Testosterone inhibits aneurysm formation and vascular inflammation in male mice

Abstract

Abdominal aortic aneurysm (AAA), one of the pathological phenotypes of vascular aging, is 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. However, the underlying mechanisms remain unclear. In this study, we investigated the effects of testosterone on AAA formation using a murine AAA model under the conditions of depletion and administration of testosterone. In wild-type male mice (C57BL/6J), AAA was induced by CaCl2 application and angiotensin II infusion at 5 weeks after castration. Exacerbated AAA formation was seen in castrated mice, compared with sham-operated mice. Histological analysis revealed marked infiltration of macrophages in the destroyed aorta and IL-6/pSTAT3 expression was significantly elevated, suggesting that AAA development by castration is attributable to pronounced inflammation. Conversely, both 4-week and 9-week administration of testosterone significantly prevented AAA formation, and improvement of histological findings was confirmed. Aortic F4/80, Il-1b and Il-6 expression were significantly inhibited both by testosterone administration. Indeed, mice with implanted flutamide exhibited exacerbated AAA formation and aortic F4/80, Il-1b and Il-6 expression were significantly increased. Taken together, these results demonstrate that testosterone depletion and AR blockade precede AAA formation, and conversely, testosterone administration could suppress AAA formation by regulating macrophage-mediated inflammatory responses. This anti-inflammatory action of testosterone/AR on AAA formation might provide a mechanistic insight into the vascular protective actions of testosterone and suggest that its proper administration or selective AR modulators might be novel therapeutic strategies for this aortic pathology.

A Novel Hypothesis: A Role for Follicle Stimulating Hormone in Abdominal Aortic Aneurysm Development in Postmenopausal Women

“…However, a recent case-control study comparing 65-year old men with and without AAA found that higher oestrogen, higher progesterone and lower testosterone levels were associated with AAA ( 170 ). The association of low testosterone levels with AAA is in line with an earlier clinical and murine study ( 70 , 77 ). This discrepancy in findings reflects the complexity of characterizing AAA development.…”

“…Testosterone activates the androgen receptor, a transcription factor similar to the oestrogen receptors, that is expressed in many different cell types, including in vasculature and immune cells (66,67). While some researchers found that pharmacological blockade of the androgen receptor or deficiency of the receptor in male mice attenuated AAA formation (68) and castration of male mice with established AAA promoted aneurysm stabilization (69), others find the opposite (70). Also in humans there is controversy as to the beneficial or detrimental roles that testosterone (replacement therapy) plays in vascular disease (60,(71)(72)(73)(74).…”

Testosterone Deficiency, Long-Term Testosterone Therapy, and Inflammation

“…They found after 9-week testosterone administration, the aortic expression of IL-6 and IL-1β was decreased, and the dilated aortic diameter was also ameliorated, indicating the anti-inflammatory actions of testosterone administration on vascular pathologies. 31 In another animal study, the authors reported testosterone therapy improved lipid accumulation in rabbits that were fed fat-rich diets. A decrease in liver and plasma TNF-α was also observed in these rabbits.…”

Aneurysms and dissections - What is new in the literature of 2019/2020 - a European Society of Vascular Medicine annual review

“…Similarly, testosterone depletion and androgen receptor (AR) blockade precede AAA formation, and conversely, testosterone administration could suppress AAA formation by regulating macrophagemediated inflammatory responses. This anti-inflammatory action of testosterone/AR on AAA formation might provide a mechanistic insight into the vascular protective actions of testosterone and suggest that its proper administration or selective AR modulators might be novel therapeutic strategies for this aortic pathology [16].…”