Altered MicroRNA Signatures in Circulating Extracellular Vesicles Reflect Aortic Dilation in Takayasu Arteritis

Abstract

BackgroundTakayasu arteritis (TAK) is a large-vessel vasculitis characterized by progressive inflammation that can lead to stenosis or aneurysmal dilation. Reliable circulating biomarkers for vascular remodeling are lacking, and extracellular vesicles (EVs), which transport molecular cargo that reflects their cellular origin, have emerged as potential biomarkers and modulators of vascular inflammation. However, their role in TAK remains unclear. This study aimed to investigate the relationship between EV-derived microRNA (miRNA) signatures and clinically relevant vascular phenotypes, with a primary focus on aortic dilation. MethodsCirculating small EVs (sEVs) were isolated from the serum of patients with TAK and healthy controls, characterized by high-sensitivity flow cytometry, were profiled for miRNA content, and analyzed using bioinformatic pathway enrichment. In vitro assays were employed in assessing their impact on endothelial activation, while the diagnostic performance of miRNAs was compared to conventional biomarkers and clinical parameters. ResultssEVs from patients with TAK upregulated the endothelial expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, thereby enhancing monocyte adhesion in vitro, consistent with a pro-inflammatory phenotype. Differentially expressed miRNAs were enriched in PI3K-Akt signaling, with phosphatase and tensin homolog identified as a key predicted target. Among patients, miR-223-3p was selectively downregulated in those with aortic dilation, regardless of disease activity or treatment status. Receiver operating characteristic analysis showed that miR-223-3p identified aortic dilation with an area under the curve of 0.748, outperforming C-reactive protein and erythrocyte sedimentation rate. Flow cytometric analysis suggested that platelet-derived EVs represent a predominant source of circulating miR-223-3p, and their proportion tended to be reduced in patients with aortic dilation. ConclusionsReduced platelet-derived EV-associated miR-223-3ps are associated with aortic dilation in TAK and demonstrate superior diagnostic accuracy over conventional inflammatory markers. EV miRNA profiling may provide a novel approach for evaluating vascular remodeling in TAK.