Endothelial celltocell junctions

Circulating cells infiltrate into tissues by migrating through intercellular junctions. These organelles are formed by a complex network of transmembrane proteins linked to a well-developed plasmalemmal undercoat. One of the typical characteristics of endothelial junctions is their dynamic organization. Endothelial cells are able to change rapidly the architecture of the junctions to allow the passage of circulating blood cells. This effect, in most cases, is quickly reversible and the endothelium is able to disorganize/reorganize its intercellular junctions within minutes. Interendothelial junctions present a different degree of complexity along the vascular tree responding to different functional requirements. For instance, they are well organized and numerous in large arteries or in the blood vessels of the brain where the control of permeability must he strict, whereas they are very primitive in the postcapillary venules, where cell extravasation and exchange of plasma constituents need to be particularly efficient. On the basis of morphologic and functional characteristics at least four types of junctions have been described in endothelial cells. These are: tight junctions, adherence junctions, gap junctions and syndesmos.

Although there is a great deal of information regarding the molecules that mediate leukocyte adhesion to the endothelium, the mechanisms by which leukocytes trigger the opening of endothelial cell junctions is still obscure. In many conditions the passage of leukocytes through endothelial junctions does not increase endothelial permeability per se or cause vascular damage.

Chemoattractants and adhesive molecules stimulate neutrophils to secrete oxygen-free radicals, lipid metabolites and proteases, each of which is a potential agonist of endothelial permeability. However, experimental evidence suggests that these reactive agents are not necessary for neutrophil extravasation. The question of how leukocytes pass through endothelial clefts remains open. An interesting possibility is that leukocyte adhesion to endothelial cells causes a cascade of events similar to that induced by soluble agonists of endothelial permeability. In particular, leukocyte ligation to endothelial adhesive molecules (such as selectins, VCAM-l or ICAM-1) could generate intracellular signals similar to those caused by permeability-increasing agents. It hs been found that endothelial cells respond to neutrophil contact and migration by increasing intracellular calcium and inhibitors of intracellular Ca2" block neutrophil transmigration. In addition, ICAM-1 activation by-specific antibodies leads to phosphorylation of the actin-binding protein cortactin. This or other signals could induce changes in cleft molccular organization (see above), leading to the opening of gaps between endothelial cells. According to this hypothesis endothelial cells would not only play an important role in regulating leukocyte attachment to their surface but also actively modulate their extravasation.

Leukocytes might find preferential pathways for their passage through the interendothelial clefts. Tight junctions and adherence junctions comprise a system of discrete ion-selective pores rather than an absolute seal around the cells. In endothelial cells, the presence of areas of junctionless clefts that regulate the transendothelial transport of high molecular weight proteins has been described. Leukocytes might be directed to these pores through the concentration gradient of specific adhesive molecules such as CD31. Their passage would require them to squeeze through the pores, accompanied by rearrangement of the endothelial cell cytoskeleton organization around these structures.

There might be differences between the modalities of leukocyte extravasation for different types of vessels where the clefts present different levels of complexity. There might also be distinct mechanisms regulating the passage of the different types of leukocytes or of other types of cells.

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