Biomedical Engineering Reference
In-Depth Information
Histamine
After its release from mastocytes, histamine excites endothelial cells, fibroblasts,
and smooth myocytes by binding to 3 receptor subtypes (H
1
-H
3
). Both receptors
H
1
and H
2
exist in endothelial cells, but histamine acts mainly via H
1
receptor. His-
tamine generates intercellular gaps (size 100-400 nm; half-life
2 mn). Histamine
elicits actin stress fiber formation in a RhoA- and Rac-dependent manner [
854
].
∼
Reactive Oxygen Species
Reactive oxygen species generated during inflammation and infection, i.e., at high
concentrations, increase endothelial permeability. Endothelial barrier dysfunction
can result from an increase in reactive oxygen species concentrations during an
oxidative stress.
Oxygen-derived free radicals with one or more unpaired electrons, such as
superoxide anion radical (O
•
2
) and hydroxyl radical (
•
OH) constitute a ROS subset.
Some reactive oxygen species are not radicals such as hydrogen peroxide (H
2
O
2
).
Superoxide formed from molecular oxygen by mitochondrial electron-transport
chains, NAD(P)H oxidases, xanthine oxidases, cyclooxygenases, lipoxygenases,
and uncoupled nitric oxide synthases, is a precursor for several reactive oxygen and
nitrogen species.
98
Reactive nitrogen species, such as peroxynitrite and nitric oxide,
are other types of signaling molecules within blood vessels.
Endothelial NADPH oxidase complexes are major producers of O
2
agent.
Oxidants cause endothelial contraction by activating RhoA GTPase and MLCK
kinase, increasing intracellular Ca
2
+
concentration, and stimulating phospholipases
PLA2, PLC, and PLD, as well as PKC, MAPK, and Src kinases [
854
].
Hydrogen peroxide, a stable and permeant reactive oxygen species, even at
low concentrations, modulates cytoskeletal reorganization with actin stress fiber
formation, vasorelaxation, and vascular remodeling. It also increases endothelial
permeability that can result from an augmented generation of stress fibers and
a disruption of cortical actin. Among mediators of H
2
O
2
-primed permeability
elevation, actin-binding myristoylated alanine-rich C-kinase substrate (MARCKS)
expressed in endothelial cells mediates H
2
O
2
-induced changes in actin cytoskeleton
architecture and endothelial permeability in bovine aortic endothelial cells [
975
].
99
98
Superoxide can be converted by superoxide dismutases to hydrogen peroxide. It can react with
nitric oxide to form peroxynitrite (ONOO
−
). It can also intereact with arachidonic acid to generate
isoprostanes.
99
Protein MARCKS links binds to actin, calcium-calmodulin, and membrane phospholipids
(PIP
2
). Once it is phosphorylated by PKC, MARCKS dissociates from the membrane and is
unable to crosslink
F
actin. Agents that increase endothelial permeability, such as thrombin and
diacylglycerol, also launch MARCKS phosphorylation in endothelial cells.
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