Hypoxia induces FoxO3a-mediated dysfunction of blood-brain barrier.

The Forkhead box O 3a (FoxO3a), a transcription factor, is known to be involve in change of endothelial permeability. During hypoxia, blood-brain barrier (BBB) permeability is increased through degradation of vascular endothelium cadherin (VE-cadherin) and clsudin-5. The hypoxia also increased mRNA levels of matrix metalloproteinase (MMP)-3/9 and promoted translocation of FoxO3a into nucleus in endothelial cells. However, little is known about the role of FoxO3a in hypoxia-induced BBB hyperpermeability. Here, we examined whether FoxO3a regulates hypoxia-induced BBB permeability through induction of MMPs. The transfection of siFoxO3a suppressed hypoxia-induced BBB hyperpermeability. The transfection of siFoxO3a also inhibited hypoxia-induced degradation of VE-cadherin and claudin-5. In addition, the transfection of siFoxO3a reduced hypoxia-induced increase of MMP-3 mRNA levels. However, transfection of siFoxO3a did not inhibits transcription of MMP-9 induced by hypoxia. Taken together, our findings suggest that FoxO3a is involved in hypoxia-induced degradation of VE-cadherin and claudin-5 through induction of MMPs indirectly.