Adventitial-medial interactions in thoracic aortic diseases

胸主动脉疾病中外膜-内侧相互作用

• 批准号: 9160051
• 负责人: Alan Daugherty
• 金额: $ 56.33万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9160051
• 关键词: Aneurysm; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Aorta; Aortic Aneurysm; Aortic Diseases; Area; Attenuated; Bicuspid; Blood Vessels; Cardiac; Chest; Communication; Complex; Data; Development; Disease; Dissection; Drug Targeting; Embryo; Employee Strikes; Expert Opinion; FBN1; Fibroblasts; Genetic; Guidelines; Heart; Hematoma; Human; Individual; Infusion procedures; Knowledge; Lead; Literature; Losartan; LoxP-flanked allele; Medial; Mediating; Medical; Modeling; Mus; Neural Crest; Pathologic Processes; Pathology; Patients; Pericytes; Phenotype; Plant Roots; Play; Process; Proteins; Recommendation; Reporting; Role; Severities; Site; Smooth Muscle Myocytes; Testing; Thoracic Aortic Aneurysm; Thoracic aorta; Transforming Growth Factor beta; Tunica Adventitia; abstracting; ascending aorta; base; cell dedifferentiation; clinical investigation; fibulin; fibulin-4; in vivo; insight; interest; migration; mouse model; mutant; receptor; research study; response; therapy development; transdifferentiation

Abstract Thoracic aortic diseases, including aneurysm and dissection, are an area of major unmet medical need due to a paucity of knowledge on the underlying mechanisms. Our long-term interest in thoracic aortic diseases using mouse models has provided compelling evidence that (1) AngII-induced thoracic aortic diseases are characterized by luminal dilation and intralamellar hematoma in the ascending aorta, which are most pronounced in the outer medial layers, resembling observations in human ascending aortic aneurysm and dissection, (2) interaction between angiotensin II (AngII) and its receptor subtype, AT1a receptor, plays a crucial role in the development of thoracic aortic aneurysm and dissection, (3) deletion of AT1a receptors in fibroblasts, not in smooth muscle cells (SMCs), is responsible for the AngII- induced thoracic aortic pathologies, (4) SMC-specific deficiency of LRP1 (an important protein in maintaining vascular integrity) augments AngII-induced thoracic aortic diseases. Consistent with our findings, thoracic aortic pathologies in mice with genetic deletions (without other manipulations) in SMCs including LRP-1, TGF-βR2, and fibulin-4 have striking similarities to AngII-induced thoracic aortic diseases. The ascending aorta is a unique aortic region in which SMCs are derived from two distinct embryonic origins, the cardiac neural crest (CNC) and second heart field (SHF). On the basis of our own data and the literature evidence, we hypothesize that thoracic aortic aneurysm and dissection result from AngII stimulation of adventitial fibroblasts interacting with subpopulations of medial SMCs that form an outer “sleeve” in disease-prone areas. Two aims are proposed to test this hypothesis. Aim 1 will determine whether fibroblast migration or plasticity is actuated by AT1a receptors and contributes to the pathological processes of thoracic aortic aneurysm and dissection. Aim 2 will determine whether SMCs from different embryonic origins have intrinsically different functions that contribute to thoracic aortic aneurysm and dissection. Lineage tracking and in vivo manipulations will be used for the experiments proposed in these two aims. Completion of the proposed aims will provide insights into understanding whether cellular communication between fibroblasts in the adventitia and SMCs in the media of the aorta plays a crucial role in the development of ascending aortic aneurysms and dissection, and whether region specific characterization of thoracic aortic diseases is attributed to the “biparental” feature of the SMC origin in the ascending aorta.

抽象的 胸主动脉疾病，包括动脉瘤和夹层，是一个未得到满足的主要医疗领域 由于缺乏对基本机制的了解而需要。我们对胸科的长期兴趣 使用小鼠模型对主动脉疾病进行的研究提供了令人信服的证据：(1) AngII 诱导的胸廓动脉疾病 主动脉疾病的特点是升主动脉管腔扩张和板层内血肿， 这在外内侧层最为明显，类似于人类上升中的观察结果 主动脉瘤和夹层，(2) 血管紧张素 II (AngII) 与其受体亚型之间的相互作用， AT1a 受体在胸主动脉瘤和夹层的发展中起着至关重要的作用，(3) 成纤维细胞中 AT1a 受体的缺失，而不是平滑肌细胞 (SMC) 中的 AT1a 受体的缺失，导致了 AngII- 诱发胸主动脉病变，(4) SMC 特异性缺乏 LRP1（一种重要的蛋白质） 维持血管完整性）会加剧 AngII 诱发的胸主动脉疾病。与我们一致 研究结果，SMC 基因缺失（未经其他操作）的小鼠的胸主动脉病变 包括 LRP-1、TGF-βR2 和 fibulin-4 与 AngII 诱导的胸主动脉具有惊人的相似性 疾病。升主动脉是一个独特的主动脉区域，其中 SMC 源自两个不同的主动脉 胚胎起源，心脏神经嵴（CNC）和第二心区（SHF）。在我们自己的基础上 根据数据和文献证据，我们假设胸主动脉瘤和夹层导致 来自 AngII 刺激外膜成纤维细胞与内侧 SMC 亚群相互作用 在疾病易发区域形成外“袖子”。提出了两个目标来检验这一假设。 目标 1 将确定成纤维细胞迁移或可塑性是否由 AT1a 受体驱动 有助于胸主动脉瘤和夹层的病理过程。目标2将 确定来自不同胚胎起源的 SMC 是否具有本质上不同的功能 有助于胸主动脉瘤和夹层。谱系追踪和体内操作将 用于这两个目标中提出的实验。完成拟议目标将提供 深入了解外膜中成纤维细胞之间是否存在细胞通讯 主动脉中层的 SMC 在升主动脉瘤的发展中起着至关重要的作用 和夹层，以及胸主动脉疾病的区域特异性特征是否归因于 升主动脉 SMC 起源的“双亲”特征。