Biomedical Engineering Reference
In-Depth Information
stimulate Rac GTPase.
93
Small Rac GTPase favors assembly of cortical actin
and adherens junction. Phospholipid S1P also induces assembly of focal adhesion
complexes.
Sphingosine 1-phosphate mobilizes Ca
2
+
from intracellular stores and activated
non-selective cation channels via Gi protein. Calcium influx from endoplasmic
reticulum induces Rac translocation to cell junctions and its activation.
Angiopoietin-1
Angiopoietin-1 activates TIE2 receptor Tyr kinase in vascular endothelial cells
during angiogenesis as well as vascular maturation and remodeling. Angiopoietin-
1 is constitutively expressed and its receptor TIE2 is constitutively phosphorylated.
It triggers endothelial cell sprouting and migration, as well as tube formation. More-
over, it prevents apoptosis. It also reduces leukocyte adhesion to the endothelium.
Angiopoietin-1 ensures protection of the endothelial barrier, avoiding endothe-
lial leakage. Angiopoietin-1 thus opposes VEGF-induced increase in endothelial
permeability, probably by inhibiting the RhoA pathway. Furthermore, angiopoietin-
1 prevents heightening of endothelial permeability caused by bradykinin, his-
tamine, platelet-activating factor, and thrombin. Angiopoietin-1 inhibits formation
of endothelial gaps, strengthens endothelial adhesion, and restore the endothelial
glycocalyx [
971
].
Nitric Oxide
Endothelial nitric oxide synthase (NOS3; Vol. 4 - Chap. 10. Other Major Sig-
naling Mediators) regulates microvascular permeability. Nitric oxide augments
cGMP concentration and consequently induces cytoskeleton relaxation and reduces
endothelial permeability. Increase in
Ca
2
+
]
i
activates endothelial nitric oxide
synthase. Furthermore, Ca
2
+
-calmodulin removes the inhibition by caveolin-1 on
NOS3 synthase.
Plasma membrane-anchored, NOS3-containing caveolae prevent endothelial
hyperpermeability induced by platelet-activating factor and vascular endothelial
growth factor [
972
].
94
In addition, caveolar NOS3 tethered to the plasma membrane
uncouples NOS3 phosphorylation (Ser1177) from NO production. Conversely,
NOS3 endocytosis allows delivery of NO to subcellular compartments to modify
junctional and/or cytoskeletal proteins and increase endothelial permeability to
macromolecules.
[
93
However, at high concentrations, S1P activates RhoA GTPase to form actin stress fibers possibly
via Gq and G12/13 subclass members.
94
Once myristoylated and palmitoylated, NOS3 targets caveolae in the plasma membrane and
binds to caveolin-1. Activators of NOS3 acts by S-nitrosylating, phosphorylating (e.g., Ser1177),
and dephosphorylating (e.g., Thr495) specific residues, as well as recruiting NOS3 to specific
subcellular loci. Among them, platelet-activating factor and VEGF stimulate PKB to phosphorylate
NOS3.
Search WWH ::
Custom Search