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2013 ; 207
(4
): 628-49
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Tonic regulation of vascular permeability
#MMPMID23374222
Curry FR
; Adamson RH
Acta Physiol (Oxf)
2013[Apr]; 207
(4
): 628-49
PMID23374222
show ga
Our major theme is that the layered structure of the endothelial barrier requires
continuous activation of signalling pathways regulated by sphingosine-1-phosphate
(S1P) and intracellular cAMP. These pathways modulate the adherens junction,
continuity of tight junction strands, and the balance of synthesis and
degradation of glycocalyx components. We evaluate recent evidence that baseline
permeability is maintained by constant activity of mechanisms involving the small
GTPases Rap1 and Rac1. In the basal state, the barrier is compromised when
activities of the small GTPases are reduced by low S1P supply or delivery. With
inflammatory stimulus, increased permeability can be understood in part as the
action of signalling to reduce Rap1 and Rac1 activation. With the hypothesis that
microvessel permeability and selectivity under both normal and inflammatory
conditions are regulated by mechanisms that are continuously active, it follows
that when S1P or intracellular cAMP are elevated at the time of inflammatory
stimulus, they can buffer changes induced by inflammatory agents and maintain
normal barrier stability. When endothelium is exposed to inflammatory conditions
and subsequently exposed to elevated S1P or intracellular cAMP, the same
processes restore the functional barrier by first re-establishing the adherens
junction, then modulating tight junctions and glycocalyx. In more extreme
inflammatory conditions, loss of the inhibitory actions of Rac1-dependent
mechanisms may promote expression of more inflammatory endothelial phenotypes by
contributing to the up-regulation of RhoA-dependent contractile mechanisms and
the sustained loss of surface glycocalyx allowing access of inflammatory cells to
the endothelium.
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