Caveolin‐1 regulates nitric oxide‐mediated matrix metalloproteinases activity and blood–brain barrier permeability in focal cerebral ischemia and reperfusion injury

J. Neurochem. (2012) 120 , 147–156. Abstract The roles of caveolin‐1 (cav‐1) in regulating blood–brain barrier (BBB) permeability are unclear yet. We previously reported that cav‐1 was down‐regulated and the production of nitric oxide (NO) induced the loss of cav‐1 in focal cerebral ischemia and reperfusion injury. The present study aims to address whether the loss of cav‐1 impacts on BBB permeability and matrix metalloproteinases (MMPs) activity during cerebral ischemia‐reperfusion injury. We found that focal cerebral ischemia‐reperfusion down‐regulated the expression of cav‐1 in isolated cortex microvessels, hippocampus, and cortex of ischemic brain. The down‐regulation of cav‐1 was correlated with the increased MMP‐2 and ‐9 activities, decreased tight junction (TJ) protein zonula occludens (ZO)‐1 expression and enhanced BBB permeability. Treatment of N G ‐nitro‐ l ‐arginine methyl ester [ l ‐NAME, a non‐selective nitric oxide synthase (NOS) inhibitor] reserved the expression of cav‐1, inhibited MMPs activity, and reduced BBB permeability. To elucidate the roles of cav‐1 in regulating MMPs and BBB permeability, we used two approaches including cav‐1 knockdown in cultured brain microvascular endothelial cells (BMECs) in vitro and cav‐1 knockout (KO) mice in vivo . Cav‐1 knockdown remarkably increased MMPs activity in BMECs. Meanwhile, with focal cerebral ischemia‐reperfusion, cav‐1 deficiency mice displayed higher MMPs activities and BBB permeability than wild‐type mice. Interestingly, the effects of l ‐NAME on MMPs activity and BBB permeability was partly reversed in cav‐1 deficiency mice. These results, when taken together, suggest that cav‐1 plays important roles in regulating MMPs activity and BBB permeability in focal cerebral ischemia and reperfusion injury. The effects of l ‐NAME on MMPs activity and BBB permeability are partly mediated by preservation of cav‐1.