Mouse Models of Atherosclerosis: What They Teach Us, What They Miss, and When to Use Them

Mouse models have been indispensable for defining the mechanisms of atherosclerosis, yet no single model reproduces the full spectrum of human disease. This review provides a practical framework for selecting mouse models according to the biological question being addressed. We compare classical lipoprotein-driven models, including Apoe−/− and Ldlr−/− mice, with models designed to study human-like lipoprotein metabolism, immune and immunometabolic mechanisms, adult-onset hypercholesterolemia, plaque complexity, coronary disease, and myocardial infarction-like outcomes. Particular emphasis is placed on how genetic background, lipoprotein composition, diet, sex, age, vascular site, and experimental design shape lesion development and influence interpretation. We also discuss discrepancies across single-cell RNA-sequencing studies, highlighting how differences in model, tissue processing, disease stage, and analytical strategy can alter the macrophage and immune-cell states detected. Rather than ranking models, we define what each model can teach, what it may miss, and when it is most appropriate to use. We conclude that future progress will depend on question-driven model selection, cross-model validation, improved reporting, and greater integration of molecular, spatial, and human benchmarking approaches.