Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 530

α q of G protein coupled to PAR 1 activates phospholipase-C that
catalyzes production of inositol trisphosphate and diacylglycerol from phosphatidyl-
inositol (4,5)-bisphosphate. Inositol trisphosphate, in turn, activates IP 3 R to rapidly
release Ca 2 + from its store. Depletion of endoplasmic reticulum elicits Ca 2 + entry
from the extracellular medium via store-operated channels. Subunits of the G12/13
subclass downstream of active PAR 1 can act on RhoA GTPase via PKC

Subunit G

α -dependent

phosphorylation of RhoGEF1 agent.
Elevated intracellular Ca 2 + concentration also activates kinases, such as PKC α

and Src, whereas it inhibits adenylate cyclase-6. Thrombin also: (1) transiently
elevates RhoA activity via RhoGEF1 phosphorylation by PKC

for contraction of
actomyosin filaments and adherens junction disassembly; (2) reduces Rac function;
and (3) causes a delayed activation of CDC42 for endothelial barrier recovery [ 854 ].
In addition, thrombin stimulation of endothelial cells provokes cortactin phos-
phorylation by Src kinase. Cortactin P associates with myosin light chain kinase.
However, thrombin induces a sustained increase in endothelial contraction, although
it generates a transient increase in myosin light chain phosphorylation. It indeed
targets low-molecular-mass form of caldesmon (caldesmon lMW )thatiswidely
expressed in non-myocytes [ 854 ]. Thrombin provokes caldesmon translocation
from the cytosol to the plasma membrane and cytoskeleton and induces caldesmon
phosphorylation 97 to form stress fibers and stabilize contraction of actin-myosin
filaments that causes a sustained increase in endothelial permeability.
Contraction of endothelial cells can lead to FAK activation. Focal adhesion
kinase enhances focal adhesion formation and can suppress RhoA activity by
activating p190RhoGAP to favor intercellular junction assembly.

α

Bradykinin

Bradykinin is a potent inflammatory and vasoactive substance generated by
kallikreins at sites of tissue injury. It also disrupts endothelial barrier. Bradykinin is
rapidly degraded (half-life 30 s) by angiotensin-converting enzyme and dipeptidyl

carboxypeptidase kininase-2 located on the endothelial cell surface. Bradykinin
targets 3 receptor subtypes (B 1 -B 3 ) that have distinct affinity for bradykinin.
Endothelial cells possess both inducible B 1 and constitutive B 2 receptors. Stim-
ulated B 1 receptor causes a prolonged response. On the other hand, B 2 activation
provokes a transient activity, as B 2 is rapidly internalized. In addition, receptor
expression depends on endothelial cell types. Activated B 1 or B 2 signal via Gq
and Gi to augment cytosolic calcium content and producte prostaglandins and
nitric oxide. Bradykinin-induced endothelial permeability increase is independent
of MLCK or the Rho pathway [ 854 ].

∼

97 Caldesmon can be phosphorylated by CamK2, ERK, P38MAPKs, and PKC.