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Cardiovascular disease remains the leading cause of mortality worldwide. Although minimally invasive interventions have improved outcomes, open surgical reconstruction using vascular grafts is still required for many patients. Autologous vessels are preferred due to superior elastic modulus and biocompatibility; however, a substantial proportion of patients lack suitable donor vessels. Synthetic grafts perform adequately in large-diameter applications but frequently fail in small-diameter settings (≤6 mm) due to thrombosis, infection, and poor long-term patency. These limitations highlight the need for next-generation arterial grafts and robust preclinical evaluation systems. Here, we present two complementary large-animal in vivo sheep models for systematic assessment of arterial graft safety, functionality and regenerative potential. One model enables implantation of short interposition grafts (≈10 cm) in the carotid artery, while a second, novel configuration accommodates long-segment grafts (≈30 cm) in a carotid-axillary setup. Both models are integrated with a comprehensive analytical framework to evaluate patency, regeneration, biomechanical stability, immune activation and transcriptomic remodeling. Method overview: • Sheep models supporting implantation of short and long arterial grafts under physiological flow • Multimodal evaluation combining imaging, biomechanics, histology, flow cytometry, and transcriptomics • Generic platform for assessing graft functionality, safety and biological characterization.