TESTOSTERONE INHIBITS AORTIC ANEURYSM FORMATION THROUGH SUPPRESSION OF INFLAMMATION

Abdominal aortic aneurysm (AAA) is one of phenotypes of vascular aging characterized by aortic dilation with impaired arterial wall integrity. Recent epidemiologic studies have shown that men with AAA have lower serum testosterone compared to men without AAA, suggesting the preventive roles of testosterone. However, underlying mechanisms are not clear. In this study, we investigated effects of testosterone administration on the formation of AAA using in vivo model. In wild-type mice (C57BL/6J, male, 12 week-old), testosterone deficiency was induced by castration. At 4 weeks after castration, AAA was induced by CaCl2 application in infrarenal aorta and angiotensinII (2000 ng/kg/min) infusion for 4 weeks. Testosterone (5 and 10 mg/kg) or control oil was administered to AAA-induced mice with castration for 8 weeks. When AAA was induced, castrated mice showed remarkable AAA formation compared to sham mice. Testosterone administration significantly prevent AAA formation. Histological analysis revealed that infiltration of F4/80-positive macrophages was seen in the developed AAA of castrated mice. We further found that circulating IL-6 and aortic IL-6 expression were elevated and aortic STAT3 phosphorylation was increased, suggesting IL-6/STAT3-dependent inflammatory responses are attributed to AAA formation in castrated mice. Testosterone administration significantly inhibited expression of inflammatory cytokines including IL-6, IL-1b in aorta. These results demonstrate that testosterone deficiency proceeds AAA by IL-6/STAT3-mediated inflammation and conversely, administration of testosterone could prevent AAA formation through inhibition of inflammation. Uncovering the effects of testosterone on inflammation in vessel provides mechanistic insight into the cardioprotective effects of testosterone.