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.
Keywords: Hypoxic preconditioning, blood-brain barrier, cerebral ischemia, VEGF.
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