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; 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 胸腔主动脉疾病，包括动脉瘤和解剖，是主要未经医疗的区域 由于缺乏对基本机制的知识而需要的需求。我们对胸腔的长期兴趣 使用小鼠模型的主动脉疾病提供了令人信服的证据，表明（1）Angii诱导的胸腔 主动脉疾病的特征是腔内主动脉中的腔扩散和腔内血肿， 在外侧层中最为明显，类似于人类上升的观察 主动脉瘤和解剖，（2）血管紧张素II（Angii）及其受体亚型之间的相互作用， AT1A受体，在胸部主动脉瘤和解剖的发展中起着至关重要的作用，（3） 缺失成纤维细胞中的AT1A受体，而不是平滑肌细胞（SMC），是造成Angii-的原因 诱导的胸动主动脉病理，（4）LRP1的SMC特异性缺陷（一种重要的蛋白质 维持血管完整性）增加了Angii诱导的胸部主动脉疾病。与我们一致 发现，在SMC中具有遗传缺失（无需其他操纵）的小鼠的胸腔主动脉病理 包括LRP-1，TGF-βR2和Fibulin-4与Angii诱导的胸动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从两个不同 胚胎起源，心脏神经rest（CNC）和第二心脏场（SHF）。根据我们自己的 数据和文献证据，我们假设胸部主动脉瘤和解剖结果 从Angii模拟冒险成纤维细胞与媒体SMC的亚群相互作用 在容易发生疾病的地区形成了外部“袖子”。提出了两个目的来检验这一假设。 AIM 1将确定成纤维细胞迁移或可塑性是否被AT1A受体激活 有助于胸腔主动脉瘤和解剖的病理过程。 AIM 2意志 确定来自不同胚胎起源的SMC是否具有本质上不同的功能 有助于胸动脉瘤和解剖。谱系跟踪和体内操作将是 用于这两个目标中提出的实验。提议的目标的完成将提供 深入了解在冒险中成纤维细胞之间的细胞通信和 主动脉介质中的SMC在升高主动脉瘤的发展中起着至关重要的作用 和解剖，以及区域特异性表征是否归因于 SMC起源在上升主动脉中的“两种态度”功能。