Introduction: The autonomic nervous system (ANS) drives blood flow regulation in peripheral arteries. This study aims to develop novel models of sympathetic denervation in peripheral arteries and to characterize subsequent vascular remodeling. We hypothesize that sympathetic denervation of murine femoral arteries can be achieved through local administration of neurotoxin 6-hydroxydopamine (6-OHDA). Methods: BALB/c mice underwent local administration of 6-OHDA to the left femoral artery, while the contralateral artery received vehicle solution. Two approaches were tested: (1) Acute: a one-time topical application following surgical exposure of femoral arteries (N=8, male, Fig. A ), and (2) Chronic: weekly subcutaneous injections near the femoral arteries (N=11, male and female, Fig. B ). Hindlimb perfusion was assessed with laser Doppler imaging, and arterial structure and remodeling were evaluated with histology and immunohistochemistry at one, two, or four weeks. Results: One-time 6-OHDA application (Acute) led to temporary femoral artery denervation (reduction in tyrosine hydroxylase) for one week ( Fig. C – D ), with inflammation observed in both 6-OHDA and vehicle-treated arteries. No vascular wall remodeling was observed after temporary denervation. Weekly subcutaneous 6-OHDA injections (Chronic) resulted in persistent denervation throughout the four-week period in male mice, while female mice displayed variable outcomes ( Fig. E – F ). Sustained sympathetic denervation in the chronic model led to reduced hindlimb blood perfusion at low core temperatures ( Fig. G – H ), though no significant differences were detected in vascular smooth muscle cell phenotype or extracellular matrix composition. Conclusions: Local administration of 6-OHDA is an effective means of peripheral artery sympathetic denervation with controllable duration. This innovative approach of targeting the ANS unveils new prospects for advancing vascular therapies.