Aging-dependent expression of vascular endothelial growth factor receptor-1 is associated with T-cell immune senescence in carotid atherosclerosis

BACKGROUND: Immune aging, characterized by altered phenotypes and functions of natural and acquired immunity, constitutes a significant threat indicator factor for atherosclerosis due to its association with chronic inflammation. However, the comprehensive understanding of the underlying biological changes driving immune aging in atherosclerosis, particularly in relation to late-stage plaque formation, remains incomplete. The objective of this research is to unravel the influence of aging-related genes on the development of carotid atherosclerotic plaques through immune cell modulation. METHODS AND RESULTS: Leveraging Gene Expression Omnibus and the Human Ageing Genomic Resources database, we examined 26 differentially expressed genes associated with aging in human advanced carotid atherosclerosis. Through the utilization of random forest trees, we identified five key genes that exhibited significant relevance. Pathway enrichment assessment of the variably expressed genes revealed a relationship linking plaque formation with the inflammatory response. Subsequently, employing the CIBERSORT algorithm, we investigated 22 distinct aspects of immune cell infiltration. In addition, examination of single-cell sequencing data disclosed that FLT1/vascular endothelial growth factor receptor-1 (VEGFR1) is predominantly expressed in memory T-cells. A notable decline (P < 0.05) in the proportion of these memory T-cells was detected in advanced plaques. Notably, CellChat analysis indicated the activation of the VEGF signaling cascade in memory T-cells via signaling from diverse immune cell populations. In addition, immunohistochemistry results demonstrated a decline in memory T-cell numbers as plaque progression ensued. CONCLUSIONS: Collectively, our findings suggest that VEGFR1 can influence plaque advancement by modulating memory T-cell senescence through the VEGF signaling pathway. Consequently, targeting VEGFR1 could represent a promising immunotherapeutic approach for preventing the development and advancement of advanced carotid atherosclerotic plaques.