Macrophage derived VEGF regulates macrophage senescence to inhibit radiation-induced dermatitis.

BACKGROUND: Macrophages are essential for maintaining tissue homeostasis and accelerating the repair processes; however, their functionality can be severely compromised in pathological conditions such as radiation-induced dermatitis. In this study we analyzed the role of macrophage derived Vascular Endothelial Growth Factor (VEGF) on regulation of macrophage senescence and its role on radiation-induced skin damage. METHODS: We used bone marrow-derived macrophages (BMMɸ) isolated from Csf1r-iCre; VEGF(fl/fl) (VEGF-null) and wild-type (WT) mice. Macrophages were exposed to oxidative and genotoxic stress using H₂O₂, doxorubicin, and radiation exposure to evaluate senescence. Senescence was assessed via SA-β-Gal staining and expression of senescence-related genes. Additionally, VEGF receptor inhibition in WT macrophages was performed to determine the role of VEGF/VEGFR signaling in senescence regulation. Phagocytosis and migration assays were conducted to evaluate functional differences. For in vivo analysis, WT and Csf1r-iCre; VEGF(fl/fl) mice were exposed to radiation, and skin toxicity, histological changes, and senescence markers in skin macrophages were assessed. RESULTS: VEGF-null macrophages showed increased sensitivity to senescence, with elevated SA-β-Gal staining and upregulated senescence-associated gene expression. WT macrophages treated with a VEGF receptor inhibitor displayed increased senescence-associated markers expression, highlighting the importance of VEGF/VEGF-R signaling in preventing macrophage senescence-like phenotypes. Additionally, VEGF-null macrophages have reduced phagocytic and migratory abilities. Our in vivo study using Csf1r-iCre; VEGF(fl/fl) mice showed more severe radiation-induced dermatitis, including increased skin toxicity, hyperkeratosis, and elevated senescence-associated markers in skin macrophages compared to WT controls. CONCLUSIONS: Absence of macrophage-derived VEGF leads to heightened macrophage dysfunction and exacerbates radiation-induced dermatitis. Targeting VEGF signaling may serve as a potential therapeutic strategy to mitigate radiation-related skin toxicity and improve patient outcomes during radiation therapy.