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S100A4-lineage Cells Contribute Modesty to Angiotensin II-mediated Thoracic Aortic Aneurysms Through Angiotensin II Type 1a Receptor in Mice

ABSTRACT: Background: Angiotensin II (AngII) exerts a critical role in thoracic aortic aneurysm (TAA) formation via AngII type 1a receptor (AT1aR). However, the principal cell type mediating this process remains unclear. Our previous study demonstrated that S100A4-lineage cells are present in the aortic wall and involved in AngII-induced vascular remodeling. In the present study, we investigated whether S100A4-lineage cells contribute to AngII-mediated TAA formation through AT1aR. Methods: Proteomic, bulk RNA sequencing, and single-cell RNA sequencing data were analyzed to assess changes in S100A4 abundance in response to AngII infusion. Lineage tracing was performed to track S100A4-lineage cells during AngII-mediated TAA formation. Either saline or AngII was infused in mice with genetic deletion of AT1aR in S100A4-lineage cells and their wild-type littermates. Results: AngII infusion increased S100A4 protein and mRNA abundance significantly in the ascending aorta, particularly within smooth muscle cells and fibroblasts. Under basal conditions, S100A4-positive cells were localized to the media and adventitia. Following AngII infusion, these cells expanded markedly and populated the entire aortic wall. Deletion of AT1aR in S100A4-lineage cells modestly reduced AngII-induced TAA formation. Conclusions: S100A4-lineage cells modestly contribute to AngII-mediated TAA development through AT1aR in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE309042 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Ascending thoracic aortopathy is a life-threatening disease significantly influenced by angiotensin II (AngII). Thoracic aortopathy exhibits regional heterogeneity with the ascending region being susceptible. Smooth muscle cells (SMCs), a major component of the aortic wall, originate from two embryonic origins in the ascending aorta: second heart field (SHF) and cardiac neural crest (CNC). However, functional differences between the origins in AngII-induced thoracic aortopathy formation remain unknown. The present study determined transcriptomic differences between origins in response to AngII by single-cell RNA sequencing using the lineage tracing approach. Mef2c-Cre +/0 mT/mG mice were infused with AngII (1,000 ng/kg/day). To investigate causative mechanisms, ascending aortas were harvested after 3 days of AngII infusion, representing the prepathological phase of thoracic aortopathy. Aortic samples were also harvested from Mef2c-Cre +/0 mT/mG mice without AngII infusion as a control. Following single-cell suspension, cells were sorted based on their origin using mTotamto and mGFP signals. mGFP proteins were present on Mef2c-Cre-driven cells indicating the cells were derived from the SHF, while cells with mTomato signal were not derived from the SHF (nSHF). After sorting cells by origin, single-cell RNA sequencing was performed. Two-way ANOVA analysis identified 1718 differentially expressed genes (DEGs) in the interaction between origin and infusion. Among these DEGs, 1207 genes significantly differed between origins in response to AngII infusion. However, the magnitude of difference in most of these DEGs was modest, ranging between −0.05 and 0.05 Log2FC. Commonly studied molecules, such as TGF-β, SMC contraction, and extracellular matrix molecules, were undetectable or modestly different. In conclusion, transcriptomic differences in SMCs between origins in response to AngII were modest in the pre-pathological phase of AngII-induced thoracic aortopathy.

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S100A4-lineage Cells Contribute Modesty to Angiotensin II-mediated Thoracic Aortic Aneurysms Through Angiotensin II Type 1a Receptor in Mice

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