Female Mice With an XY Sex Chromosome Complement Develop Severe Angiotensin II–Induced Abdominal Aortic AneurysmsClinical Perspective

Background—Abdominal aortic aneurysms (AAAs) are a deadly pathology with strong sexual dimorphism. Similar to humans, female mice exhibit far lower incidences of angiotensin II (AngII)-induced AAAs than males. In addition to sex hormones, the X and Y sex chromosomes, and their unique complements of genes, may contribute to sexually dimorphic AAA pathology. Here, we defined the effect of female (XX) versus male (XY) sex chromosome complement on AngII-induced AAA formation and rupture in phenotypically female mice. Methods—Female low density lipoprotein receptor (Ldlr) mice with an XX or XY sex chromosome complement were infused with AngII for 28 days to induce AAAs. Abdominal aortic lumen diameters were quantified by ultrasound, while AAA diameters were quantified at study endpoint. DNA microarrays were performed on abdominal aortas. To mimic males, female mice were administered a single dose of testosterone as neonates or as adults prior to AngII infusions. Results—Female Ldlr -/- deficient mice with an XX and XY sex chromosome complement had similar sex organ weights and low serum testosterone concentrations. Abdominal aortas from female XY mice se ectivel ea e ce selec ve y e pressed Y chromos exp essed d c o osome genes, while e ge es, w e genes known to escape ow o escape X- ina tivation we nactivation were higher in XX females. The majorit rity of aortic g of aortic gene differences in XY versus differences in XY vers sus XX females fell within inflammatory pathways. females fell within inflammatory pathways. AAA incidences doubled and ane rysms nd aneur eurysms ruptured in XY f males. AAAs from XY females exhibited inflammation ??????????? uptured in XY females. AAAs from XY females exhibited inflammation??????????????????? ?? concentra ons were increased in XY fema es. concentrattiions were increased in XY females. Moreover, aortas from XY females had reover, aortas from XY females had aug ugmented ma r x nted mattriix metalloproteinase activity and ncreased oxidative stress. and i increased oxidative stress. Finally, t stosterone , testosterone ex osure applied hr expo posure applied chronic e ch onically, or as a single bolus at postnatal day 1, ma le bolus at postnatal da 1, mark dl arkedly worsened AAA ened AAA outc outcomes in XY compare to XX adult f comes in XY compared to o XX adult females.les Conc Conc n lusions—An XY sex chromosome complement in pheno ypic female An n XY s sex chromosome comp pleme ent in phenottypic fema es profoun ly m les profoundl und y influenced nflluenced aortic gene expression profiles and promoted AAA se rtic gene expresession profiiles and e d promoted AAA severity When XY femafem les were ev rity. When XY f males were exposed to testo er exposed to testosterone, aneurysm rupture ratese were stri osterone, aneu urysm um ruptur rates re re strikining. Mechanism f r augmented AAA r ki g Mechanisms for augmented AAA ms fo severit in XY f males i clude incre sed inflammation, aug everity in XY females include increased infl f ammation, augmented matrix metallloproteineases d matrix metalloproteineases and oxidative stress. Our results demonstrate that genes on the sex chromosomes regulate aortic vascular biology and contribute to sexual dimorphism of AAAs. Sex chromosome genes may serve as novel targets for sex-specific AAA therapeutics.