Female Mice With an XY Sex Chromosome Complement Develop Severe Angiotensin II-Induced Abdominal Aortic Aneurysms.
Female Mice With an XY Sex Chromosome Complement Develop Severe Angiotensin II-Induced Abdominal Aortic Aneurysms.
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DOI：
10.1161/circulationaha.116.023789
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发表时间：
2017-01-24
期刊：
影响因子：
37.8
通讯作者：
Cassis LA
中科院分区：
文献类型：
--
作者：
Alsiraj Y;Thatcher SE;Charnigo R;Chen K;Blalock E;Daugherty A;Cassis LA
腹主动脉瘤（AAA）是一种致命的病理与强烈的两性异形。与人类相似，雌性小鼠血管紧张素II（AngII）诱导的AAA发生率远低于雄性小鼠。除了性激素，X和Y性染色体，以及它们独特的基因互补，可能有助于性二态性AAA病理。在这里，我们定义了雌性（XX）与雄性（XY）性染色体补体对表型雌性小鼠中AngII诱导的AAA形成和破裂的影响。雌性低密度脂蛋白受体（Ldlr）小鼠与XX或XY性染色体补体输注血管紧张素Ⅱ 28天，以诱导AAAs。通过超声定量腹主动脉管腔直径，而在研究终点时定量AAA直径。在腹部肿块上进行DNA微阵列。为了模拟雄性，在AngII输注之前，将雌性小鼠作为新生儿或作为成年人给予单剂量的睾酮。具有XX和XY性染色体补体的雌性Ldlr−/−缺陷小鼠具有相似的性器官重量和低血清睾酮浓度。来自雌性XY小鼠的腹部脂肪选择性地表达Y染色体基因，而已知逃避X失活的基因在XX雌性中更高。XY与XX雌性动物中的大部分主动脉基因差异属于炎症途径。XY女性的AAA发生率加倍，动脉瘤破裂。XY雌性的AAA表现出炎症，XY雌性的血浆IL 1 β浓度升高。此外，从XY女性子宫内膜有增强的基质金属蛋白酶活性和增加氧化应激。最后，与XX成年女性相比，XY中长期或在出生后第1天单次给予睾酮暴露显著恶化了AAA结局。表型女性的XY性染色体补体深刻影响主动脉基因表达谱，并促进AAA的严重程度。当XY女性暴露于睾酮时，动脉瘤破裂率是惊人的。XY女性AAA严重程度增加的机制包括炎症增加、基质金属蛋白酶增加和氧化应激。我们的研究结果表明，性染色体上的基因调节主动脉血管生物学，并有助于两性异形的AAA。性染色体基因可以作为性别特异性AAA治疗的新靶点。
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. 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. 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, while 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 IL1β concentrations were increased in XY females. Moreover, aortas from XY females had augmented matrix metalloproteinase activity and increased oxidative stress. Finally, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY compared to 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.