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.

Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood–Spinal Cord Barrier and Functional Recovery

“…In several models of adult brain injuries, Cav-1 is increased in the endothelium for several days following cold cortical injury and brain ischemia [10,11]. The knockdown of Cav-1 reduces matrix metalloproteinase (MMPs) activity in endothelial cells and their angiogenic response to vascular endothelial growth factor (VEGF) [12].…”

“…However, views of the role of Cav-1 in different pathologies are contradictory. In several models of adult brain injuries, Cav-1 is increased in the endothelium for several days following cold cortical injury and brain ischemia [10,11]. In the cortical cold injury model in rats, an increased expression of Cav-1 precedes the decreased expression of occludin and claudin-5 at 2 d postinjury [11].…”

“…In several models of adult brain injuries, Cav-1 is increased in the endothelium for several days following cold cortical injury and brain ischemia [10,11]. In the cortical cold injury model in rats, an increased expression of Cav-1 precedes the decreased expression of occludin and claudin-5 at 2 d postinjury [11]. The Cav-1 protein in the membrane fraction of microvessels begins to upregulate at 5 min and reached a peak 10 min after treatment, which was associated with diminished expression of several TJ-associated proteins (ZO-1, occludin, and claudin-5), which led to increased BBB permeability [10].…”

Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury

“…While it is well accepted that the BBB is damaged in cases of TBI, the BBB becomes dysfunctional and levels of expression of a range of tight junction proteins are transcriptionally increased or decreased at varying time points post-injury 20 . Moreover, the dramatic neuroinflammatory response, observed in cases of cerebral oedema, causes the upregulation of a range of cytokines that may have the potential to impact on the integrity of the tight junction on the BBB 25 .…”

“…Claudin-5 has a key role in the formation of paracellular pores or channels that function in mediating selective ion permeability at the BBB 18,19 . It has previously been reported that dynamic changes occur at the level of tight junction protein expression at the BBB in response to TBI, with levels of claudin-5, occludin and ZO-1 being transcriptionally regulated at various time points post-injury 20 . While these changes have traditionally been purported to represent a pathological hallmark of oedema, we suggest that the initial decreases in tight junction protein expression are in direct response to fluid accumulation in the extra-cellular microenvironment.…”