TY - JOUR
T1 - Sex Chromosome Complement Defines Diffuse Versus Focal Angiotensin II-Induced Aortic Pathology
AU - Alsiraj, Yasir
AU - Thatcher, Sean E.
AU - Blalock, Eric
AU - Fleenor, Bradley
AU - Daugherty, Alan
AU - Cassis, Lisa A.
N1 - Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Objective - Aortic pathologies exhibit sexual dimorphism, with aneurysms in both the thoracic and abdominal aorta (ie, abdominal aortic aneurysm [AAA]) exhibiting higher male prevalence. Women have lower prevalence of aneurysms, but when they occur, aneurysms progress rapidly. To define mechanisms for these sex differences, we determined the role of sex chromosome complement and testosterone on the location and progression of angiotensin II (AngII)-induced aortic pathologies. Approach and Results - We used transgenic male mice expressing Sry (sex-determining region Y) on an autosome to create Ldlr (low-density lipoprotein receptor)-deficient male mice with an XY or XX sex chromosome complement. Transcriptional profiling was performed on abdominal aortas from XY or XX males, demonstrating 1746 genes influenced by sex chromosomes or sex hormones. Males (XY or XX) were either sham-operated or orchiectomized before AngII infusions. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, whereas XX males developed focal AAAs. Castration reduced all AngII-induced aortic pathologies in XY and XX males. Thoracic aortas from AngII-infused XY males exhibited adventitial thickening that was not present in XX males. We infused male XY and XX mice with either saline or AngII and quantified mRNA abundance of key genes in both thoracic and abdominal aortas. Regional differences in mRNA abundance existed before AngII infusions, which were differentially influenced by AngII between genotypes. Prolonged AngII infusions resulted in aortic wall thickening of AAAs from XY males, whereas XX males had dilated focal AAAs. Conclusions - An XY sex chromosome complement mediates diffuse aortic pathology, whereas an XX sex chromosome complement contributes to focal AngII-induced AAAs.
AB - Objective - Aortic pathologies exhibit sexual dimorphism, with aneurysms in both the thoracic and abdominal aorta (ie, abdominal aortic aneurysm [AAA]) exhibiting higher male prevalence. Women have lower prevalence of aneurysms, but when they occur, aneurysms progress rapidly. To define mechanisms for these sex differences, we determined the role of sex chromosome complement and testosterone on the location and progression of angiotensin II (AngII)-induced aortic pathologies. Approach and Results - We used transgenic male mice expressing Sry (sex-determining region Y) on an autosome to create Ldlr (low-density lipoprotein receptor)-deficient male mice with an XY or XX sex chromosome complement. Transcriptional profiling was performed on abdominal aortas from XY or XX males, demonstrating 1746 genes influenced by sex chromosomes or sex hormones. Males (XY or XX) were either sham-operated or orchiectomized before AngII infusions. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, whereas XX males developed focal AAAs. Castration reduced all AngII-induced aortic pathologies in XY and XX males. Thoracic aortas from AngII-infused XY males exhibited adventitial thickening that was not present in XX males. We infused male XY and XX mice with either saline or AngII and quantified mRNA abundance of key genes in both thoracic and abdominal aortas. Regional differences in mRNA abundance existed before AngII infusions, which were differentially influenced by AngII between genotypes. Prolonged AngII infusions resulted in aortic wall thickening of AAAs from XY males, whereas XX males had dilated focal AAAs. Conclusions - An XY sex chromosome complement mediates diffuse aortic pathology, whereas an XX sex chromosome complement contributes to focal AngII-induced AAAs.
KW - aneurysm
KW - aorta
KW - pathology
KW - sex chromosomes
KW - testosterone
UR - http://www.scopus.com/inward/record.url?scp=85039425413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85039425413&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.117.310035
DO - 10.1161/ATVBAHA.117.310035
M3 - Article
C2 - 29097367
AN - SCOPUS:85039425413
SN - 1079-5642
VL - 38
SP - 143
EP - 153
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 1
ER -