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

项目总结/摘要 在美国，动脉功能障碍是导致死亡的主要原因之一。性别差异 动脉病变的表现、弹性和风险状况已得到很好的确立，但要澄清 这些差异的分子决定因素仍然稀少。主动脉瘤和夹层表现出明显的， 他们的表现和治疗结果存在一致的性别差异。女性被诊断出 甚至在遗传性动脉瘤如马凡氏综合征（MFS）的情况下， 其中因果突变在男性和女性之间以相同的频率遗传。当确诊时， 然而，由于可能归因于两者的原因，女性相对于男性表现出较差的结果和预后， 生物和社会驱动因素。生物学基础驱动对主动脉瘤的弹性 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， 可以用来改善男性的疾病预防和管理，2）了解 表现出严重疾病的女性的复原力下降。在本提案中，我们利用了一个行之有效的 MFS，性腺切除术和激素替代的小鼠模型，以及尖端蛋白质组学，以检查 女性性激素雌激素（E2）和孕激素（P4）如何与染色体定义的性别交叉 影响已确立的AoR动脉瘤表型（Aim 1）。然后我们将联合收割机在人体内进行体外实验 正常和MFS血管细胞的iPSC-模型，在小鼠中进行体内验证，以测试两种特异性 关于E2和P4如何影响动脉瘤发病机制中已知通路的假说;血管紧张素 II（Ang II）信号传导（Aim 2）和由特异性整合素异二聚体（Aim）驱动的机械/基质感受失衡 3）。有趣的是，虽然严重的主动脉根（AoR）动脉瘤和夹层似乎偏向于男性， 动脉粥样硬化性自发性冠状动脉夹层（SCAD）明显偏向于女性， 是年轻女性急性冠状动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，如马凡氏综合征（MFS）。有意思的是，导致纤维蛋白-1（Fbn 1） 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 问题研究主动脉和冠状动脉之间的关键分子差异可能导致关键的分子生物学效应。 对荷尔蒙的反应差异，导致不同的风险和弹性，由于性别。作为附加 在上述每个目的的探索性研究组中，我们将研究冠状动脉病理学是否显示 “镜像”的风险或弹性签名之间的雄性和雌性MFS小鼠在努力改变， 提供了一些第一个基本模型的女性偏置条件的SCAD的研究。的见解 从我们的研究中获得的信息将揭示可用于预防的假定风险和弹性机制 和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.