Mechanisms of thoracic aortic aneurysms

胸主动脉瘤的发病机制

• 批准号: 8828764
• 负责人: Alan Daugherty
• 金额: $ 54.41万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828764
• 关键词: Abdominal Aortic Aneurysm; Address; Affect; Angiotensin II; Anterior; Aorta; Area; Attenuated; Blood; CC chemokine receptor 2; CCL2 gene; Cardiac; Cells; Cessation of life; Characteristics; 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; Ruptured Abdominal Aortic Aneurysm; Smooth Muscle Myocytes; Source; Specificity; Structure; Surface; Testing; Therapeutic; Thoracic Aortic Aneurysm; Thoracic aorta; Tissues; Tunica Adventitia; Ulcer; abdominal aorta; ascending aorta; attenuation; base; cell type; chemokine; 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?

描述（由申请人提供）：胸主动脉瘤（TAAs）最常见于上升区，无症状。通常，它存在的第一个迹象是破裂，通常导致死亡。taa对患有一系列由基因决定的疾病的患者是危及生命的后果；其中最常见的是马凡氏病。目前诊断为TAAs的个体唯一的治疗策略是手术选择。因此，迫切需要了解TAAs的机制，以开发有效的治疗方法。我们最近证明，AngII输注也会导致局限于升主动脉的taa。由于CC趋化因子受体2 （CCR2）缺乏，血管i诱导的TAAs被减弱。这推断单核细胞趋化蛋白-1 （MCP-1）在TAAs中的作用，尽管CCR2也与其他趋化因子相互作用。我们最近证明，AT1a受体的内皮特异性缺乏与全身CCR2缺乏具有相似程度的血管i诱导的TAAs衰减。这两种观察结果可能与旁分泌机制有关，AngII刺激MCP-1释放，MCP-1是决定CCR2刺激主要作用的配体。血管诱导的TAAs的特点是大量巨噬细胞在内侧积聚，主要集中在血管外。基于这一简要描述的背景，我们建议验证MCP-1-CCR2轴通过内皮介导的巨噬细胞从外膜募集的机制，通过主动脉区域特异性作用，促进血管i诱导的TAAs定位于上升区域的中心假设。为了验证这一假设，将解决以下具体目标：目标1。确定MCP-1-CCR2轴在血管诱导TAAs发展中的作用。