Regulation of Caveolin-1 Expression Determines Early Brain Edema After Experimental Focal Cerebral Ischemia

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Abstract

Background and Purpose—

Most patients with cerebral infarction die of brain edema because of the breakdown of the blood–brain barrier (BBB) in ischemic tissue. Caveolins (a group of proteins) are key modulators of vascular permeability; however, a direct role of caveolin-1 (Cav-1) in the regulation of BBB permeability during ischemic injury has yet to be identified.

Methods—

Cav-1 expression was measured by immunoblotting after photothrombotic ischemia. A direct functional role of Cav-1 in cerebral edema and BBB permeability during cerebral ischemia was investigated by genetic manipulation (gene disruption and re-expression) of Cav-1 protein expression in mice.

Results—

There was a significant correlation between the extent of BBB disruption and the Cav-1 expression. In Cav-1–deficient (Cav-1−/−) mice, the extent of BBB disruption after cerebral ischemia was increased compared with wild-type (Cav-1+/+) mice, whereas the increase in cerebral edema volume was ameliorated by lentiviral-mediated re-expression of Cav-1. Furthermore, Cav-1−/− mice had significantly higher degradation of tight junction proteins and proteolytic activity of matrix metalloproteinase than Cav-1+/+ mice. Conversely, re-expression of Cav-1 in Cav-1−/− mice restored tight junction protein expression and reduced matrix metalloproteinase proteolytic activity.

Conclusions—

These results indicate that Cav-1 is a critical determinant of BBB permeability. Strategies for regulating Cav-1 represent a novel therapeutic approach to controlling BBB disruption and subsequent neurological deterioration during cerebral ischemia.

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