The Metabolite Differences in Vascular Smooth Muscle Cells of Abdominal Aortic Aneurysm Revealed by Untargeted Metabolomics

<b>Background</b>: Abdominal aortic aneurysm (AAA) is a vascular disease with a high mortality rate upon rupture (85-90%). Surgical repair remains the most effective intervention, whereas pharmacological treatments to prevent aneurysm expansion or rupture are limited. Vascular smooth muscle cells (VSMCs) play a crucial role in AAA pathogenesis, and metabolic dysregulation is increasingly recognized as a contributor to disease progression. This study investigated metabolic changes in VSMCs and their association with AAA pathology using untargeted metabolomics. <b>Methods</b>: Angiotensin II (Ang II) was used to stimulate rat VSMCs and induce AAA in ApoE-/- mice. Untargeted metabolomic analysis was performed using liquid chromatography-tandem mass spectrometry to detect metabolite changes. Differential metabolites were identified using orthogonal partial least squares discriminant analysis, and metabolic pathways were analyzed using Kyoto Encyclopedia of Genes and Genomes and metabolic set enrichment analysis. <b>Results</b>: In Ang II-treated VSMCs, 54 differential metabolites (24 upregulated; 30 downregulated) were identified, whereas 470 differential metabolites (206 upregulated; 264 downregulated) were detected in mouse aortas. Three metabolites-carnitine, lysophosphatidylcholine (0:0/20:4), and 5-hydroxyeicosatetraenoic acid-were common in both models and were enriched in bile secretion and tryptophan metabolism pathways. The carnitine-FXR signaling axis emerged as a potential therapeutic target. <b>Conclusions</b>: This study revealed Ang II-induced metabolic changes in VSMCs and their association with AAA pathology. The carnitine-FXR signaling axis may contribute to AAA development, providing new directions for diagnostic biomarkers and therapeutic targets. Future studies should validate these findings in human AAA samples to determine their clinical relevance.