Enhanced VEGF secretion and blood–brain barrier disruption: Radiation‐mediated inhibition of astrocyte autophagy via PI3K‐AKT pathway activation

Abstract Radiation‐induced damage to the blood–brain barrier (BBB) is the recognized pathological basis of radiation‐induced brain injury (RBI), a side effect of head and neck cancer treatments. There is currently a lack of therapeutic approaches for RBI due to the ambiguity of its underlying mechanisms. Therefore, it is essential to identify these mechanisms in order to prevent RBI or provide early interventions. One crucial factor contributing to BBB disruption is the radiation‐induced activation of astrocytes and oversecretion of vascular endothelial growth factor (VEGF). Mechanistically, the PI3K‐AKT pathway can inhibit cellular autophagy, leading to pathological cell aggregation. Moreover, it acts as an upstream pathway of VEGF. In this study, we observed the upregulation of the PI3K‐AKT pathway in irradiated cultured astrocytes through bioinformatics analysis, we then validated these findings in animal brains and in vitro astrocytes following radiation exposure. Additionally, we also found the inhibition of autophagy and the oversecretion of VEGF in irradiated astrocytes. By inhibiting the PI3K‐AKT pathway or promoting cellular autophagy, we observed a significant amelioration of the inhibitory effect on autophagy, leading to reductions in VEGF oversecretion and BBB disruption. In conclusion, our study suggests that radiation can inhibit autophagy and promote VEGF oversecretion by upregulating the PI3K‐AKT pathway in astrocytes. Blocking the PI3K pathway can alleviate both of these effects, thereby mitigating damage to the BBB in patients undergoing radiation treatment.