Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood-brain barrier breakdown.
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.
Nag
Sukriti
S
Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada. su.nag@utoronto.ca
Venugopalan
Roopa
R
Stewart
Duncan J
DJ
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D021941:Caveolae / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D002536:Cerebral Arteries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D062507:Claudin-5; D003080:Cold Temperature / Q000009:adverse effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D062793:Occludin; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
D051242:Caveolin 1; D062507:Claudin-5; C491510:Cldn5 protein, rat; D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat