Potential Contribution of Hypoxia-Inducible Factor-1α, Aquaporin-4, and Matrix Metalloproteinase-9 to Blood-Brain Barrier Disruption and Brain Edema After Experimental Subarachnoid Hemorrhage

The current research aimed to investigate the role of hypoxia-inducible factor-1 alpha (HIF-1 alpha), 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 s. Anti-AQP-4 antibody, minocycline (an inhibitor of MMP-9), or 2-methoxyestradiol (an inhibitor of HIF-1 alpha), was administered intravenously at 2 and 24 h after SAH. Brain samples were extracted at 48 h after SAH and examined for protein expressions, BBB impairment, and brain edema. Following SAH, remarkable edema and BBB extravasations were observed. Compared with the control group, the SAH animals have significantly upregulated expressions of HIF-1 alpha, 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-1 alpha. Although BBB permeability was also ameliorated after inhibition of either HIF-1 alpha 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-1 alpha 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-1 alpha 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.