Arterial stiffness, a hallmark of diabetes, increases the risk of cardiovascular complications. Potential mechanisms that promote arterial stiffness in diabetes include oxidative stress, glycation and inflammation. The anti-inflammatory protein annexin-A1 (AnxA1) has cardioprotective properties, particularly in the context of ischaemia. However, the role of endogenous AnxA1 in the vasculature in both normal physiology and pathophysiology remains largely unknown. Hence, this study investigated the role of endogenous AnxA1 in diabetes-induced remodelling of mouse mesenteric vasculature.Insulin-resistance was induced in male mice (AnxA1 and AnxA1 ) with the combination of streptozotocin (55mg/kg i.p. x 3 days) with high fat diet (42% energy from fat) or citrate vehicle with normal chow diet (20-weeks). Insulin-deficiency was induced in a separate cohort of mice using a higher total streptozocin dose (55mg/kg i.p. x 5 days) on chow diet (16-weeks). At study endpoint, mesenteric artery passive mechanics were assessed by pressure myography.+/+Insulin-resistance induced significant outward remodelling, but had no impact on passive stiffness. Interestingly, vascular stiffness was significantly increased in AnxA1 mice when subjected to insulin-resistance. In contrast, insulin-deficiency induced outward remodelling and increased volume compliance in mesenteric arteries, regardless of genotype. In addition, the AnxA1/FPR axis is upregulated in both insulin-resistance and insulin-deficiency mice.-/-Our study provided the first evidence that endogenous AnxA1 may play an important vasoprotective role in the context of insulin-resistance. AnxA1-based therapies may be used to provide additional benefits over traditional anti-inflammatory strategies for reducing vascular injury in settings of diabetes.