Biomedical Engineering Reference
In-Depth Information
damaged tissue and destroy microorganisms via hydrogen peroxide and superoxide
release, which is referred to as ''respiratory burst'' [
37
]. Reoxygenation following
hypoxia leads to ROS formation [
38
]. Changes in the extracellular tissue envi-
ronment, including elevated glucose, ethanol, UV light, and ionizing radiation can
also stimulate high levels of cell-produced ROS [
39
-
42
]. For in vitro and in vivo
studies of ROS effects on angiogenesis, hydrogen peroxide or the ROS of interest
is often applied directly.
While early, high ROS doses (e.g., 250-1000 lMH
2
O
2
) damage cells and tissue,
after the initial injury lower ROS concentrations initiate angiogenesis and tissue
repair [
43
,
44
]. Endothelial cell exposure to hydrogen peroxide induced actin stress
fiber formation and focal adhesion kinase (FAK) activation, likely through hydroxyl
radical formation [
45
]. Hydrogen peroxide and ROS donors further stimulated cell
proliferation, migration, and tube formation when added to 2- and 3-dimensional
endothelial cell culture [
46
-
48
]. When ROS came from hypoxia, ischemic precon-
ditioning, or ethanol instead of being exogenously added, actin reorganization, cell
migration, and capillary tube still occurred [
38
,
40
,
49
]. Similarly, inflammatory
cell-mediated angiogenic activity, including that from activated polymorphonuclear
leukocytes, also appeared to be related to ROS [
50
-
55
].
Exogenous ROS affect angiogenic pathways in a variety of ways. Independent
of ligand binding, UV light clustered growth factor receptors via ROS, and
exogenous H
2
O
2
activated PDGF and EGF receptors [
41
,
56
-
58
]. Exogenous ROS
stimulated VEGF mRNA and VEGF secretion, perhaps via enhanced NF-jB
binding [
59
]. Additional evidence suggests the important of NF-jB in ROS-
mediated angiogenesis, since NF-jB antisense nucleotides inhibited tube forma-
tion in response to hydrogen peroxide [
48
]. In a 3D collagen gel model, hydrogen
peroxide stimulated tube formation, which was blocked by an ets-1 antisense
oligonucleotide. Ets-1 regulates genes involved in matrix degradation, such as
urokinase plasminogen activator and matrix metalloproteinase-1, therefore ROS
may also promote endothelial cell invasion by controlling matrix degradation [
47
].
Exogenous ROS may also signal via secondary ROS production. Hydrogen per-
oxide activated NADPH oxidase superoxide production in vascular smooth muscle
cells, fibroblasts, and mouse pulmonary arteries [
60
,
61
]. These secondary ROS
may contribute to vascular cell injury due to ROS, however they have also been
shown to induce cell proliferation [
46
]. Exogenous H
2
O
2
has even been shown to
mimic growth factors by directly inducing protein tyrosine phosphorylation and
MAPK activation [
62
-
64
].
Exogenous ROS also contribute to angiogenesis through FGF-2, also known as
basic fibroblast growth factor (bFGF) [
65
]. FGF-2 is associated with cell survival,
proliferation, migration and differentiation [
66
-
68
], however it does not have a
recognized signal sequence for secretion. FGF-2 is therefore released following
cell injury often caused by ROS, for example by ionizing radiation, pulsed elec-
tromagnetic field, or elevated glucose [
39
,
69
-
71
]. Released FGF-2 promotes cell
survival and also increases FGF-2 and VEGF expression in endothelial cells,
smooth muscle cells, and cardiac myocytes [
72
-
77
]. FGF-2 signaling in turn acts
through ROS. Exogenous FGF-2 increased FGF-2 expression in pulmonary arterial
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