Development of a Novel Murine Model of In-Stent Neoatherosclerosis

In-stent neoatherosclerosis is a complication of percutaneous coronary intervention with stenting. Although similar to de novo atherosclerosis, it develops rapidly within 1 to 5 years rather than over a lifetime. No preclinical small animal model exists to fully elucidate neoatherosclerosis biology or evaluate targeted therapies. This study aimed to establish and validate a novel murine model of in-stent neoatherosclerosis.

Murine stainless-steel stents (2.5×0.7 mm) were deployed into donor descending aortas of atherosclerosis-prone (Apo)e^-/- (apolipoprotein E) mice, then carotid-interposition grafted into Apoe^-/- recipients. Mice (n=6-8/group) received chow or a high-cholesterol diet for 7 or 28 days post surgery. A novel miniaturized probe was used to image the stented vessel of a mouse fed high-cholesterol diet for 28 days. Neointimas in stented vessels were histologically and flow cytometrically assessed.

Bimodal intravascular imaging combined optical coherence tomography (plaque burden) with fluorescence detection of indocyanine green (plaque instability) to visualize in-stent neoatherosclerosis along the entire stented segment. Histological analyses revealed that stented vessels from mice fed high-cholesterol diet had neointimas with prominent lipid cores and abundant CD68⁺ macrophages, reminiscent of human neoatherosclerosis. Mice fed chow post stenting had distinctly different neointimas that were smooth muscle cell rich, resembling neointimal hyperplasia. Flow cytometry revealed a higher content of monocytes/macrophages in stented aortas from mice fed high-cholesterol diet than in nonstented aortas.

We have developed and validated the first murine model that replicates the unique characteristics of human in-stent neoatherosclerosis. This has implications for exploring the mechanisms that promote neoatherosclerosis and testing targeted new therapies.