Glutamine synthetase regulates the changes of vascular permeability in glioma induced by radiotherapy

Glioma, as a common malignant tumor of the central nervous system, is characterized by high invasiveness and a strong tendency for recurrence. Although radiotherapy is one of the main treatment strategies, it may also increase vascular permeability, thereby affecting the tumor microenvironment and facilitating tumor metastasis and recurrence. Previous studies have shown that glutamine plays an important role in maintaining the structure and function of vascular endothelium. However, the involvement of glutamine synthetase (GS) in regulating radiotherapy-induced changes in vascular permeability has not yet been systematically investigated. This study evaluated the role of glutamine synthetase (GS) in radiotherapy-induced vascular permeability using C166 mouse endothelial cells, subcutaneous xenografts in nude mice, and an orthotopic rat model. Following treatment with the GS inhibitor L-methionine sulfoximine (MSO) combined with 10 Gy irradiation, we assessed vascular permeability, glutamate levels, and the expression/activity of N-methyl-D-aspartate receptors (NMDAR), nitric oxide synthase (NOS), and nitric oxide (NO). Our results demonstrate that GS inhibition significantly augmented radiation-induced endothelial hyperpermeability. This process was mediated by increased glutamate levels, which activated NMDAR signaling, thereby promoting NOS expression and NO production. These mechanistic findings were consistently validated in both the subcutaneous and orthotopic glioma models. Our findings indicate that GS plays a critical role in regulating glioma vascular permeability following radiotherapy, providing a novel perspective for understanding radiation-induced vascular dysfunction and tumor recurrence.