Influence of Perivascular Adipose Tissue on Atherosclerotic Smooth Muscle Cell Phenotype Switching in Cancer Progression: Unraveling the Atherosclerosis-Cancer Link Through a Multi-Omics Approach

Atherosclerosis is a chronic inflammatory condition that significantly contributes to cardiovascular disease, often progressing silently until clinical events like myocardial infarction or stroke occur. Vascular smooth muscle cell (VSMC) phenotype switching—from a contractile to synthetic state—plays a pivotal role in plaque formation and instability. Emerging evidence suggests a potential link between atherosclerosis and cancer, with shared pathways of chronic inflammation and cellular remodeling. Perivascular adipose tissue (PVAT), which surrounds blood vessels, secretes signaling molecules that influence vascular and immune functions, yet its role in promoting VSMC phenotypic transitions during both atherosclerosis and cancer progression remains poorly understood. This study investigates the impact of PVAT on VSMC phenotype switching in the context of atherosclerosis and explores its potential role in cancer progression by employing a multi-omics approach integrating single-cell and spatial transcriptomics. Methodology: Single-cell transcriptomic datasets (GSE۱۳۱۷۷۸ and GSE۲۳۳۸۷۰) from atherosclerotic coronary arteries and PVAT were analyzed. GSE۱۳۱۷۷۸ included atherosclerotic plaque samples, while GSE۲۳۳۸۷۰ comprised coronary PVAT from various stages of atherosclerosis and non-atherosclerotic controls. Additionally, spatial transcriptomic data (GSE۲۴۳۱۷۹) from coronary artery sections with plaque erosion were used to map spatial gene expression. After pre-processing, data were normalized using the SCTransform function in Seurat and integrated via Reciprocal PCA. Dimensionality reduction was performed using UMAP, followed by cell-type annotation based on the Azimuth reference database. VSMC clusters were isolated to identify distinct subtypes associated with different disease stages. Trajectory analysis was performed to track VSMC phenotypic transitions, and cell-cell communication and functional enrichment analyses were conducted to explore PVAT-mediated effects on VSMC states. Spatial transcriptomic data were integrated to uncover spatially variable genes linked to VSMC phenotype changes and assess their relevance in tumor microenvironment, metastasis and prognosis using TCGA data. Results: VSMCs exhibited multiple phenotypic states across atherosclerotic stages, each contributing to plaque development and stability. Five distinct VSMC phenotypes were identified: mesenchymal-like, macrophage-like, fibroblast-like, osteoblast-like, and adipocyte-like. Trajectory analysis pinpointed key drivers of VSMC transitions, with signaling pathways such as MIF, PDGF, VEGF, FN۱, and NOTCH playing critical roles in PVAT-VSMC interactions. Functional enrichment analyses revealed substantial overlap in inflammatory signaling pathways involved in both atherosclerosis and cancer progression. Spatial transcriptomic data highlighted spatially variable genes such as MMP۹, APOD, SPP۱, and CCL۱۴, which may contribute to both atherosclerotic plaque remodeling and tumor microenvironment interactions, suggesting a potential mechanistic link between atherosclerosis and cancer. Conclusion: This study provides novel insights into the role of PVAT in modulating VSMC phenotype switching within atherosclerotic plaques and its potential implications for cancer progression. The findings highlight shared inflammatory and cellular remodeling pathways between atherosclerosis and cancer, offering a foundation for future therapeutic strategies targeting these interconnected diseases.

کلیدواژه ها:

Atherosclerosis ، Perivascular adipose tissue ، Vascular smooth muscle cells ، Phenotypic switching ، Spatial transcriptomics