Sex Differences in Angiotensin-Induced Vascular Diseases

描述(申请人提供)：腹主动脉瘤(AAA)是一种常见的危及生命的疾病，没有有效抑制疾病生长和进展的治疗策略。男性是AAA的一个强烈的危险因素。同样，注射血管紧张素II(AngII)诱导的AAA表现出明显的性别二型性，雄性小鼠的患病率是雌性小鼠的4倍。以往的研究结果表明，睾酮对腹主动脉血管紧张素1a受体(AT1aR)的表达具有区域特异性调节作用，从而促进血管紧张素Ⅱ诱导的腹主动脉硬化。我们还证明，新生儿女性暴露于睾丸素会导致成年AAAs易感性的永久性增加。这种模拟男性出生后不久睾丸激素激增的女性雄激素化模型，导致腹主动脉AT1aR表达增加，并显著增强成年女性AAA的易感性。由于男性需要持续接触睾丸素才能表现出高度的AAA敏感性，我们的结果表明，男性和女性在发育过程中对睾酮的反应不同。我们认为性激素和性染色体共同作用于血管紧张素转换酶诱导的AAA的性别二型性。这一建议的中心假设是，除了性染色体效应外，关键细胞类型的睾酮效应(发育和/或成人)还促进主动脉AT1aR表达和血管紧张素Ⅱ诱导的AAA的区域特异性增加。目的1明确雄激素受体在睾酮对腹主动脉AT1aR表达和血管紧张素Ⅱ诱导的AAA的发育和/或成人效应中的细胞特异性作用。目的2明确性激素与性染色体在发育和/或成人睾酮对腹主动脉AT1aR表达和血管紧张素Ⅱ诱导的AAA的影响中的相对作用。在这两个目标中，方法将包括旨在量化对AAA形成和进展的影响的研究。除了确定血管紧张素Ⅱ诱导的AAA的性二型性机制外，这些研究的结果还可能确定可接受治疗的靶点，保护(女性)或增强(男性)AAA的易感性。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAAs) are a common life-threatening disorder with no therapeutic strategies that effectively blunt growth and progression of the disease. Male sex is a strong risk factor for AAAs. Similarly, AAAs induced by infusion of angiotensin II (AngII) exhibit marked sexual dimorphism with a 4-fold higher prevalence in male compared to female mice. Previous results demonstrated that testosterone exhibits region-specific regulation of angiotensin type 1a receptor (AT1aR) expression in abdominal aortas to promote AngII-induced AAAs. We also demonstrated that exposures of neonatal females to testosterone induced permanent increases in adult susceptibility to AAAs. This model of female androgenization, which mimics surges in testosterone shortly after birth in males, resulted in increased AT1aR expression in abdominal aortas and markedly enhanced AAA susceptibility of adult females. Since males require continued testosterone exposures to exhibit high AAA susceptibility, our results demonstrate that males and females respond differently to testosterone during development. We propose that sex hormones, as well as sex chromosomes, mediate sexual dimorphism of AngII-induced AAAs. The central hypothesis of this proposal is that testosterone effects (developmental and/or adult) at pivotal cell types, in addition to sex chromosome effects, promote region- specific increases in aortic AT1aR expression and AngII-induced AAAs. Aim 1 will define the cell-specific role of androgen receptors in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs. Aim 2 will define the relative contribution of sex hormones versus sex chromosomes in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs. In both aims, approaches will include studies designed to quantify effects on AAA formation versus progression. In addition to identifying mechanisms for sexual dimorphism of AngII-induced AAAs, results from these studies may identify targets, amenable to therapy, that either protect (females) or augment (males) AAA susceptibility.