Intra-aortic infusion of nicotine can induce a novel mouse model of abdominal aortic aneurysm

Abstract

Objective

Smoking is one of the most important independent risk factors for abdominal aortic aneurysm (AAA). However, harmful tobacco substances, such as nicotine, are not directly used to induce experimental AAAs in animals to mimic smokers with an AAA status similar to that of humans. To facilitate the study of the relationship between smoking and AAA, this study presents a novel model of nicotine-induced AAA.

Methods

In the present study, Mendelian randomization (MR) analyses were used to validate that smoking and its main harmful substance, nicotine, are independent risk factors for AAA. We then evaluated the intraluminal infusion of four doses of nicotine into mouse abdominal aortas to establish a novel AAA model.

Results

MR analysis revealed that smoking, daily cigarette consumption, and smoking cessation history were positively associated with AAA pathogenesis, and the associations between the nicotine metabolism rate and AAA approached statistical significance. On day 14 after nicotine infusion in the mice, the mean diameter of the abdominal aorta increased from approximately 0.50 mm (baseline) to 0.94 to 1.0 mm in the four groups. Almost all of the mice developed abdominal aortic aneurysms, but aortic dilation did not show a clear dose‒dependent relationship. Compared with the sham and PBS infusion groups, the nicotine infusion group (5 mg/mL dose was selected for subsequent analysis) presented more severe aortic dilation, aortic elastin degradation, medial smooth muscle cell loss and aortic leukocyte accumulation. A more severe inflammatory status also increased aortic matrix metalloproteinase (MMP)2 and MMP9 expression and promoted mural neovessel sprouting. Notably, the lesions in the nicotine infusion group were generally not as severe as those in the PPE infusion group, which served as a positive control. To test whether the effect of nicotine on AAA pathogenesis is dependent on its corresponding receptors, we blocked its main receptor, the α7 subunit nicotinic acetylcholine receptor, with the antagonist methyllycaconitine (MLA). The results showed that the aneurysmal lesions were significantly improved by MLA treatment.

Conclusion

In this study, we established a novel and highly efficient experimental AAA model via direct intraluminal nicotine infusion. We also demonstrated that nicotine-induced AAA formation is partially dependent on the activation of its receptors, thus providing a research tool for studying the management of smoking-induced AAAs.