Abstract 454: An XX Sex Chromosome Complement, in the Presence of Testosterone, Markedly Promotes Angiotensin II-Induced Abdominal Aortic Aneurysms in Hypercholesterolemic Male Mice

Abstract

Objective: Male sex is a strong risk factor for abdominal aortic aneurysms (AAAs). Similarly, angiotensin II (AngII)-induced AAAs exhibit a 4-fold higher prevalence in male compared to female hypercholesterolemic mice, which is abolished by removal of testosterone. We recently demonstrated that acute administration of testosterone to neonatal female mice markedly promoted their adult susceptibility to AngII-induced AAAs in the absence of a requirement for adult testosterone. In this study, we tested the hypothesis that testosterone acts through the sex chromosome complement (SCC) to promote AngII-induced AAAs. Methods and Results: Male transgenic mice with deletion of Sry from the Y-chromosome expressing Sry on autosomes (8-12 weeks of age) were bred to female Ldlr-/- mice to generate male mice with an XY or an XX SCC. Mice were fed a western diet and segregated into sham and orchiectomized (ORC) groups. Two weeks later, mice were implanted with osmotic micropumps to infuse AngII (1,000 ng/kg/min) for 28 days. Internal abdominal aortic lumen diameters were significantly larger in sham XX versus XY male mice at day 27 (XX, 1.77 ± 0.08; XY, 1.59 ± 0.05, p= 0.019). Castration decreased internal aortic lumen diameters in both genotypes, eliminating group differences (p=0.389). AAA external diameters were significantly increased in sham XX versus XY males (XX, 2.12 ± 0.17; XY, 1.55 ± 0.12, p=0.004), and this effect was abolished by castration. The presence of an additional X chromosome increased AAA incidence from 75% to 95% (p=0.136) and rupture rate from 11% to 30% (p=0.238). In contrast, an XY SCC promoted AngII-induced atherosclerosis (ORC: XY, 32.1 ± 6.5%; XX, 14.9 ± 1.6%, p=0.02), and this effect was reversed by castration (sham, XY: 19.4 ± 4.2, p=0.036). Conclusion: These results demonstrate that testosterone acts at an XX SCC to markedly promote the severity of AngII-induced AAAs in male mice. In contrast, testosterone acts at an XY SCC to protect against AngII-induced atherosclerosis in male mice. These results demonstrate, for the first time, that complex interactions between sex hormones and sex chromosomes diversely influence vascular diseases promoted by AngII.