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.
Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada. su.nag@utoronto.ca
Sukriti
S
Nag
Roopa
R
Venugopalan
Duncan J
DJ
Stewart
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