Inhibition of neutrophil extracellular trap formation alleviates vascular dysfunction in type 1 diabetic mice

Abstract

While neutrophil extracellular traps (NETs) have previously been linked to some diabetes-associated complications, such as dysfunctional wound healing, their potential role in diabetic vascular dysfunction has not been studied. Diabetic Akita mice were crossed with either Elane −/− or Pad4 −/− mice to generate NET-deficient diabetic mice. By 24 weeks of age, Akita aortae showed markedly impaired relaxation in response to acetylcholine, indicative of vascular dysfunction. Both Akita- Elane −/− mice and Akita- Pad4 −/− mice had reduced levels of circulating NETs and improved acetylcholine-mediated aortic relaxation. Compared with wild-type aortae, the thromboxane metabolite TXB 2 was roughly 10-fold higher in both intact and endothelium-denuded aortae of Akita mice. In contrast, Akita- Elane −/− and Akita- Pad4 −/− aortae had TXB 2 levels similar to wild type. In summary, inhibition of NETosis by two independent strategies prevented the development of vascular dysfunction in diabetic Akita mice. Thromboxane was up-regulated in the vessel walls of NETosis-competent diabetic mice, suggesting a role for neutrophils in driving the production of this vasoconstrictive and atherogenic prostanoid.