Mechanisms of thoracic aortic aneurysms

胸主动脉瘤的发病机制

• 批准号: 8257040
• 负责人: Alan Daugherty
• 金额: $ 54.34万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257040
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Address; Affect; Angiotensin II; Anterior; Aorta; Area; Attenuated; Blood; CC chemokine receptor 2; CCL2 gene; Cardiac; Cells; Cessation of life; Complex; Defect; Development; Diagnosis; Disease; Embryo; Endothelial Cells; Fibroblasts; Growth; Health; Heart; Human; Individual; Infiltration; Infusion procedures; Leukocytes; Life; Ligands; Literature; Medial; Mediating; Mediator of activation protein; Medical; Monocyte Chemoattractant Protein-1; Mus; Neural Crest; Operative Surgical Procedures; Pathology; Patients; Pericytes; Population; Public Health; Research; Role; Rupture; Smooth Muscle Myocytes; Source; Specificity; Structure; Surface; Testing; Therapeutic; Thoracic Aortic Aneurysm; Thoracic aorta; Tissues; Tunica Adventitia; Ulcer; ascending aorta; attenuation; base; cell type; chemokine; disease characteristic; insight; macrophage; neutralizing antibody; paracrine; receptor

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.

描述（由申请人提供）：胸主动脉瘤（TAA）最常以无症状的方式发生在升区。通常，其存在的第一个迹象是破裂，通常会导致死亡。对于患有多种遗传性疾病的患者来说，TAAs 会危及生命；最常见的疾病之一是马凡氏病。对于诊断为 TAA 的个体，目前唯一的治疗策略是手术选择。因此，迫切需要深入了解 TAA 的机制，以开发有效的治疗方法。 我们最近证明，AngII 输注也会导致定位于升主动脉的 TAA。 CC 趋化因子受体 2 (CCR2) 缺陷会减弱 AngII 诱导的 TAA。这表明单核细胞趋化蛋白 1 (MCP-1) 在 TAA 中发挥作用，尽管 CCR2 也与其他趋化因子相互作用。我们最近证明，内皮特异性 AT1a 受体缺陷会导致 AngII 诱导的 TAA 减弱程度与全身 CCR2 缺陷相似。这两个观察结果可能通过旁分泌机制相关联，AngII 通过旁分泌机制刺激 MCP-1 释放，而 MCP-1 是决定 CCR2 刺激主要作用的配体。 AngII 诱导的 TAA 的特点是内侧巨噬细胞大量积累，主要集中在外膜方面。基于这个简要描述的背景，我们建议测试以下中心假设：MCP-1-CCR2 轴通过主动脉区域特异性效应从外膜招募巨噬细胞的内皮介导机制，促进 AngII 诱导的 TAA 定位于上升区域。为了检验这一假设，将解决以下具体目标： 目标 1. 确定 MCP-1-CCR2 轴在 AngII 诱导的 TAA 发育中的作用。 A. MCP-1 或 CCR2 的全身缺乏是否会促进 AngII 诱导的 TAA 的同等减少，这种减少是持久的并与内侧巨噬细胞积累减少有关？ B. MCP-1 促进 TAA 的来源是由于 AngII 直接从内皮细胞释放这种趋化因子还是通过特定的 SMC 群体间接释放这种趋化因子？目标 2. 确定 AngII 诱导的 TAA 发育过程中升主动脉中积累的内侧巨噬细胞的起源。 A. AngII 诱导的 TAA 发育过程中白细胞浸润的顺序是什么？这与 MCP-1 和 CCR2 的表达相关吗？ B. AngII 输注期间在升主动脉中膜和外膜中积聚的巨噬细胞是否源自血液或组织？ C. 人升主动脉瘤组织中的白细胞积聚与 MCP-1 和 CCR2 表达相关吗？ 公共卫生相关性：主动脉瘤疾病对健康造成破坏性后果，而且越来越常见。尽管对公共卫生影响很大，但对这些疾病的调查工作相对较少。因此，没有开发出明确的医疗选择来提供手术干预的替代方案。主动脉瘤疾病的进一步研究是公共卫生的当务之急。