Sex Differences in Angiotensin-Induced Vascular Diseases

血管紧张素诱发的血管疾病的性别差异

基本信息

批准号：
8447500
负责人：
Lisa A Cassis
金额：
$ 40.33万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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/8447500
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 Intervention 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

项目摘要

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.

描述（由申请人提供）：腹主动脉瘤（AAAS）是一种常见的威胁生命的疾病，没有治疗策略有效地钝化了疾病的生长和进展。男性是AAA的强大风险因素。同样，与雌性小鼠相比，由血管紧张素II（Angii）输注的AAA表现出明显的性二态性，男性患病率高4倍。先前的结果表明，睾丸激素表现出腹主动脉中血管紧张素1A受体（AT1AR）表达的区域特异性调节，以促进血管诱导的AAAS。我们还证明，新生儿女性对睾丸激素的暴露会导致成人对AAAS的敏感性永久增加。这种女性雄激素化模型模仿男性出生后不久在睾丸激素中涌现，导致腹主动脉的AT1AR表达增加，并显着增强了成年女性的AAA敏感性。由于男性需要继续睾丸激素暴露才能表现出高AAA敏感性，因此我们的结果表明，在发育过程中，男性和女性对睾丸激素的反应不同。我们建议性激素以及性染色体介导Angii引起的AAAS的性二态性。该提案的中心假设是，除性染色体效应外，睾丸激素的作用（发育和/或成人）在性别染色体效应外，促进了主动脉AT1AR表达和ANGII诱导的AAA的区域特异性增加。 AIM 1将定义雄激素受体在睾丸激素对腹主动脉AT1AR表达和ANGII诱导的AAAS的发育和/或成年作用中的细胞特异性作用。 AIM 2将定义性激素与性染色体在睾丸激素对腹主动脉AT1AR表达和Angii诱导的AAAS的发育和/或成人作用中的相对贡献。在这两个目标中，方法都将包括旨在量化对AAA形成与进展的影响的研究。除了确定Angii诱导的AAA的性二态性的机制外，这些研究的结果还可以确定可保护治疗的靶标的，即保护（女性）或增强（男性）AAA AAA敏感性。