Co-exposure to ionizing irradiation and high-fat diet induces low-grade neuroinflammation and neurovascular remodeling in the mouse hippocampus

Abstract Epidemiological evidence suggests that exposure to ionizing radiation (IR) may increase the risk of cerebrovascular diseases, yet the long-term effects of moderate doses and their interaction with obesity-related metabolic stress remain unclear. This study investigated whether high-fat diet (HFD) modifies cerebrovascular responses to moderate doses of gamma radiation. Male C57BL/6J mice were exposed to acute whole-body gamma radiation at 300 or 1000 mGy and maintained six months on either a standard diet (SD) or a HFD. Hippocampal oxidative stress, inflammation, endothelial activation, and vascular remodeling markers were assessed by RT-qPCR, immunofluorescence, and Western blot. Untargeted plasma metabolomics was performed to identify systemic metabolic alterations associated with irradiation. Exposure to 300 mGy did not significantly alter hippocampal vascular features, either alone or with HFD. In contrast, co-exposure to 1000 mGy and HFD induced low-grade neuroinflammation, characterized by increased microglial activation, upregulation of chemokine expression, and increased LYVE-1 immunostaining, suggesting recruitment of perivascular macrophages. Co-exposure also resulted in increased hippocampal vascular density and elevated ZO-1 expression, suggesting vascular remodeling. Metabolomic pathway enrichment analysis identified purine metabolism and the malate-aspartate shuttle as major pathways associated with irradiation-induced metabolic changes. These findings demonstrate that metabolic stress enhances the long-term neurovascular consequences of moderate-dose gamma radiation.