Adventitial-medial interactions in thoracic aortic diseases

摘要 胸主动脉疾病，包括动脉瘤和夹层，是一个尚未满足的主要医学领域。 由于缺乏对潜在机制的了解，这是一种需要。我们对胸片的长期兴趣 使用小鼠模型的主动脉疾病提供了令人信服的证据：(1)血管紧张素转换酶诱导的胸腔 主动脉疾病的特征是升主动脉管腔扩张和板层内血肿， 它们在外层内层最明显，类似于人类提升中的观察 主动脉瘤和夹层；(2)血管紧张素II(AngII)与其受体亚型的相互作用； AT1a受体在胸主动脉瘤和夹层的发生发展中起关键作用 AT1a受体在成纤维细胞中的缺失，而不是在平滑肌细胞(SMCs)中，是导致血管紧张素转换酶抑制剂的原因。 诱发的胸主动脉病变，(4)LRP1的SMC特异性缺陷(一种重要的 维持血管完整性)增加了血管紧张素Ⅱ诱导的胸主动脉疾病。与我们的 SMC基因缺失(无其他操作)小鼠的胸主动脉病理学研究 包括lrp-1、转化生长因子-βR2和纤维蛋白-4与血管紧张素转换酶诱导的胸主动脉有显著的相似性。 疾病。升主动脉是一个独特的主动脉区域，其中的SMC来自两个不同的 胚胎起源，心脏神经脊(Cnc)和第二心区(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导致 血管紧张素Ⅱ刺激外膜成纤维细胞与中膜SMC亚群相互作用 这在疾病易发地区形成了一个外层的“袖子”。为了检验这一假设，本文提出了两个目标。 目标1将确定成纤维细胞的迁移或可塑性是否由AT1a受体和 参与了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。血统追踪和体内操作将是 用于这两个目标中提出的实验。完成拟议的目标将提供 对理解外膜和外膜成纤维细胞之间细胞通讯的见解 升主动脉中膜的SMC在升主动脉瘤的发生发展中起着重要作用。 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。

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.