Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain

Formation of cerebral oedema caused by vascular leakage is a major problem in various injuries of the CNS, such as stroke, head injury and high-altitude illness. A common feature of all these disorders is the fact that they are associated with tissue hypoxia. Hypoxia has therefore been suggested to be an important pathogenic factor for the induction of vascular leakage in the brain. Vascular endothelial growth factor (VEGF) is known as the major inducer of angiogenesis. Originally, however, it was described as a vascular permeability factor. As VEGF gene expression was shown to be upregulated by hypoxia, increased VEGF expression may link hypoxia and vascular leakage in the CNS in vivo. To delineate the role of VEGF in vascular leakage in the brain, we studied the effect of hypoxia on VEGF expression and vascular permeability in the brains of mice in vivo. Hypoxic exposure led to a significant increase in the levels of VEGF mRNA and protein in mouse brain that correlated with the severity of the hypoxic stimulus. Measurement of vascular permeability using the fluorescent marker sodium fluorescein revealed a two-fold increase in fluorescence intensity in hypoxic brains, indicative of significant vascular leakage. Inhibition of VEGF activity by a neutralizing antibody completely blocked the hypoxia-induced increase in vascular permeability. In conclusion, our data show that VEGF is responsible for hypoxia-induced augmentation in vascular leakage following tissue hypoxia. Our findings might provide the basis for new therapeutic concepts for the treatment of cerebral oedema.