Sex Differences in Angiotensin-Induced Vascular Diseases

腹主动脉瘤(AAA)表现出明显的性别二型性。与人类相似，我们 先前证明，睾丸激素是导致血管紧张素II发病率增加4倍的主要因素。 (AngII)在雄性小鼠和雌性小鼠中诱导的AAA的比较。除了性激素，性染色体还有 被认为与心血管疾病的性别二型性有关。初步数据显示 将雌性小鼠的性染色体从XX改变为XY会导致AAA的发生 与雄性相似。在XY男性中，由于睾酮促进血管紧张素转换酶诱导的AAA，所以我们使用了睾酮 对新生儿(1剂)和成年XY女性。睾酮导致73%的成年XY患者动脉瘤破裂 女性。这些结果表明，性染色体补体对AAA的严重程度有显著影响， 而这些效应被睾丸激素放大了。XX与XX对照的平滑肌细胞基因芯片 与AngiI或睾酮孵育的XY雌性鉴定为Neprilysin和HO_1(HO1)基因 可能以性别特有的方式导致更高的AAA发生率、严重性和进展的目标 男性与女性相比。这一提议的中心假设是性行为之间的相互作用 激素和染色体促进了AAAs的发生和严重程度。此外，我们假设一个 精准医学治疗靶向受性激素影响的特定途径， 染色体，或血管紧张素转换酶，将提供针对AAA形成和进展的性别特异性疗效。目标1将 验证XY性染色体互补增加血管紧张素Ⅱ诱导的AAA易感性的假设 由于Y染色体上存在基因。我们将使用一种新的小鼠模型(XY*)，当饲养时 对于XX女性，能够描述XX、XO、XXY或XY性染色体互补是否影响 血管紧张素转换酶诱导的AAA的发展和/或进展。目标2将检验以下假设：特定性别 针对男性的neprilysin抑制和女性的HO1刺激的治疗方法将提供 对血管紧张素转换酶诱导的腹主动脉硬化形成和/或进展的疗效。这些研究将增加基础 了解性染色体对血管系统的影响，确定针对性别的治疗方法 对AAA的治疗适用性，并增加对性激素使用率的心血管知识 不断增长的变性人人口。

Abdominal aortic aneurysms (AAAs) exhibit pronounced sexual dimorphism. Similar to humans, we demonstrated previously that testosterone is a primary contributor to a 4-fold higher incidence of angiotensin II (AngII)-induced AAAs in male compared to female mice. In addition to sex hormones, sex chromosomes have been suggested to contribute to sexual dimorphism of cardiovascular diseases. Preliminary data demonstrate that changing the sex chromosome complement from XX to XY in female mice results in an AAA incidence that is similar to males. As testosterone promotes AngII-induced AAAs in XY males, we administered testosterone to neonatal (1 dose) and adult XY females. Testosterone caused aneurysm rupture in 73% of adult XY females. These results demonstrate that sex chromosome complement has a striking impact on AAA severity, and that these effects are augmented by testosterone. Gene arrays on smooth muscle cells from XX versus XY females incubated with AngII or testosterone identified neprilysin and heme oxygenase 1 (HO1) as gene targets that may contribute in a sex-specific manner to higher AAA incidences, severity and progression in males compared to females. The central hypothesis of this proposal is that an interplay between sex hormones and chromosomes promotes the incidence and severity of AAAs. Moreover, we hypothesize that a Precision Medicine approach to therapeutically target specific pathways influenced by sex hormones, chromosomes, or AngII will provide sex-specific efficacy against AAA formation and progression. Aim 1 will test the hypothesis that an XY sex chromosome complement increases susceptibility to AngII-induced AAAs due to the presence of genes on the Y chromosome. We will use a novel mouse model (XY*) that when bred to XX females enables delineation of whether XX, XO, XXY, or XY sex chromosome complement influences the development and/or progression of AngII-induced AAAs. Aim 2 will test the hypothesis that sex-specific therapeutic approaches, targeting neprilysin inhibition in males versus HO1 stimulation in females will provide efficacy against the formation and/or progression of AngII-induced AAAs. These studies will increase basic knowledge of sex chromosome influences on the vasculature, identify sex-specific therapies that may have therapeutic applicability against AAAs, and increase cardiovascular knowledge for the use of sex hormones in the growing trans-gender population.