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(Stroke. 2005;36:1047.)
© 2005 American Heart Association, Inc.

Original Contributions

NF-B Activation Plays a Role in Superoxide-Mediated Cerebral Endothelial Dysfunction After Hypoxia/Reoxygenation

From the Department of Neonatology (H.X., B.L.S.), Centers for Molecular Genetics and Neuroscience, Children’s Research Institute (H.X., P.E.R., B.L.S.), Children’s National Medical Center, the George Washington University, Washington, DC.

Correspondence to Dr Hui Xie, Room R-165, 3.5^th Floor, Children’s National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010. E-mail hxie{at}cnmc.org

Background and Purpose— Cerebral vascular injury occurs in response to hypoxia/reoxygenation (H/R). However, the cellular signaling pathways that regulate this event remain unclear. The present study was designed to determine whether reactive oxygen species (ROS) mediate endothelial dysfunction after H/R in cerebral resistance arteries and, if so, the relative contribution of ROS, NADPH oxidase, and a nuclear factor-B (NF-B) pathway.

Methods— Arterial diameter and intraluminal pressure were simultaneously measured on rat posterior cerebral arteries (PCA). Superoxide was measured by 5-µmol/L lucigenin-enhanced chemiluminescence.

Results— Hypoxia/reoxygenation selectively inhibited cerebral vasodilation to the endothelium-dependent agonist acetylcholine (Ach) (0.01 to 10 µmol/L) by 50%. Impaired vasodilation after H/R was reversed by 2,2,6,6-tetramethylpiperidine-N-oxyl (Tempo) (100 µmol/L), a cell-permeable superoxide dismutase mimetic, and partially by ebselen (10 µmol/L), a peroxynitrite scavenger. H/R-impaired vasodilation to Ach was also preserved by apocynin (1 mmol/L), a specific inhibitor for NADPH oxidase. Correspondingly, H/R significantly increased lucigenin-detectable superoxide, which was reduced by either Tempo or apocynin, but not by allopurinol (10 µmol/L), an inhibitor of xanthine oxidase. Finally, the NF-B inhibitors helenalin (10 µmol/L) and MG-132 (1 µmol/L) independently antagonized H/R-impaired Ach-induced vasodilation without affecting dilator response to sodium nitroprusside, an endothelium-independent vasodilator.

Conclusions— These results indicate that superoxide mediates cerebral endothelial dysfunction after hypoxia/reoxygenation largely via activation of NADPH oxidase and possibly activation of NF-B pathway.

Key Words: cerebral arteries • endothelium • hypoxia • superoxide

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