β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice

The purpose of this study was to determine whether lysyl oxidase inhibition using β-aminopropionitrile (BAPN) induced region-specific aortopathies in mice. The effects of BAPN were first characterized with regard to dose, strain, age, and sex. Subsequently, BAPN was administered to young male C57BL/6J mice. BAPN-induced aortic rupture predominantly occured or originated in the descending thoracic aorta. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while relatively sporadic in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissection with false lumen formation, macrophage infiltration, collagen deposition, and remodeling of the media and adventitia. Cells surrounding the false lumen were predominantly positive for α-smooth muscle actin. To investigate the molecular basis of the regional heterogeneity, ascending and descending thoracic aortas were harvested after one week of BAPN administration prior to the appearance of overt pathology. BAPN compromised contractile properties in both regions equivalently, while RNA sequencing demonstrated that BAPN altered transcriptomes related to extracellular matrix and cell division differentially between the two regions. In conclusion, BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in young mice. Comparative gene expression analysis of RNA-seq data for ascending and descending aortas of C57BL/6J mice administered with either water or BAPN for 1 week.

本研究旨在明确使用β-氨基丙腈（β-aminopropionitrile, BAPN）抑制赖氨酰氧化酶是否会在小鼠体内诱导区域特异性主动脉病变。首先从剂量、小鼠品系、年龄及性别四个维度对BAPN的作用效果进行了系统表征。随后，向年轻雄性C57BL/6J小鼠施用BAPN。BAPN诱导的主动脉破裂主要发生或起源于胸降主动脉。对于完成12周BAPN给药后仍存活的小鼠，升主动脉区域始终观察到显著的管腔扩张，而胸降主动脉区域的扩张则相对零星。升主动脉与胸降主动脉的病理特征存在显著差异。升主动脉的主动脉病理以管腔扩张及全层中膜弹性纤维断裂为特征。胸降主动脉区域则常出现主动脉夹层伴假腔形成、巨噬细胞浸润、胶原沉积以及中膜与外膜重塑。假腔周围的细胞主要呈α-平滑肌肌动蛋白（α-smooth muscle actin）阳性表达。为探究该区域异质性的分子机制，在明显病理特征出现前，即BAPN给药1周后，收集了小鼠的升主动脉与胸降主动脉样本。BAPN对两个区域的血管收缩功能均造成了同等程度的损伤；而RNA测序（RNA sequencing, RNA-seq）结果显示，BAPN对两个区域的细胞分裂及细胞外基质相关转录组的调控存在显著差异。综上，在年轻小鼠体内，BAPN诱导的主动脉病变在升主动脉与胸降主动脉区域内部及区域之间均表现出独特的异质性特征。本数据集包含对给药1周的C57BL/6J小鼠升主动脉与胸降主动脉的RNA-seq数据进行的比较基因表达分析结果，受试小鼠分别接受饮用水或BAPN处理。