Female Mice With an XY Sex Chromosome Complement Develop Severe Angiotensin II-Induced Abdominal Aortic Aneurysms.
Abdominal aortic aneurysms (AAAs) are a deadly pathology with strong sexual dimorphism. Similar to humans, female mice exhibit far lower incidences of angiotensin II-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 angiotensin II-induced AAA formation and rupture in phenotypically female mice.



Female low-density lipoprotein receptor (Ldlr) deficient mice with an XX or XY sex chromosome complement were infused with angiotensin II for 28 days to induce AAAs. Abdominal aortic lumen diameters were quantified by ultrasound, whereas AAA diameters were quantified at study end point. DNA microarrays were performed on abdominal aortas. To mimic males, female mice were administered a single dose of testosterone as neonates or as adults before angiotensin II infusions.



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 selectively expressed Y chromosome genes, whereas genes known to escape X inactivation were higher in XX females. The majority of aortic gene differences in XY versus XX females fell within inflammatory pathways. AAA incidences doubled and aneurysms ruptured in XY females. AAAs from XY females exhibited inflammation, and plasma interleukin-1β concentrations were increased in XY females. Moreover, aortas from XY females had augmented matrix metalloproteinase activity and increased oxidative stress. Last, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY in comparison with XX adult females.



An XY sex chromosome complement in phenotypic females profoundly influenced aortic gene expression profiles and promoted AAA severity. When XY females were exposed to testosterone, aneurysm rupture rates were striking. Mechanisms for augmented AAA severity in XY females include increased inflammation, augmented 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.
From Department of Pharmacology and Nutritional Sciences (Y.A., S.E.T., K.C., E.B., L.A.C.), Department of Biostatistics (R.C.), Department of Physiology and Saha Cardiovascular Research Center (A.D.), University of Kentucky, Lexington, KY.
Yasir
Y
Alsiraj
From Department of Pharmacology and Nutritional Sciences (Y.A., S.E.T., K.C., E.B., L.A.C.), Department of Biostatistics (R.C.), Department of Physiology and Saha Cardiovascular Research Center (A.D.), University of Kentucky, Lexington, KY.
Sean E
SE
Thatcher
From Department of Pharmacology and Nutritional Sciences (Y.A., S.E.T., K.C., E.B., L.A.C.), Department of Biostatistics (R.C.), Department of Physiology and Saha Cardiovascular Research Center (A.D.), University of Kentucky, Lexington, KY.
Richard
R
Charnigo
From Department of Pharmacology and Nutritional Sciences (Y.A., S.E.T., K.C., E.B., L.A.C.), Department of Biostatistics (R.C.), Department of Physiology and Saha Cardiovascular Research Center (A.D.), University of Kentucky, Lexington, KY.
Kuey
K
Chen
From Department of Pharmacology and Nutritional Sciences (Y.A., S.E.T., K.C., E.B., L.A.C.), Department of Biostatistics (R.C.), Department of Physiology and Saha Cardiovascular Research Center (A.D.), University of Kentucky, Lexington, KY.
Eric
E
Blalock
From Department of Pharmacology and Nutritional Sciences (Y.A., S.E.T., K.C., E.B., L.A.C.), Department of Biostatistics (R.C.), Department of Physiology and Saha Cardiovascular Research Center (A.D.), University of Kentucky, Lexington, KY.
Alan
A
Daugherty
From Department of Pharmacology and Nutritional Sciences (Y.A., S.E.T., K.C., E.B., L.A.C.), Department of Biostatistics (R.C.), Department of Physiology and Saha Cardiovascular Research Center (A.D.), University of Kentucky, Lexington, KY. lcassis@uky.edu.
Lisa A
LA
Cassis
D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012730:Sex Chromosomes; D014662:Vasoconstrictor Agents / Q000009:adverse effects* / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D000804:Angiotensin II
angiotensins; aortic aneurysm, abdominal; sex chromosomes; testosterone