Biomedical Engineering Reference
In-Depth Information
various cell types in remodeling tissues. It can interfere with the binding of angio-
genic stimulators, such as vascular endothelial (VEGF), platelet-derived (PDGF),
and fibroblast (FGF2) growth factor, to their receptors in endothelial cells. Schwann
cells influence neuroblastoma growth by secreting inhibitors of angiogenesis, the
most potent of which is SPARC protein. Full-length SPARC (SPARC
FL
)and
SPARC-derived peptides (SPARC
f
) that correspond to the follistatin domain of the
protein as well as its N- and C-termini block angiogenesis [
1189
].
23
Involved peptidases include matrix metallopeptidases mt1MMP (MMP14) to
mt3MMP (MMP16), MMP2, MMP3, MMP7, MMP9, and MMP13, and mem-
bers of the adamlysine family, such as ADAM10, ADAM15, ADAM17, and
ADAMTS1 [
1185
].
10.5.2.1
Endostatin and Endorepellin - Endogenous Angiogenesis
Inhibitors
Endostatin, a fragment of collagen-18, and endorepellin, an inhibitor of angiogene-
sis derived from the basement membrane proteoglycan perlecan, have dual roles as
structural constituents and functional regulators of tissue growth. They modulate the
activity of growth factors. They can inhibit the growth of blood vessels and stabilize
the basement membrane [
1190
].
Endostatin increases the production of nitric oxide in endothelial and smooth
muscle cells [
1191
]. Hypertension is a major drawback of VEGF inhibitor admin-
istration, which necessitate to limit the dose. On the other hand, NO, a potent
vasodilator, lowers blood pressure. Endostatin reduces blood pressure via the
NOS3-NO axis and/or improved NO availability.
10.5.3
Cell Adhesion Molecules
Angiogenesis is regulated by endothelial cell adhesion molecules, such as vascular
endothelial cadherin, integrins, and platelet-endothelial cell adhesion molecule. A
mechanosensory complex composed of PECAM, cadherin-5, and VEGFR2 causes
the response initiated by activated integrins [
1192
].
α
-(2,6)-Sialic acid is necessary for the cell-surface residency and mainte-
nance as well as homophilic interactions of platelet-endothelial cell-adhesion
23
Peptides derived from SPARC domain-4 binds to endothelial cells and impedes endothelial cell
proliferation, like SPARC. This inhibition also results from the action of a peptide derived from the
follistatin-like domain-2. On the other hand, peptides from SPARC domain-1 and -3 have no effect
on VEGF-stimulated DNA synthesis in endothelial cells [
1187
]. The inhibition of proliferation of
human microvascular endothelial cells is caused by, at least partly, VEGF-SPARC binding.
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