Biology Reference
In-Depth Information
3 Signaling Pathways Shown to Regulate Endothelial
Permeability
There are a large number of studies on endothelial permeability focused on trying
to unravel the mechanisms by which permeability is both increased and decreased
and how these mechanisms are regulated. The majority of the studies have
addressed paracellular mechanisms of barrier function. Similar to smooth muscle,
endothelial cells have a contractile system that requires actin, nonmuscle myosin,
ATP, calcium, and calmodulin. Stimulation of endothelial contraction leads to the
formation of small gaps between endothelial cells that, in time, lead to increased
permeability. A variety of agents, including thrombin, VEGF, bradykinin, and
histamine, have been found to increase endothelial permeability via increases in
intracellular calcium. As with smooth muscle, increases in intracellular calcium
will lead to the activation of myosin light chain kinase (MLCK). MLCK can then
phosphorylate myosin light chains leading to actin-myosin-mediated endothelial
cell contraction.
In addition to pathways that increase calcium, activation of other signaling
pathways can also increase endothelial cell contraction. Thrombin has been
shown to activate the small GTPase, RhoA. RhoA, via activation of Rho kinase,
inhibits PP1M, the phosphatase that dephosphorylates myosin light chain. Thus,
thrombin, in addition to increasing calcium and phosphorylation of myosin light
chain via MLCK, inhibits dephosphorylation of myosin light chain via a RhoA-
mediated mechanism. The cumulative effect is an increase in contraction. Other
agents known to increase endothelial permeability such as TNF- a and H 2 O 2 have
also been shown to regulate RhoA and thus the contractile function of endothelial
cells. All of these agents have also been shown to activate a variety of kinases that
can lead to changes in the phosphorylation status of junctional proteins and barrier
function and also to changes in gene expression.
While there are several pharmacological agonists that have been shown to
decrease endothelial barrier function, there are only a few endogenous factors
that have been shown to increase barrier function. These include sphingosine-
1-phosphate (S1P), angiopoietin-1, and cAMP (Jho et al. 2005 ; Komarova et al.
2007 ; Moore et al. 1998 ; Satchell et al. 2004 ). S1P is a phospholipid formed by the
phosphorylation of sphingosine by sphingosine kinase. S1P is found in and released
from platelets. The lack of sphingosine lysase, a key regulator of S1P degradation,
leads to S1P storage in platelet granules (Yatomi et al. 1995 ). Endothelial cells
express G-coupled receptors for S1P and the endothelial differentiation gene (EDG)
receptors, Edg-1, Edg-3, and Edg-5 (Ozaki et al. 2003 ). These receptors are Gi
coupled and lead to activation of the small GTPase Rac and adherent junction
assembly (Takuwa 2002 ).
Finally, angiopoietin-1 is a ligand for the endothelial-specific tyrosine kinase
receptor, Tie-2 (Tsigkos et al. 2003 ). Angiopoietin-1 has been shown to inhibit
permeability induced by thrombin, bradykinin, histamine, and VEGF (Pizurki et al.
2003 ). In studies with VEGF, angiopoietin-1 was shown to prevent Ca 2+ influx and
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