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（TAA）最常见于升主动脉区，无症状。通常，它存在的第一个迹象是破裂，通常导致死亡。TAA是患有广泛的遗传决定性疾病的患者的危及生命的后果;最常见的疾病之一是马凡氏病。目前唯一的治疗策略诊断为TAA的个人是手术选择。因此，迫切需要对TAAs的机理进行深入了解，以开发有效的治疗方法。 我们最近已经证明，血管紧张素II输注也导致TAA是本地化的升主动脉。血管紧张素II诱导的TAA被CC趋化因子受体2（CCR 2）缺陷减弱。这推断了单核细胞趋化蛋白-1（MCP-1）在TAA中的作用，尽管CCR 2也与其他趋化因子相互作用。我们最近已经证明，内皮特异性的AT 1a受体的缺陷赋予了类似程度的衰减血管紧张素II诱导的TAAs作为全身CCR 2缺陷。这两个观察结果可能通过旁分泌机制相关联，通过该机制AngII刺激MCP-1释放，MCP-1是决定CCR 2刺激的主要作用的配体。AngII诱导的TAA的特征在于显著的中膜巨噬细胞蓄积，主要在外膜方面。基于这一简要描述的背景，我们提出检验中心假设，即MCP-1-CCR 2轴通过内皮介导的巨噬细胞经由主动脉区域特异性效应从外膜募集的机制，促进AngII诱导的TAA定位于升区。为了检验这一假设，将讨论以下具体目标：目标1。确定MCP-1-CCR 2轴在AngII诱导的TAA发展中的作用。 A. MCP-1或CCR 2的全身缺乏是否促进AngII诱导的TAA的等效减少，这些TAA是持续的并与减少的中巨噬细胞积聚相关？ 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？ 目标2.确定AngII诱导的TAA发生过程中膜巨噬细胞在上行动脉中积聚的起源。A.在AngII诱导的TAAs的发展过程中，白细胞浸润的顺序是什么？这与MCP-1和CCR 2的表达相关吗？B。血管紧张素II输注过程中，在升支动脉中膜和外膜中聚集的巨噬细胞是否来源于血液或组织？C.人升主动脉瘤组织中白细胞积聚与MCP-1和CCR 2表达相关吗？