Sex Differences in Angiotensin-Induced Vascular Diseases

描述（由申请人提供）：腹主动脉瘤（AAAs）是一种常见的危及生命的疾病，没有有效的治疗策略来延缓疾病的生长和进展。男性性别是AAAs的一个重要风险因素。同样，注入血管紧张素II （AngII）诱导的AAAs表现出明显的性别二态性，雄性小鼠的患病率是雌性小鼠的4倍。先前的研究结果表明，睾酮在腹主动脉中表现出对血管紧张素1a型受体（AT1aR）表达的区域特异性调节，以促进血管i诱导的AAAs。我们还证明，新生儿雌性暴露于睾酮会导致成年后对AAAs的易感性永久增加。这种雌性雄激素化模型，模仿雄性出生后不久睾酮的激增，导致腹主动脉中AT1aR表达增加，并显着增强成年雌性的AAA易感性。由于男性需要持续的睾酮暴露才能表现出高度的AAA易感性，我们的研究结果表明，男性和女性在发育过程中对睾酮的反应不同。我们认为性激素以及性染色体介导了血管诱导的AAAs的两性二态性。该建议的中心假设是睾酮对关键细胞类型（发育和/或成人）的影响，以及性染色体的影响，促进了主动脉AT1aR表达和血管i诱导的AAAs的区域特异性增加。目的1将确定雄激素受体在发育和/或成人睾酮对腹主动脉AT1aR表达和血管内皮诱导的AAAs的影响中的细胞特异性作用。目的2将确定性激素与性染色体在发育和/或成年时睾酮对腹主动脉AT1aR表达和血管血管诱导的AAAs的影响中的相对贡献。在这两个目标中，方法将包括旨在量化AAA地层与进展影响的研究。除了确定血管血管诱导的AAA性二态性的机制外，这些研究的结果还可以确定可治疗的靶点，保护（女性）或增加（男性）AAA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.