Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 477

Tabl e 9. 7. Activation by thrombin and APC of peptidase-activated receptor PAR 1 and opposite
effects (Source: [ 882 ]; Arr: arrestin; Dvl: Disheveled; EPCR: endothelial protein-C receptor).

Messenger Effect Pathway

PAR 1 -G α q -Ca 2 + -PKC Thrombin Endothelial barrier

disruption PAR 1 -G α 12 / 13 -RhoA

Activated Endothelial barrier PAR 1 -EPCR-Cav- β Arr-

protein-C maintenance -Dvl2-Rac1

interacts with Disheveled-2, a scaffold and mediator of the Wnt-Frizzled signaling,
which polymerizes and protect the endothelial barrier. 32

9.5.3.2 Peptidase-Activated Receptors

Peptidase-activated receptor PAR 1 on endothelial cells contributes to cell responses
that trigger or prevent blood coagulation and ensures cell protection [ 882 ]. Both
thrombin and activated protein-C stimulate PAR 1 , but cause opposite effects.
Serine peptidase thrombin binds to PAR 1 and cleaves its extracellular domain
to form a tethered ligand to activate PAR 1 -mediated inflammation and increase
endothelial barrier permeability.
The anticoagulant peptidase activated protein-C stimulates a subpopulation of
PA R 1 that colocalizes with their coreceptor, endothelial protein-C receptor, PAR 1 ,
in membrane nanodomains enriched in caveolin, to promote endothelial barrier
protection (Table 9.7 ). Receptor PAR 1 localizes to caveolae connected to

-arrestin
in unstimulated cells. The PAR 1 -EPCR couple supports cytoprotection. Activated
protein-C recruits and activates Disheveled-2 [ 882 ].
Hypoxia primes an angiogenic phenotype in endothelial cells. Hypoxic can-
cer cells upregulates in endothelial cells protease-activated receptor PAR 2 and
pro-angiogenic heparin-binding EGF-like growth factor (HBEGF) and increases
phosphorylation of ERK1 and ERK2 [ 883 ]. Tissue factor that triggers PAR signaling
is induced by hypoxia in several types of cancer cells; however, tissue factor
remains undetectable in hypoxic endothelial cells, although several stimuli (e.g.,
shear stress and growth factors) transiently cause induce tissue factor production TF
in endothelial cells.

β

32 Disheveled-

β β

-arrestin intervenes in Wnt5a-Rac1 signaling. -Arrestin is required for internal-

ization of Frizzled-4 by Wnt5a ligand.