A mathematical model for smooth muscle cell phenotype switching in atherosclerotic plaque

TL;DR

This paper develops a mathematical ODE model to study how smooth muscle cell phenotype switching influences atherosclerotic plaque stability, revealing that such switching increases lipid accumulation and plaque vulnerability.

Contribution

It introduces a novel ODE model capturing SMC phenotype switching and its impact on plaque development, highlighting mechanisms of plaque vulnerability.

Findings

SMC phenotype switching increases lipid load in plaques.

Switching reduces SMCs in fibrous cap, increasing rupture risk.

Highly proliferative SDMs lead to rapid, pathological plaque growth.

Abstract

Smooth muscle cells (SMCs) play a fundamental role in the development of atherosclerotic plaques. They ingest lipids in a similar way to monocyte-derived macrophages (MDMs) in the plaque. This can stimulate SMCs to undergo a phenotypic switch to a macrophage-like phenotype. We formulate an ordinary differential equation (ODE) model for the populations of SMCs, MDMs and smooth muscle cell-derived macrophages (SDMs) and the internalised lipid load in each population. We use this model to explore the effect on plaque fate of SMC phenotype switching. We find that when SMCs switch to a macrophage-like phenotype, the total lipid contained in the model plaque that is internalised inside cells increases. Additionally, removal of SMCs from the plaque via phenotype switching reduces the number of SMCs in the plaque fibrous cap, increases the lipid in the necrotic core, and increases plaque inflammation. This makes the plaque more vulnerable to rupture, which can lead to heart attacks and strokes. When SDMs are highly proliferative or resistant to cell death, the plaque grows rapidly and becomes highly pathological. The model suggests that plaque dynamics, driven by the switch of SMCs to a macrophage-like phenotype, may drive the development of unstable, vulnerable and pathological plaques.