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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE241968 | GEO | 2023/09/30

REPOSITORIES: GEO

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Project description:BACKGROUND: Ascending thoracic aortic aneurysm (ATAA) is caused by the progressive weakening and dilatation of the aortic wall and can lead to aortic dissection, rupture, and other life-threatening complications. To improve our understanding of ATAA pathogenesis, we sought to comprehensively characterize the cellular composition of the ascending aortic wall and to identify molecular alterations in each cell population of human ATAA tissues. METHODS: We performed single-cell RNA sequencing (sc-RNAseq) analysis of ascending aortic tissues from 11 study participants, including 8 patients with ATAA (4 women and 4 men) and 3 controls (2 women and 1 man). Cells extracted from aortic tissue were analyzed and categorized by using sc-RNAseq data to perform cluster identification. ATAA-related changes were then examined by comparing the proportions of each cell type and the gene expression profiles between ATAA and control tissues. We also examined which genes may be critical for ATAA by performing the integrative analysis of our sc-RNAseq data with publicly available data from genome-wide association studies (GWAS). RESULTS: We identified 11 major cell types in human ascending aortic tissue; the high-resolution reclustering of these cells further divided them into 40 subtypes. Multiple subtypes were observed for smooth muscle cells, macrophages, and T lymphocytes, suggesting that these cells have multiple functional populations in the aortic wall. Generally, ATAA tissues had fewer nonimmune cells and more immune cells, especially T lymphocytes, than did control tissues. Differential gene expression data suggested the presence of extensive mitochondrial dysfunction in ATAA tissues. In addition, integrative analysis of our sc-RNAseq data with public GWAS data and promoter capture Hi-C data suggested that ERG (ETS [erythroblast transformation-specific] related gene) exerts an important role in maintaining normal aortic wall function. CONCLUSIONS: Our study provides a comprehensive evaluation of the cellular composition of the ascending aortic wall and reveals how the gene expression landscape is altered in human ATAA tissue. The information from this study makes important contributions to our understanding of ATAA formation and progression.

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

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