Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood-brain barrier breakdown.

Abstract

The significance of caveolin-1, a major constituent of caveolae, and the tight junction proteins occludin and claudin-5 in early blood-brain barrier (BBB) breakdown was assessed by sequential demonstration of the expression of these proteins over a period of 12 h to 6 days post-lesion in the rat cortical cold injury model. Pial and intracerebral vessels of control rats showed punctuate endothelial immunoreactivity for caveolin-1 and caveolin-2, while claudin-5 and occludin were localized as longitudinal strands in endothelium. During the early phase of BBB breakdown following injury at 12 h and on day 2, western blot analyses detected a significant increase in caveolin-1 expression at the lesion site while immunohistochemistry showed that the caveolin-1 increase was localized to the endothelium of lesion vessels. Decreased expression of occludin occurred at the lesion site only on days 2 and 4 post-lesion while claudin-5 expression was decreased only on day 2. Dual labeling for fibronectin, a marker of BBB breakdown, and caveolin-1 or the tight junction proteins demonstrated that only lesion vessels with BBB breakdown showed a marked increase of caveolin-1, loss of occludin and reduced localization of claudin-5. The issue whether these alterations precede or follow BBB breakdown is uncertain; however, increased expression of caveolin-1 preceded the decreased expression of occludin and claudin-5. Thus caveolae and caveolin-1 have an important role in early BBB breakdown and could be potential therapeutic targets in the control of early brain edema.