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

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.

Keywords: blood-brain barrier; brain edema; brain ischemia; caveolin-1; tight junction proteins.