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

J Neurochem. 2012 Jan;120(1):147-56. doi: 10.1111/j.1471-4159.2011.07542.x. Epub 2011 Nov 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / physiopathology*
  • Blotting, Western
  • Brain Chemistry / drug effects
  • Brain Ischemia / enzymology*
  • Brain Ischemia / physiopathology*
  • Capillaries / drug effects
  • Capillaries / enzymology
  • Caveolin 1 / physiology*
  • Coloring Agents
  • Enzyme Inhibitors / pharmacology
  • Evans Blue
  • Infarction, Middle Cerebral Artery / enzymology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinases / metabolism*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Permeability
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / enzymology*
  • Reperfusion Injury / physiopathology*


  • Caveolin 1
  • Coloring Agents
  • Enzyme Inhibitors
  • Nitric Oxide
  • Evans Blue
  • Nitric Oxide Synthase Type I
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • NG-Nitroarginine Methyl Ester