Background: Constrictive remodeling after arterial injury is related to collagen accumulation. Cross-linking has been shown to induce a scar process in cutaneous wound healing and is increased after after arterial injury. We therefore evaluated the effect of cross-linking inhibition by APN on qualitative and quantitative changes of collagen, elastin and arterial remodeling after balloon injury in the atherosclerotic rabbit model. Methods and results: Atherosclerotic-like lesions were induced in femoral arteries of 28 New Zealand white rabbits by the association of air-desiccation and high cholesterol diet. One month later, balloon angioplasty was performed in both femoral arteries. Fourteen rabbits were fed with APN (100mg/kg) and were compared to 14 untreated animals. Remodeling index was defined as the ratio of the external elastic lamina of the lesion site to the reference site. Comparisons between both groups were performed 4 weeks after angioplasty. Pyridinoline was significantly decreased in arteries of animals treated by APN as compared to control animals, confirming the inhibition of collagen cross-linking (0.30±0.03 vs 0.52±0.02 mM/M Hydroxyproline respectively, p=0.002). Scanning and transmission electron microscopy exhibited a profound disorganization of collagen fibers in arteries of APN treated animals. The remodeling index was significantly higher in animals treated with APN than in untreated animals (1.1±0.3 vs 0.8±0.3 respectively, p=0.03) indicating favourable remodeling. Restenosis decreased by 33% in animals treated with APN (32±16% vs 48±24% respectively, p=0.02). Neointimal collagen density was significantly lower in animals fed with APN than in controls (23.0±3.8% vs 29.4±4.0% respectively, p=0.004). Conclusions: These findings suggest that collagen and elastin cross-linking play a role in the healing process via constrictive remodeling and restenosis after balloon injury in the atherosclerotic rabbit model.