Adventitial-medial interactions in thoracic aortic diseases

摘要 胸主动脉疾病，包括动脉瘤和夹层，是一个主要的未满足的医疗领域， 由于缺乏对基本机制的了解，我们对胸科的长期兴趣 使用小鼠模型的主动脉疾病提供了令人信服的证据，（1）AngII诱导的胸主动脉疾病 主动脉疾病的特征在于升主动脉中的管腔扩张和层间血肿， 这是最明显的外中层，类似于观察人类上升 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， AT 1a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AT 1a受体的缺失，而不是平滑肌细胞（SMC）中的AT 1a受体的缺失，是导致AngII-1表达的原因。 诱导的胸主动脉病变，（4）SMC特异性LRP 1（一种重要的蛋白质， 维持血管完整性）增加AngII诱导的胸主动脉疾病。符合我们 结果，SMC中存在基因缺失（无其他操作）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 疾病升主动脉是一个独特的主动脉区域，其中SMC来自两种不同的细胞， 胚胎起源，心脏神经嵴（CNC）和第二心脏领域（SHF）。在我们自己的基础上 数据和文献证据，我们假设胸主动脉瘤和夹层的结果 来自AngII刺激外膜成纤维细胞与中膜SMC亚群相互作用 在疾病易发区形成一个外部“套筒”。提出了两个目标来检验这一假设。 目的1将确定成纤维细胞迁移或可塑性是否由AT 1a受体激活， 有助于胸主动脉瘤和夹层的病理过程。目标2将 确定来自不同胚胎来源的SMC是否具有本质上不同的功能， 导致胸主动脉瘤和夹层谱系追踪和体内操作将是 用于这两个目标中提出的实验。完成拟议目标将提供 了解外膜成纤维细胞之间的细胞通讯和 主动脉中膜平滑肌细胞在升主动脉瘤的发生发展中起着重要作用 和夹层，以及胸主动脉疾病的区域特异性特征是否归因于 在升主动脉中SMC起源的“双亲”特征。

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.