The current research aimed to investigate the role of hypoxia-inducible factor-1α (HIF-1 α),aquaporin-4 (AQP-4),and matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) dysfunction and cerebral edema formation in a rat subarachnoid hemorrhage (SAH) model.The SAH model was induced by injection of 0.3 ml fresh arterial,non-heparinized blood into the prechiasmatic cistern in 20 seconds.Anti-AQP-4 antibody,minocycline (an inhibitor of MMP-9),or 2-methoxyestradiol (2ME2,an inhibitor of HIF-1 α),was administered intravenously at 2 h and 24 h after SAH. Brain samples were extracted at 48 h after SAH and examined for protein expressions,blood-brain barrier (BBB) impairment,and brain edema.Following SAH,remarkable edema and BBB extravasations were observed.Compared with control group,the SAH animals have significantly up-regulated expressions of HIF-1α,AQP-4,and MMP-9,in addition to decreased amounts of laminin and tight junction proteins.Brain edema was repressed after inhibition of AQP-4,MMP-9,or HIF-1α.Although BBB permeability was also ameliorated after inhibition of either HIF-1 α or MMP-9,it was not modulated after inhibition of AQP-4.Inhibition of MMP-9 reversed the loss of laminin.Finally,inhibition of HIF-1α significantly suppressed the level of AQP-4 and MMP-9,which could induce the expression of laminin and tight junction proteins. Our results suggest that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular signaling pathway involving AQP-4 and MMP-9.Pharmacological intervention of this pathway in patients with SAH may provide a novel therapeutic strategy for early brain injury (EBI).