Mechanisms of thoracic aortic aneurysms

描述(申请人提供)：胸主动脉瘤(TAA)最常发生在无症状的上升部位。通常，它存在的第一个迹象是破裂，通常会导致死亡。TAAS是患有一系列由基因决定的疾病的患者的危及生命的后果，其中最常见的是马凡氏病。对于被诊断为TAAS的患者，目前唯一的治疗策略是手术治疗。因此，迫切需要对TAA进行机械性的洞察，以开发有效的治疗方法。我们最近证明，血管紧张素转换酶抑制剂的输注也会导致局部位于升主动脉的动脉血栓形成。CC趋化因子受体2(CCR2)缺乏可减弱血管紧张素Ⅱ诱导的TAAs。这推测单核细胞趋化蛋白-1(MCP-1)在TAAs中的作用，尽管CCR2也与其他趋化因子相互作用。我们最近已经证明，血管内皮细胞特异性AT1a受体缺陷对血管紧张素Ⅱ诱导的TAAs的减弱程度与全身CCR2缺陷相似。这两个观察结果可能通过Angii刺激MCP-1释放的旁分泌机制相关联，MCP-1是决定CCR2刺激的主要效应的配体。血管紧张素Ⅱ诱导的TAA的特点是内侧巨噬细胞大量积聚，主要集中在外膜方面。基于这一简要描述的背景，我们建议检验中央假设，即MCP-1-CCR2轴促进血管紧张素Ⅱ诱导的TAA定位于升行区，其机制是内皮介导的巨噬细胞通过主动脉区域特异性作用从外膜募集。为了验证这一假说，将解决以下具体目标：目的1.确定MCP-1-CCR2轴在血管紧张素Ⅱ诱导的TAAs发生发展中的作用。答：全身缺乏MCP-1或CCR2是否会促进血管紧张素转换酶抑制剂诱导的持续的、与中层巨噬细胞聚集减少相关的同等程度的TAA减少？单核细胞趋化蛋白-1促进动脉粥样硬化的来源是由于血管内皮细胞直接释放趋化因子还是通过特定的SMC群体间接释放这种趋化因子？目的2.探讨血管紧张素Ⅱ诱导的动脉粥样硬化形成过程中升主动脉内膜巨噬细胞聚集的来源。在血管紧张素Ⅱ诱导的动脉粥样硬化形成过程中，白细胞浸润的顺序是什么？这是否与单核细胞趋化蛋白-1和CCR2的表达有关？血管内注射时聚集在升主动脉中层和外膜的巨噬细胞是否来源于血液或组织？人类升主动脉瘤组织中的白细胞聚集是否与MCP-1和CCR2的表达有关？ 公共卫生相关性：主动脉瘤性疾病具有破坏性的健康后果，并且越来越常见。尽管这些疾病对公众健康有很大影响，但对这些疾病的调查工作相对较少。因此，还没有明确的医学选择来提供手术干预的替代方案。进一步研究主动脉瘤疾病是公共卫生的当务之急。

DESCRIPTION (provided by applicant): Thoracic aortic aneurysms (TAAs) most commonly develop in the ascending region in an asymptomatic manner. Frequently, the first indication of its presence is rupture that commonly leads to death. TAAs are the life-threatening consequence in patients afflicted with a broad range of genetically determined diseases; one of the most common being Marfan's disease. The only current therapeutic strategy for individuals diagnosed with TAAs is surgical options. Consequently, there is a pressing need for mechanistic insight into TAAs to develop effective therapeutics. We have recently demonstrated that AngII infusion also leads to TAAs that are localized to the ascending aorta. AngII-induced TAAs are attenuated by CC Chemokine receptor 2 (CCR2) deficiency. This infers a role for monocyte chemoattractant protein-1 (MCP-1) in TAAs, although CCR2 also interacts with other chemokines. We have recently demonstrated that endothelial-specific deficiency of AT1a receptors imparts a similar degree of attenuation of AngII-induced TAAs as whole body CCR2 deficiency. These two observations could potentially be associated via a paracrine mechanism by which AngII stimulates MCP-1 release, the ligand that determines the major effects of CCR2 stimulation. The AngII-induced TAAs are characterized by profound medial macrophage accumulation that is predominantly on the adventitial aspect. On the basis of this briefly described background, we are proposing to test the central hypothesis that the MCP-1-CCR2 axis promotes AngII-induced TAAs localized to the ascending region through an endothelial-mediated mechanism of macrophage recruitment from the adventitia via aortic region- specific effects. To test this hypothesis, the following specific aims will be addressed: Aim 1. Determine the role of the MCP-1-CCR2 axis in development of AngII-induced TAAs. A. Does whole body deficiency of either MCP-1 or CCR2 promote equivalent reductions in AngII-induced TAAs that are persistent and associated with reduced medial macrophage accumulation? B. Is the source of MCP-1 in promoting TAAs due to AngII releasing this chemokine directly from endothelial or indirectly via specific SMC populations? Aim 2. Determine the origin of medial macrophages accumulating in ascending aortas during development of AngII-induced TAAs. A. What is the sequence of leukocytic infiltration in the development of AngII-induced TAAs and does this correlate to the expression of MCP-1 and CCR2? B. Are macrophages that accumulate in media and adventitia of ascending aortas during AngII infusion derived from blood or tissue origin? C. Is leukocyte accumulation in human ascending aortic aneurysmal tissue associated with MCP-1 and CCR2 expression? PUBLIC HEALTH RELEVANCE: Aortic aneurysmal diseases have devastating health consequences and are increasingly more common. Despite the large impact on public health, there is a relatively paucity of investigative efforts on these diseases. Consequently, there are no defined medical options developed to provide an alternative to surgical intervention. Further research in aortic aneurysmal diseases is a public health imperative.