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

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.