Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 527

Table 9.22. Regulation of myosin light chain phosphatase (MLCP), hence of the endothelial
barrier maintenance, by cAMP signal (Source: [ 969 ]).

MLCP Involved cAMP signaling

substrates mediator effector

PP1 r12a -PP1 RoCK PKA (not the cAMP-RapGEF axis)

PP1 r14a -PP1 PKA (not the cAMP-RapGEF axis)

is synthesized in endothelial cells and colocalizes with SOCs and at sites of
intercellular junctions possesses both high- and low-affinity Ca 2 + -binding sites.
Permeability-increasing factors that raise cytosolic Ca 2 + concentration can tran-
siently preclude AC6 activity. Upregulation of AC8 isoform in endothelial cells
reverses Ca 2 + -induced inhibition of cAMP production, hence impeding intercellular
gap formation.
Activation of cAMP signaling suppresses thrombin-induced increase in
endothelial permeability, as it inactivates endothelial contractile apparartus, mainly
myosin light chain phosphatase [ 969 ]. Two cAMP effectors, PKA and RapGEF3,
cooperate to promote intercellular adhesion; however, PKA, but not RapGEF3,
impedes thrombin-induced phosphorylation of myosin light chain and PP1 r12a
regulatory subunit, as it precludes the RhoA-RoCK pathway. In addition, the MLCP
catalytic subunit PP1 can be activated via dephosphorylation and dissociation of
PP1 r14a inhibitor, 92 thereby also increasing the free pool of active PP1 phosphatase;
this mechanism that is also used by the cAMP-PKA axis does not intervene in the
cAMP-RapGEF3 pathway (Table 9.22 )[ 969 ].

Sphingosine 1-Phosphate

Sphingosine kinase phosphorylates sphingosine and generates S1P, whereas
sphingosine phosphatase or sphingosine lyase catalyzes phosphate-dependent
transformation of S1P to phosphoethanolamine. Sphingosine kinase, phosphatase,
and lyase thus regulate S1P plasma level. Circulating S1P can target endothelial cells
and binds to S1P 1 to S1P 3 receptors. These liganded receptors prime endothelial
programs for cell migration and proliferation.
Platelets that lack sphingosine 1-lyase constitute a primary S1P storage. Once
released from platelets, S1P binds to serum albumin. Sphingosine 1-phosphate also
connects to apolipoprotein-M of HDL particles [ 970 ]. ApoM

HDL causes S1P 1
receptor internalization, MAPK and PKB activation, endothelial cell migration, and
formation of endothelial adherens junctions.
Protection of the endothelial barrier ensured by S1P at physiological level (250-
500 nmol) results from activation of Gi-coupled S1P 1 and S1P 3 receptors that

+

92 A.k.a. 17-kDa PKC-primed inhibitor of PP1 (CPI17).