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Other Junctional Components

Although tight and adherens junctions are important components of the BBB, inte- grins also contribute to CEC integrity. Although alpha V integrin deficiency does not impair pericyte-endothelial interactions, it does disturb endothelial and nervous system parenchymal connections leading to BBB failure [40]. Additionally, con- nexons between endothelial cells (containing connexin 43) modulate calcium and BBB organization [41], and astrocyte connexin 43 modulates endothelial immune activation and enhances immune cell emigration.

Cerebral Endothelial Junctional Disorganization in MS

MS has a strong association with BBB dysfunction as well as loss of structural integrity [42], both of which together reflect several levels of BEC dysfunction (Fig. 1.1). Immunofluorescence staining of postmortem MS brain samples revealed an abnormal TJ molecule distribution, including occludin, JAM-A, and ZO-1, which correlated with patterns of serum protein leakage in active lesions [43]. This suggests that TJ disruption strongly contributes to BBB dysfunction seen in MS. Disintegration of the BBB by degradation and downregulation of TJ and AJ appear to play central roles in relapsing-remitting, primary progressive, and secondary progressive MS. The critical role TJ plays in BBB maintenance has been

Are cerebral endothelial cell and vascular dysfunction contributing to MS pathophysiology? The barrier maintained by CEC involves several junctional complexes

Fig. 1.1 Are cerebral endothelial cell and vascular dysfunction contributing to MS pathophysiology? The barrier maintained by CEC involves several junctional complexes, which are supported and regulated by pericytes, astrocytes, and neurons. During inflammatory conditions, CEC monolayers express and present selectins and several IgCAMs to become hyper-adhesive and permit extravasation of blood-borne tracers. Activated CEC is less effective at excluding immune cells from trans-BBB penetration. These inflammatory stimuli may include cytokines, altered NO production, viruses, trauma, etc. Once activated, endothelial cells may progress toward apoptosis and may also shed membrane fragments called “microparticles” which are both mediators and markers of CEC injury in MS demonstrated using EAE model of MS. Inducible endothelial-specific expression of claudin-1 alleviated clinical symptoms of EAE by preventing BBB leakiness [44]. However, ectopic claudin-1 expression did not affect immune cell trafficking into the CNS, which suggests that BBB TJs may be critical structures regulating BBB solute exchange but not immune cell diapedesis. Nonetheless, immune cell migration may amplify BBB TJ pathology as is illustrated by the loss of claudin-3 and claudin-5 as mentioned above [28]. We have demonstrated that serum from MS patients in relapse (known to contain higher levels of inflammatory cytokines) diminishes occludin and VE-cadherin expression in cultured brain endothelial cells [45]. More recently, Shimizu and colleagues have also described barrier disturbances in response to serum from RRMS and SPMS [46]. During MS flares, Th1 cytokine levels increase in the CNS interstitium as well as in the circulation. We have demonstrated that endothelial cell exposure with inflammatory mediators or calcium chelation initiates the reversible internalization (endocytosis) of classical and VE-cadherins from inter-endothelial junctions by a PKC [33, 47, 48]. Among these, IFN-y in particular may directly modulate BBB function by suppressing the expression of TJ and AJ components [45] as well as triggering internalization of TJ proteins (e.g., occludin, JAM-A) [49]. In addition, inflammatory cytokines can also indirectly influence the BBB function by disturbing the adventitial cells that can stabilize and enhance BBB [50].

Disruptions of cell-cell contact and communication resulting from breakdown of intercellular junctions not only lead to a decline in barrier function but can also cause endothelial apoptosis through the extrinsic pathway [51]. Although TJ disruption is sometimes regarded as a consequence of apoptosis, mislocalization of clau- dins that also leads to occludin disruption (and hence of TJ) can activate caspases and eventually promote cell death [52]. The association of the two events is influenced by interferon-p1b (Betaseron), which has been shown to protect endothelial cells from apoptosis in vitro [53] and while at the same time preserving junctional integrity [45]. Interestingly, despite diverse pathways for immune cell passage across the intact CEC monolayer, tricellular junctions containing LSR are down- regulated during EAE and may increase the penetration of immune cells at tricellular junctions [39], possibly consistent with a preference for the paracellular route when junctions are less well organized (as may exist in MS).

 
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