Sex Differences in Angiotensin-Induced Vascular Diseases

描述（由申请方提供）：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AAAs的一个强风险因素。同样，血管紧张素II（AngII）诱导的AAAs表现出显着的性二型性，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，睾丸激素表现出区域特异性调节血管紧张素1a型受体（AT 1aR）的表达在腹主动脉瘤，以促进血管紧张素II诱导的AAAs。我们还表明，暴露的新生儿女性睾酮诱导永久性增加成年人对AAAs的易感性。这种女性雄激素化模型，模仿男性出生后不久睾酮激增，导致腹部腹主动脉瘤中AT 1aR表达增加，并显着增强成年女性AAA的易感性。由于男性需要持续的睾酮暴露表现出高AAA的易感性，我们的研究结果表明，男性和女性在发展过程中对睾酮的反应不同。我们建议，性激素，以及性染色体，调解AngII诱导的AAAs的性二型性。该提议的中心假设是，除了性染色体效应之外，关键细胞类型中的睾酮效应（发育和/或成人）促进主动脉AT 1aR表达和AngII诱导的AAA的区域特异性增加。目的1将确定雄激素受体在发育和/或成年睾酮对腹主动脉AT 1aR表达和AngII诱导的AAA的影响中的细胞特异性作用。目的2将定义性激素与性染色体在睾酮对腹主动脉AT 1aR表达和AngII诱导的AAA的发育和/或成人效应中的相对贡献。在这两个目标中，方法将包括旨在量化对AAA形成与进展的影响的研究。除了确定AngII诱导的AAA的性二态性的机制之外，这些研究的结果还可以确定适合治疗的靶点，即保护（女性）或增加（男性）AAA易感性。 公共卫生相关性：拟议的研究将确定腹主动脉瘤（AAA）易感性的性别差异机制。这些研究的一个独特和相关的方面是关注男性性激素暴露在发育过程中的影响，作为成年男性对AAAs更敏感的媒介。这种关注发展的转变可能会在生命早期发现新的干预措施，可以预防或减少老年男性和女性的血管疾病。此外，这些是第一个研究，以确定性染色体的作用，在AAA的形成和/或进展的显着性二型性的介质。

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. PUBLIC HEALTH RELEVANCE: The proposed research will define mechanisms for sex differences in susceptibility to abdominal aortic aneurysms (AAAs). A unique and relevant aspect of these studies is a focus on effects of male sex hormone exposures during development as a mediator of greater susceptibility to AAAs in adult males. This shift in focus to development may identify novel interventions early in life that can prevent or decrease vascular disease in aging males and females. In addition, these are the first studies to define the role of sex chromosomes as mediators of the pronounced sexual dimorphism in AAA formation and/or progression.