Hypoxic Preconditioning Increases Blood-Brain Barrier Disruption in the Early Stages of Cerebral Ischemia

Even though hypoxic preconditioning has been reported to produce neuroprotection, its effect on blood-brain barrier (BBB) disruption in the early stages of cerebral ischemia within the therapeutic window is not clear. Since hypoxic preconditioning increases expression of vascular endothelial growth factor (VEGF) that modulates vascular permeability, the effects of hypoxic preconditioning and VEGF on BBB permeability were investigated after one hour of focal cerebral ischemia. Rats were exposed to 8% of oxygen for two hours or room air and then 24 hours later, permanent middle cerebral artery (MCA) occlusion was performed. In some of the hypoxic preconditioned rats, a VEGF-A antibody was applied to the ischemic cortex one hour before MCA occlusion. One hour after MCA occlusion, the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid was determined to measure the degree of BBB disruption. MCA occlusion increased the Ki when compared with the contralateral cortex (14.1 ± 4.0 vs 4.2 ± 1.9 μL/g/min, p < 0.0001). Hypoxic preconditioning further increased the Ki in the ischemic cortex when compared with the control rats (25.1 ± 8.7 μL/g/min, p < 0.01). Application of VEGF antibody to the ischemic cortex of the hypoxic preconditioned animals reduced the Ki to the level of the control rats (13.6 ± 5.1 μL/g/min, p < 0.01). Our data demonstrated that hypoxic preconditioning increased BBB disruption through a VEGF related pathway and suggest the possibility of aggravation of brain edema by hypoxic preconditioning in the early stages of cerebral ischemia.