Biomedical Engineering Reference
In-Depth Information
10.6.12
Tissue Factor
Tissue factor, an initiator of coagulation,
74
mediates angiogenesis in interaction with
coagulation factor VIIa. Interactions between tissue factor and activated clotting
factor VIIa promote VEGF synthesis and secretion. Full-length tissue factor (TF
FL
)
complexed with factor VIIa influences angiogenesis via peptidase-activated receptor
PA R
2
[
1320
]. This signaling axis promotes the synthesis not only of VEGF, but
also matrix metallopeptidase MMP7 as well as CXCL1 chemokine and CXCR1
and CXCR2 receptors.
An alternatively spliced variant of tissue factor (TF
AS
) can cause angiogenesis in
vitro at low concentrations (1 nmol), independently of PAR
2
or clotting factor VIIa,
whereas a soluble TF
FL
form (TF
FL
) has smaller promigratory effect [
1320
]. Pro-
angiogenic action of asTF relies on integrin ligation. Migration of endothelial cell
depends on interaction between TF
AS
and
α
V
β
3
-integrin as well as P38MAPK and
PI3K enzymes. Formation of capillaries depends on interaction between TF
AS
and
α
6
β
1
-integrin as well as ERK1, ERK2, and PI3K.
10.6.13
Tissue Kallikrein and Kininogen
Tissue kallikrein that produces kinin from kininogen promotes angiogenesis and ar-
teriogenesis. The signaling cascade downstream from tissue kallikrein that involves
protein kinase-B and glycogen synthase kinase GSK3
in human coronary artery
endothelium [
1321
] or endothelial nitric oxide synthase in human umbilical vein
endothelium [
1322
] upregulates vascular endothelial growth factor and VEGFR2
receptor. In addition, GSK-3
β
protects cardiomyocyte against hypoxia-induced
apoptosis. It is associated with the Wnt pathway in endothelium. Moreover, GSK-
3
β
regulates energy metabolism of many tissues.
High-molecular-weight kininogen is a plasma protein that serves as a cofactor
in the intrinsic coagulation cascade (Sect.
9.8
) and inhibits cysteine peptidases.
Proteolytic cleavage of high-molecular-weight kininogen by kallikrein in endothe-
lial cells produces 2 active molecules: (1) bradykinin that mediates nitric oxide
release and (2) cleaved 2-chain high-molecular-weight kininogen. The latter inhibits
angiogenesis, whereas the former is an angiogenesis stimulator.
Ferritin that intervenes in iron storage binds to cleaved high-molecular-weight
kininogen with high affinity to antagonize its anti-angiogenic effect [
1323
]. There-
fore, plasma ferritin regulates vascular remodeling and angiogenesis.
In addition, cleaved high-molecular weight kininogen can stimulate inflamma-
tory cytokine and chemokine secretion from human monocytes [
1324
]. It can
upregulate tissue factor in human monocytes via its receptor
β
α
M
β
2
-integrin. It
74
After blood vessel injury, tissue factor with factor VIIa activates factor Xa, thrombin, and fibrin
to build a hemostatic plug.
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