A guide to cell-type-specific Cre mouse models in atherosclerosis: from background strains to future directions

Atherosclerosis is a chronic vascular inflammatory disease, and mouse models are essential for studying its pathogenesis. The Cre/loxP technology has become the gold standard for cell-type-specific gene targeting. However, the rapid proliferation of Cre driver lines has made model selection increasingly challenging. In this review, we provide a practical guide to choosing appropriate Cre mouse models. We compare the two most common backgrounds (Apoe and Ldlr knockout) in terms of lipid profiles, inflammatory dynamics, dietary dependence, and suitability for studying metabolic comorbidities to guide the selection of background strains, and systematically evaluate Cre models targeting all major cell types in atherosclerotic plaques (endothelial cells, smooth muscle cells, macrophages, neutrophils, dendritic cells, T cells, B cells, fibroblasts, NKT cells, and platelets), as well as lipid metabolism, hematopoietic cells and emerging AAV-based approaches. We also compare conventional knockout with conditional and inducible systems, emphasizing critical considerations, including Cre toxicity, tamoxifen leakiness, and experimental controls. Finally, we discuss future directions such as dual-recombinase, lineage tracing, comorbidity modeling, single-cell technologies, and cross-species validation, to better align mouse models with human atherosclerosis. By clarifying how model choice influences experimental outcomes, this review aims to help researchers select optimal models and accelerate mechanistic and therapeutic discoveries.