Annexin-A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin-resistant, but not insulin-deficient, mice.
Maria Jelinic; Nicola Kahlberg; Chen Huei Leo; Hooi Hooi Ng; Sarah Rosli; Minh Deo; Mandy Li; Siobhan Finlayson; Jesse Walsh; Laura J Parry; Rebecca H Ritchie; Cheng Xue Qin
Arterial stiffness, a characteristic feature 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 has cardioprotective properties, particularly in the context of ischaemia. However, the role of endogenous annexin-A1 in the vasculature in both normal physiology and pathophysiology remains largely unknown. Hence, this study investigated the role of endogenous annexin-A1 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 annexin-A1 / formyl peptide receptor axis is upregulated in both insulin-resistant and insulin-deficient 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 provide additional benefits over traditional anti-inflammatory strategies for reducing vascular injury in diabetes.
|Journal||BRITISH JOURNAL OF PHARMACOLOGY|
|Published||01 Apr 2020|