Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 707

Transendothelial Migration
Signals generated by interactions between leukocytes and endothelial cells as well
as antibody-induced clustering of adhesion receptors cooperate to disassemble
inter-endothelial junctions to raise endothelial paracellular permeability. Involved
molecules include small GTPases Rac1, RhoA, and RhoG, second messengers
calcium and reactive oxygen species, FAK2 and Src kinases, and cytosolic PTPn1
as well as receptor PTPRb and PTPRm protein Tyr phosphatases [ 1452 ].
Transcellular Migration
Molecule ICAM1 is involved in the transcellular migration of lymphocytes, during
which it remains bound to the leukocyte. Internalization of ICAM1 depends on
PKC and Src kinases as well as RhoA GTPase, in addition to caveolin-1-mediated
endocytosis that is regulated by filamin-A [ 1452 ].
Homophilic interaction of leukocyte PECAM1 with endothelial PECAM1 is
needed for leukocyte extravasation. Molecule PECAM1 induces the recruitment of
PTPn6 and PTPn11 as well as SHIP phosphatases. PECAM1 may contribute to
both para- and transcellular routes [ 1449 ]. The functional role of PECAM1 may be
governed by differences in endothelial cell phenotype in different vascular beds.
Paracellular Migration
Between-endothelial cell adhesion is primarily mediated by adherens and tight
junctions. Adherens and tight junctions are intermingled and regulate each other.
Junctional (JAM) and endothelial cell-selective (ESAM) adhesion molecule of
tight junctions modulate paracellular mode of leukocyte transendothelial migra-
tion [ 1452 ].
Cadherin-5 is a major constituent of adherens junctions that are stabilized by
PTPRb phosphatase. Leukocyte adhesion to endothelial cells triggers signaling
from ICAM1 and VCAM1 that dissociates cadherin-5 from PTPRb and subsequent
phosphorylation by Src and FAK2 kinases for junction disassembly [ 1452 ].
Reactive oxygen species produced by the Rac1-NADPH oxidase pathway
also participate in cadherin-5 and catenin phosphorylation. Activity of RhoA
and calcium influx provoke stress fiber contraction that increases the endothelial
permeability.
In addition, a disintegrin and metallopeptidase ADAM10 cleaves and generates
soluble cadherin-5 ectodomain fragment as well as soluble JAMa that facilitates
T-cell and antagonizes neutrophil diapedesis [ 1453 , 1454 ]. However, JAMa is
cleaved predominantly by ADAM17 and, to a lesser extent, by ADAM10 peptidase.