Transformation of perivascular adipose tissue and its influence on vascular cell phenotype: mechanistic insights into AAA progression

Abstract Background Perivascular adipose tissue (PVAT) undergoes phenotypic changes in abdominal aortic aneurysm (AAA), contributing to vascular remodeling and inflammation. This study investigates the transformation of PVAT and its influence on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) in AAA progression through transcriptomic profiling and functional analysis. Methods A total of 112 patients (AAA, n = 84; non-AAA controls, n = 28) were included. PVAT samples were analyzed using single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing to identify cell-type-specific transformations. Flow cytometry and immunohistochemistry validated cell subtype distributions. Functional assays evaluated PVAT-derived cytokine effects on VSMC phenotype switching and EC dysfunction. Differential expression analysis was performed using DESeq2, and pathway enrichment was analyzed via KEGG and Gene Ontology. Statistical comparisons included Mann-Whitney U test, Kruskal-Wallis test, and Cox proportional hazards modeling for aneurysm expansion risk prediction. Results ScRNA-seq identified PVAT cell clusters with distinct transcriptional profiles, including pro-inflammatory macrophages (CD68^+ TNFα^+), fibrotic fibroblasts (COL1A1^+ COL3A1^+), and dysfunctional adipocytes (FABP4^low ADIPOQ^low). AAA-PVAT exhibited increased CCL8 expression (log2FC = 2.48, p = 0.001), correlating with VSMC dedifferentiation (MYH11^low ACTA2^low) and EC dysfunction (VCAM1^high SELE^high). ELISA confirmed elevated CCL8 protein in PVAT-conditioned media (AAA vs. control: 93.4 ± 14.2 pg/mL vs. 41.7 ± 10.6 pg/mL, p < 0.001). Multivariable Cox analysis demonstrated CCL8 levels as an independent predictor of AAA expansion (HR 2.37, 95% CI: 1.41–3.98, p = 0.002). Conclusion PVAT transformation in AAA fosters a pro-inflammatory and fibrotic microenvironment, driving VSMC dedifferentiation and EC dysfunction. CCL8 emerges as a key regulatory target, warranting further investigation for therapeutic intervention.

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