Abstract 100: An XY Sex Chromosome Complement in Females Confers Susceptibility and Rupture of Angiotensin II-induced Abdominal Aortic Aneurysms in Hypercholesterolemic Female Mice

Abstract

Objective: We previously demonstrated that female mice are less susceptible to angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) compared to males, a sex difference present in humans. Sex chromosome abnormalities, such as Turner’s syndrome (monosomy X), are associated with aortic vascular disease. In this study, we tested the hypothesis that an XY sex chromosome complement in females promotes AngII-induced AAAs. In addition, as previous studies demonstrated that testosterone promotes AngII-induced AAAs in male mice, we determined if testosterone would augment AAA severity in XY females. Methods and Results: Transgenic male 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 female mice with an XY or an XX sex chromosome complement. Female mice (XX and XY) were fed a Western diet and segregated into sham and ovariectomized (OVX) groups. Two weeks later, mice were implanted with osmotic minipumps to infuse AngII (1,000 ng/kg/min) for 28 days. The AAA incidence (XX sham, 40%; XX OVX 29%; XY sham, 71%; XY OVX, 57%, p=0.031) and rupture rate (XX sham, 0%; XX OVX 0%; XY sham, 35%; XY OVX, 29%, p=0.003) were significantly increased in XY compared to XX females. Internal abdominal aortic lumen diameters were significantly increased in XY OVX versus XX OVX female mice at day 27 (XY, 2.31 ± 0.14; XX, 1.58 ± 0.2, p= 0.009). Moreover, AAA external diameters were significantly increased in XY OVX versus XX OVX females (XY, 2.34 ± 0.15; XX, 1.71 ± 0.18, p=0.0004). Administration of testosterone to adult female XY mice as well as neonatal female mice markedly enhanced AAA rupture (maximum of 73%). DNA microarrays of abdominal aortas revealed that male specific genes on the Y chromosome and inflammatory genes were enriched in aortas from XY females, while genes that escape X-inactivation were enriched in aortas from XX females. Conclusion: These results demonstrate that an XY sex chromosome complement is sufficient to promote a high AAA incidence, and markedly increase AAA severity in female mice. Moreover, testosterone augmented AAA ruptures in XY females. Future studies will identify gene targets influenced by sex chromosome complement and/or testosterone.