Mechanisms of sex-biased risk and resiliency in aneurysm and dissection

项目摘要/摘要 动脉功能障碍是导致美国人死亡的主要原因之一。男女学生的性别差异 动脉病变的表现形式、弹性和风险概况已得到很好的证实，但仍有知识澄清 这些差异的分子决定因素仍然很少。主动脉瘤和夹层显示清晰和 在他们的表现和治疗结果上一致的性别差异。女性被确诊的比例明显较低 甚至在马凡综合征(MFS)等遗传性动脉瘤的病例中也是如此 其中因果突变在男性和女性之间以相同的频率遗传。一旦确诊， 然而，与男性相比，女性表现出更差的结局和预后，原因可能是两者都有 生物和社会驱动因素。推动抗主动脉瘤弹性的生物学基础 对女性的解剖仍不清楚，但它们的定义将1)确定女性的保护途径 可用于改善男性的疾病预防和管理，以及2)了解 那些确实表现出严重疾病的女性的弹性降低。在这项提案中，我们利用了一个历史悠久的 MFS小鼠模型，性腺切除和激素替代，以及前沿蛋白质组学，以检查 女性性激素雌激素(E_2)和孕酮(P_4)如何与染色体决定的性别相交 影响已确立的AOR动脉瘤表型(目标1)。然后我们将结合人体的体外实验 IPSC-正常和MFS血管细胞模型在小鼠体内的验证以测试两种特异性 关于E2和P4如何影响与动脉瘤发病相关的已知通路的假说；血管紧张素 血管紧张素Ⅱ(Ang II)信号转导(AIM 2)与特定整合素异源二聚体(AIM)驱动的机械/基质感觉失衡 3)。有趣的是，虽然重症主动脉根部(AOR)动脉瘤和夹层似乎偏向男性，但非 动脉粥样硬化性自发性冠状动脉夹层(SCAD)明显偏向女性，是一种 导致年轻女性急性冠脉综合征的主要原因。其危险因素包括怀孕和存在 遗传性动脉病变，如马凡综合征(MFS)。有趣的是，纤维蛋白-1(Fbn1)是导致 在最近的全基因组关联中，MFS已被确定为SCAD患者的候选基因 学习。主动脉和冠状动脉之间的关键分子差异可能赋予关键分子 因性别而导致不同风险和弹性的荷尔蒙反应的差异。作为额外的 探查臂在上述每个目的中，我们将调查冠状动脉病理是否显示 激素改变的雄性和雌性MFS小鼠之间的“镜像”风险或弹性特征，以努力 为研究SCAD的女性偏向状况提供了一些初步的基本模型。洞察力 我们的研究将揭示可用于预防的假定风险和弹性机制 以及适用于两性的治疗策略。

PROJECT SUMMARY / ABSTRACT Arterial dysfunction is a causal factor in the leading causes of death in the United States. Sex differences in the presentation, resiliency and risk profile of arterial pathologies are well established, yet knowledge to clarify the molecular determinants of these differences remain sparse. Aortic aneurysms and dissections exhibit clear and consistent sex differences in their presentation and treatment outcomes. Women are diagnosed significantly less frequently and at later ages than males, even in cases of hereditary aneurysm such as Marfan Syndrome (MFS) where causal mutations are inherited with equal frequency between males and females. When diagnosed, however, women exhibit poorer outcomes and prognosis relative to men for reasons likely attributable to both biological and socially driven factors. The biological underpinnings driving resiliency against aortic aneurysms and dissections in women remain unclear, but their definition will 1) identify protective pathways in females that could be leveraged to improve disease prevention and management in males and 2) understand the drivers of reduced resiliency in the females who do exhibit severe disease. In this proposal, we leverage a well-established mouse model of MFS, gonadectomy and hormone replacement, and cutting-edge proteomics in order to examine how the female sex hormones estrogen (E2) and progesterone (P4) intersect with chromosomally defined sex to affect well established AoR aneurysm phenotype (Aim 1). We will then combine in vitro experiments in human iPSC-models of normal and MFS vascular cells with in vivo validation in mice in order to test two specific hypotheses regarding how E2 and P4 affect known pathways involved in aneurysm pathogenesis; Angiotensin II (Ang II) signaling (Aim 2) and mechano/matrixsensing imbalance driven by specific integrin heterodimers (Aim 3). Interestingly, while severe of aortic root (AoR) aneurysm and dissection appear biased toward males, non- atherosclerotic Spontaneous Coronary Artery Dissection (SCAD) is clearly biased toward females and is a leading cause of acute coronary syndromes in young women. Among its risk factors are pregnancy and existing hereditary arteriopathies, such as Marfan Syndrome (MFS). Interestingly, Fibrillin-1 (Fbn1), the gene that causes MFS, has been identified as a candidate gene among patients with SCAD in recent genome wide association studies. Key molecular differences between the aortic and coronary arteries may confer critical molecular variance in response to hormones that results in disparate risk and resiliency due to sex. As an additional exploratory arm in each of the above Aims, we will investigate whether coronary artery pathology demonstrate ‘mirror image’ risk or resiliency signatures between hormone-altered male and female MFS mice in an effort to provide some of the first fundamental models for the study of the female-biased condition of SCAD. The insights gained from our studies will reveal putative risk and resiliency mechanisms that can be leveraged for prevention and therapeutic strategies applicable to both sexes.