Transcriptomic profiling of senescence effects on blood-brain barrier-related gene expression in brain capillary endothelial cells in a mouse model of paclitaxel-induced chemobrain.

Chemotherapy-induced cognitive impairment (CICI), commonly referred to as "chemobrain," is a frequent and debilitating side effect experienced by cancer survivors treated with paclitaxel (PTX). Preclinical models have shown that PTX promotes cerebromicrovascular endothelial cell senescence, leading to chronic blood-brain barrier (BBB) disruption and neuroinflammation. Conversely, the elimination of senescent cells through senolytic therapies has been shown to restore BBB integrity, reduce neuroinflammation, and alleviate PTX-induced cognitive impairment. In this study, we tested the hypothesis that PTX-induced endothelial senescence alters gene expression patterns associated with BBB integrity. To investigate this, we analyzed a scRNA-seq dataset from the brains of mice treated with a clinically relevant PTX regimen alongside vehicle-treated control mice. We identified capillary endothelial cells by their distinct transcriptomic profiles and matched these profiles to known transcriptomic markers of cellular senescence. Our analysis confirmed that PTX induces senescence in capillary endothelial cells and revealed significant transcriptional alterations linked to impaired BBB function. In senescent endothelial cells, gene set enrichment analysis (GSEA) highlighted downregulated pathways associated with cell junction assembly and upregulated pathways involved in extracellular matrix remodeling and inflammatory signaling, including Vitronectin (VTN) and Pleiotrophin (PTN) pathways. Additionally, cell-cell communication analysis revealed reduced Junctional Adhesion Molecule (JAM) signaling, further implicating senescence in BBB disruption. These findings highlight endothelial senescence as a driver of BBB dysfunction through transcriptional changes and altered intercellular signaling. The enrichment of VTN and PTN pathways in the senescent state indicates a shift toward vascular remodeling and inflammation, exacerbating microvascular fragility and BBB disruption. Supported by prior experimental findings, this study suggests that targeting endothelial senescence and its downstream effects could mitigate PTX-induced BBB dysfunction and associated cognitive impairments. These results advance our understanding of CICI pathogenesis and provide a foundation for developing therapeutic strategies aimed at preserving vascular integrity.