Gender Differences in Experimental Aortic Aneurysms

腹主动脉瘤（AAA）是白人男性死亡的第10大原因65-74 2000年，共有近16，000人死亡。了解 AAAs的病理生理学是一项重要的工作。临床上，多种风险因素与 AAAs的发展，包括年龄增加，吸烟史和高血压。男性性别是 也是AAA发展的一个公认的风险因素，男女比例为4：1。的原因 这种性别差异是未知的。AAAs形成的发病机制是复杂且多因素的。 在组织学上，AAA的特征是早期趋化因子驱动的白细胞浸润到主动脉壁中 随后由于过度的局部产生而破坏中膜和外膜中的弹性蛋白和胶原 基质降解酶和平滑肌细胞损失与主动脉壁变薄。而目前 没有可用的药物治疗主动脉瘤患者，仅使用粗 测量主动脉直径作为阈值，患者必须接受危及生命和昂贵的 手术，开放或血管内。因此，界定与性别有关的 AAA形成的差异是关键的，并且将是本研究的焦点。 了解基于性别的疾病模式差异可能使我们能够开发新的翻译 主动脉瘤患者的预防和治疗方法。总体假设：性别- 主动脉瘤形成的相关差异由激素（雄激素：雌激素比例）介导 调节白细胞进入主动脉壁。具体目标1。为了定义早期 在AAA形成期间，雄性中的炎性细胞募集加速。研究将检验这一假设 男性AAA发生率增加继发于主动脉白细胞募集增加 由雄激素相对于雌激素过量驱动的壁。具体目标2。为了证明性腺 激素可用于调节伴随AAA形成的炎症反应。研究将 检验改变雄激素：雌激素环境可以决定动脉瘤患病率的假设 通过改变上述特异性可溶性介质依赖性白细胞运输，最终 促使基质降解和修复的平衡朝向动脉瘤形成。

Abdominal aortic aneurysms (AAAs) comprise the 10th leading cause of death in Caucasian males 65-74 years of age and accounted for nearly 16,000 deaths overall in the year 2000. Understanding the pathophysiology of AAAs is an important undertaking. Clinically, multiple risk factors are associated with the development of AAAs, including increasing age, positive smoking history, and hypertension. Male gender is also a well-established risk factor for the development of an AAA with a 4:1 male to female ratio. The reason for this gender disparity is unknown. The pathogenesis of AAAs formation is complex and multifactorial. Histologically, AAAs are characterized by early chemokine driven leukocyte infiltration into the aortic wall with subsequent destruction of elastin and collagen in the media and adventitia by excessive local production of matrix degrading enzymes, and smooth muscle cell loss with thinning of the aortic wall. At present, there are no medical therapies available to treat patients with aortic aneurysms, using only the crude measurement of aortic diameter as a threshold for which patients must undergo life-threatening and costly surgery, either open or endovascularly. Therefore, defining the early mechanisms underlying gender-related differences in AAA formation are critical and will be the focus of the present investigation. Understanding differences in disease patterns based on gender may allow us to develop new translational approaches to the prevention and treatment of patients with aortic aneurysms. Overall hypothesis: Gender- related differences in aortic aneurysm formation are mediated by the hormonal (androgen: estrogen ratio) regulation of leukocyte trafficking into the aortic wall. Specific Aim 1. To define the mechanism by which early inflammatory cell recruitment is accelerated in males during AAA formation. Studies will test the hypothesis that increased incidence of AAAs in males is secondary to increased recruitment of leukocytes into the aortic wall driven by an excess of androgens relative to estrogens. Specific Aim 2. To demonstrate that gonadal hormones can be used to modulate the inflammatory response accompanying AAA formation. Studies will test the hypothesis that altering the androgen: estrogen environment can dictate the prevalence of aneurysm formation by altering the forementioned specific soluble mediator dependent leukocyte trafficking, ultimately driving the balance of matrix degradation and repair toward aneurysm formation.