From the Department of Pharmacology and Nutritional Sciences (Y.A., S.E.T., E.B., L.A.C.), Department of Kinesiology (B.F.), Department of Physiology (A.D.), and Saha Cardiovascular Research Center (A.D.), University of Kentucky, Lexington.
Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):143-153. doi: 10.1161/ATVBAHA.117.310035. Epub 2017 Nov 2.
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.
We used transgenic male mice expressing (sex-determining region Y) on an autosome to create (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.
An XY sex chromosome complement mediates diffuse aortic pathology, whereas an XX sex chromosome complement contributes to focal AngII-induced AAAs.
主动脉病变存在性别二态性，胸主动脉和腹主动脉（即腹主动脉瘤[AAA]）的动脉瘤均表现出更高的男性患病率。女性的动脉瘤患病率较低，但当发生动脉瘤时，其进展迅速。为了确定这些性别差异的机制，我们确定了性染色体组成和睾酮对血管紧张素 II（AngII）诱导的主动脉病变部位和进展的作用。
我们使用在常染色体上表达 （性别决定区 Y）的转基因雄性小鼠，创建具有 XY 或 XX 性染色体组成的 （低密度脂蛋白受体）缺陷雄性小鼠。对 XY 或 XX 雄性的腹主动脉进行转录谱分析，结果显示有 1746 个基因受性染色体或性激素影响。雄性（XY 或 XX）在接受 AngII 输注前接受假手术或去势。XY AngII 输注雄性出现弥漫性主动脉瘤病变，而 XX 雄性出现局灶性 AAA。去势可减少 XY 和 XX 雄性所有 AngII 诱导的主动脉病变。来自 AngII 输注的 XY 雄性的胸主动脉表现出不存在于 XX 雄性中的外膜增厚。我们分别向 XY 和 XX 雄性 AngII 输注雄性 XY 和 XX 小鼠盐水或 AngII，并定量分析胸主动脉和腹主动脉中关键基因的 mRNA 丰度。在 AngII 输注之前就存在 mRNA 丰度的区域差异，这些差异在基因型之间受 AngII 的影响不同。延长 AngII 输注导致 XY 雄性的 AAA 主动脉壁增厚，而 XX 雄性的 AAA 则扩张。
XY 性染色体组成介导弥漫性主动脉病变，而 XX 性染色体组成有助于局灶性 AngII 诱导的 AAA。
