Cell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct

Vascular endothelial growth factor (VEGF) is an endothelial cell specific m itogen that has been implicated in hypoxia-mediated angiogenesis under phys iological and pathological conditions. We used the middle cerebral artery o cclusion model (MCAO) in the rat to investigate VEGF mRNA and protein local ization, and VEGFR-1 mRNA and VEGFR-2 mRNA expression in cerebral ischemia. By nonradioactive in situ hybridization we observed upregulation of VEGF m RNA and VEGFR-1 mRNA, but not of VEGFR-2 mRNA in the hemisphere ipsilateral to MCA occlusion. VEGF mRNA was upregulated in the periphery of the ischem ic area commencing 3 hours (h) after onset of MCAO, reached a peak after 24 h, and remained expressed at lower levels until 7 days (d) after MCAO. Dou ble labelling experiments revealed that the majority of VEGF expressing cel ls in the penumbra and within the infarct were immunoreactive for Ox-42, Ib a-1, and Ed1, but not for GFAP and neurofilament proteins, suggesting that microglial cells/macrophages are the major cell type expressing VEGF Since VEGF was also expressed in Ox-42 immunoreactive cells distant from the infa rct (e.g. in the corpus callosum and hippocampus), activated microglial cel ls expressing VEGF may migrate towards the ischemic stimulus. VEGF protein was also detected on capillaries within the peri-ischemic area, suggesting that VEGF produced and secreted by microglial cells/macrophages binds to it s receptors on nearby vascular endothelial cells and initiates an angiogeni c response which counterbalances tissue hypoxia. Accordingly, apoptosis of neuroectodermal cells in the penumbra was highly depressed after the onset of angiogenesis. The spatial and temporal correlation between the induction of angiogenesis with VEGF and VEGFR-1 expression suggests that the ischemi c upregulation of VEGF represents a physiological response of the brain to counterbalance hypoxia/ischemia in order to protect neuroectodermal tissue.