Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 529

Klotho

Klotho is a circulating protein involved in the maintenance of the integrity of
the endothelial barrier. Absence of Klotho actually causes hyperpermeability with
increased endothelial cell apoptosis and downregulation of cadherin-5 that result
from an increase in VEGF-mediated cytosolic Ca 2 + concentration and activation
of Ca 2 + -dependent peptidases [ 973 ]. Klotho binds to VEGFR2 and TRPC1 Ca 2 +
channel; it fosters their co-internalization.

9.6.4.8 Permeability-Increasing Factors

Inflammatory mediators, such as thrombin, histamine, and platelet-activating factor,
activate various signaling axes in endothelial cells to increase vascular permeability.
Agents that increase endothelial paracellular permeability, such as histamine
and thrombin, cause distinct cell response features (magnitude and time of recov-
ery) [ 854 ]. Thrombin is a procoagulant serine peptidase 95

that also regulates cell

proliferation and smooth muscle contraction.

Thrombin

Thrombin binds to Gq- and G12/13-coupled peptidase-activating receptor PAR 1
and causes a transient increase in endothelial permeability. The predominant G

β

endothelial isoform G β 1 is sequestered by receptor for activated C kinase RACK1.

Thrombin dissociates G , Fyn kinase, and focal

adhesion kinase form a complex in endothelial cells stimulated by thrombin. Sub-
unit G

β 1 from RACK1. Subsequently, G βγ

activates Fyn kinase that phosphorylates FAK that can then be recruited
to adherens junctions, thereby enabling recovery of endothelial barrier [ 974 ].
Upon stimulation of peptidase-activated receptor PAR 1 , 96 thrombin provokes:
(1) Ca 2 + influx via, at least partly, receptor-operated channels (TRPC); (2) phos-
phorylation of endothelial Ca 2 + -calmodulin-dependent myosin light chain kinase to
increase its activity and myosin light chain phosphatase by RoCK kinase to attenuate
its functioning; and (3) endothelial contraction. Resulting centripetal force develops
within 5 mn after stimulus onset. Reversal of the response occurs within 2 h after
removal of or in the continuous presence of thrombin [ 854 ].

βγ

95 Thrombin is generated by proteolytic cleavage of inactive prothrombin by factors V and X
with cofactors calcium ions and membrane phospholipids. Short-lived thrombin is eliminated by
activated protein-C.
96 Among peptidase-activated receptor isoforms in endothelial cells (PAR 1 -PAR 4 ), only 2 (PAR 1
and PAR 2 ) are activated by thrombin. Magnitude of the permeability response mainly depends on
PA R 1 number and affinity, as small and larger populations of distinct types exist with different
dissociation constants.