under normotensive conditions and transient increases in blood pressure and by analyzing sensitivity of the model to variations in the rule parameters of the ABM. These simulations proved that the model is stable under normotensive conditions and can recover from transient increases in blood pressure. Sensitivity studies revealed that the model is most sensitive to variations in the concentration of growth factors that affect cellular proliferation and regulate extracellular matrix composition (mainly collagen).

Keywords: Agent-based modeling; Coronary artery; Finite element analysis; Multiscale modeling.

Fig. 1

Schema of the agent-based model and GUI. a The GUI allows for defining blood vessel geometry. b Spheres represent cells within the ABM; green spheres are ECs, red spheres are SMCs, and yellow spheres are AFs

Fig. 2

Evolution of maximum principal stress (kPa), amounts per patch of PDGF-AB (pg), TGF-β (pg), collagen (pg), MMP-2 (pg) and MMP-9 (pg) in porcine LAD under normotensive conditions. Values are plotted at tick times of 0 (initial), 200 (50 days) and 400 (100 days) at each patch in a cross section at the middle of the artery. Variation of PDGF-AB and TGF-β is minimal under normotensive conditions

Fig. 3

Effect of transient periodic increases in blood pressure on a average maximum principal stress, b, c growth factors, d–f structurally significant proteins of ECM, g–i proteases and j–l cell population. All values are normalized to initial baseline value. Blood pressure was increased by 30% for one time step (6h) at tick = 2, 102, 202 and 302 and results (average (solid line) standard error (shaded region)) were plotted against that of normotensive conditions. No significant change was observed in any of the parameters

Fig. 4

Effect of varying parameter b in rule No. 23 (production of MMP-1 by fibroblasts) on a, b average adventitial and medial maximum principal stress, c, d growth factors, e–g structurally significant proteins of ECM, h, i proteases and k, l cell population. All values are normalized to initial baseline value. Parameter b was increased and decreased by an order of magnitude as shown in (h). Increased MMP-1 production in adventitia enhanced collagen degradation, decreased average maximum principal stress and eventually led to higher TGF-β production by SMCs