Sex Differences in Angiotensin-Induced Vascular Diseases

血管紧张素诱发的血管疾病的性别差异

• 批准号: 8295633
• 负责人: Lisa A Cassis
• 金额: $ 42.37万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-21 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295633
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Adult; Affect; Aging; Androgen Receptor; Androgenization; Angiotensin II; Angiotensin Type 1a Receptor; Angiotensins; Aorta; Aortic Aneurysm; Apolipoprotein E; Atherosclerosis; Birth; Blood Pressure; Blood Vessels; Cardiovascular system; Cells; Cessation of life; Chromosomes; Development; Disease; Disease Progression; Dose; Early treatment; Embryo; Employee Strikes; Exhibits; Exposure to; Female; Genes; Genotype; Goals; Gonadal Steroid Hormones; Growth; High Prevalence; Infusion procedures; Life; Low-Density Lipoproteins; Medial; Mediating; Mediator of activation protein; Mesoderm; Mesoderm Cell; Messenger RNA; Modeling; Mus; Neonatal; Operative Surgical Procedures; Pathology; Predisposition; Prevalence; Regulation; Relative (related person); Research; Research Design; Risk Factors; Role; Rupture; Sex Characteristics; Sex Chromosomes; Site; Smooth Muscle; Smooth Muscle Myocytes; Testing; Testosterone; Therapeutic; Thoracic aorta; Vascular Diseases; abdominal aorta; aged; base; blastomere structure; cell type; effective therapy; human disease; interest; male; mouse model; neonatal exposure; novel; prevent; receptor expression; response; sex; sexual dimorphism

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.

描述（由申请人提供）：腹主动脉瘤（AAA）是一种常见的危及生命的疾病，没有有效减缓疾病生长和进展的治疗策略。男性是 AAA 的一个重要危险因素。同样，输注血管紧张素 II (AngII) 诱导的 AAA 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。先前的结果表明，睾酮对腹主动脉中血管紧张素 1a 型受体 (AT1aR) 的表达表现出区域特异性调节，以促进 AngII 诱导的 AAA。我们还证明，新生女性接触睾酮会导致成人对 AAA 的易感性永久性增加。这种女性雄激素化模型模仿男性出生后不久睾酮的激增，导致腹主动脉 AT1aR 表达增加，并显着增强成年女性 AAA 的易感性。由于男性需要持续接触睾酮才能表现出高 AAA 易感性，因此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。我们认为性激素以及性染色体介导 AngII 诱导的 AAA 的性二态性。该提议的中心假设是，除了性染色体效应之外，睾酮对关键细胞类型的效应（发育和/或成体）还促进主动脉 AT1aR 表达和 AngII 诱导的 AAA 的区域特异性增加。目标 1 将定义雄激素受体在睾酮对腹主动脉 AT1aR 表达和 AngII 诱导的 AAA 的发育和/或成人影响中的细胞特异性作用。目标 2 将定义性激素与性染色体在睾酮对腹主动脉 AT1aR 表达和 AngII 诱导的 AAA 的发育和/或成人影响中的相对贡献。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 的性别二态性机制外，这些研究的结果还可以确定适合治疗的靶标，以保护（女性）或增强（男性）AAA 的易感性。 公共健康相关性：拟议的研究将确定腹主动脉瘤 (AAA) 易感性性别差异的机制。这些研究的一个独特且相关的方面是关注发育过程中雄性激素暴露的影响，作为成年男性对 AAA 更易感性的调节因素。这种对发展的关注点的转变可能会在生命早期发现新的干预措施，从而预防或减少老年男性和女性的血管疾病。此外，这些是首次定义性染色体作为 AAA 形成和/或进展中明显性二态性中介者的作用的研究。