Upregulation of vascular endothelial growth factor is associated with radiation-induced blood-spinal cord barrier breakdown

The pathogenesis of radiation-induced injury to the central nervous system (CNS) remains unclear. Dysfunction of the blood-brain barrier (BBB) is asso ciated with radiation-induced white matter lesions. The aim of this study w as to determine if vascular endothelial growth factor (VEGF) is implicated in radiation-induced BBB disruption. Adult rats were irradiated with a sing le dose of 8 or 22 Gy to the spinal cord from C2 to T2. At various times up to 20 weeks following irradiation, blood-spinal cord barrier (BSCB) permea bility was assessed using immunohistochemistry with anti-albumin antibody. Cell proliferation was assessed using bromodeoxyuridine (BrdU), and endothe lial cell identity was assessed morphologically and using immunostaining fo r factor VIII-related antigen. Expression of VEGF protein and message was a ssessed using immunohistochemistry and in situ hybridization respectively. In the unirradiated rat spinal cord, there was no evidence of albumin immun oreactivity and little evidence of VEGF expression. After a dose of 22 Gy, focal albumin staining in white matter was observed at 16 weeks. Diffuse st aining was seen at 20 weeks and was associated with necrosis and demyelinat ion in white matter. This was associated with a significant increase in whi te matter glial cells that showed immunoreactivity and in situ hybridizatio n signal for VEGF. VEGF expressing cells showed dual immunoreactivity for g lial fibrillary acidic protein. No increase in VEGF positive cells was obse rved in gray matter after 22 Gy. After a dose of 8 Gy, there was no increas e in VEGF expression or albumin immunostaining in either white or gray matt er. Microvessel endothelial cell density showed a trend towards a decrease with time after 22 Gy as compared with 8 Gy or unirradiated controls. BrdU immunostaining provided no evidence for endothelial cell proliferation in c ontrol or in the irradiated spinal cord. It is concluded that radiation-ind uced BSCB dysfunction is associated with upregulation of VEGF in astrocytes without associated endothelial proliferation. The temporal and spatial ass ociation of VEGF upregulation with the white matter lesions suggests a role of VEGF in radiation-induced late CNS injury.