Background <p>Abdominal aortic aneurysm (AAA) is the most common type of arterial dilation disease. Once ruptured and bleeding, AAA can be life-threatening, with a mortality rate as high as 90%. Vascular smooth muscle cells(VSMCs) dyshomeostasis is the main pathological factor for AAA formation, but the specific regulatory process remains unclear.</p> Methods <p>Firstly, we employed single-cell RNA sequencing (scRNA-seq) to reveal the heterogeneity and intercellular communication network of VSMCs in the aorta of AAA patients. We further integrated the data from the public database to clarify differences of the target signal in AAA, and also collected clinical data to analyze both differences and predictive performance for AAA. Subsequently, we generated VSMCs-specific knockout mice in the PPE-induced AAA mouse model to observe formation of AAA and VSMCs dyshomeostasis. Finally, we combined methods such as immunoprecipitation, bioinformatics, western blotting, qPCR, transwell co-culture and luciferase reporter assays to clarify the specific molecular mechanisms underlying VSMCs dyshomeostasis.</p> Results <p>Through multi-level analysis and experiments, we confirmed that the Tenascin C (TNC) communication signal was significantly highly expressed in the arterial tissue and plasma of AAA, and elevated TNC levels in plasma could predict the occurrence of human AAA. In mouse models, we found that VSMCs-specific TNC knockout could inhibit PPE-induced AAA formation and VSMCs dyshomeostasis. Mechanistically, we revealed that TNC promoted nuclear translocation of NF-κB p50 and p65 through TLR4, thereby causing VSMCs dyshomeostasis, while the endoplasmic reticulum stress factor CHOP could induce TNC production in VSMCs.</p> Conclusion <p>Our research demonstrates the existence of a TNC-centered signaling axis mediating VSMCs dyshomeostasis in the formation of AAA.</p>