Biomedical Engineering Reference
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cells, in which Notch signaling is weak or absent. In low Notch activity, VEGFR3
upregulation allows ligand-independent, excessive, deregulated angiogenesis even
in the absence of VEGF-VEGFR2 signaling.
Notch and VEGFR2 are antagonists in the regulation of VEGFR3 level. Notch
regulates VEGFR3 activity independently of VEGFR2 receptor. Conversely,
VEGFR3 kinase activity enables Notch-regulated sprouting. On the other hand,
VEGFR2 strongly improves VEGFR3 density (but not DLL4) at the angiogenic
front. Therefore, VEGFR3 may have an active, ligand-dependent, pro-angiogenic
and a Notch-mediated, passive signaling modes [
1246
].
The non-canonical Notch ligand Delta-like homolog DLk1,
44
a transmembrane
glycoprotein expressed in the endothelium that lacks the DSL domain, impedes
angiogenic sprouting, endothelial cell migration, and tubulogenesis via Notch
receptors [
1247
].
Transmembrane syndecans are heparan sulfate proteoglycans that function as
coreceptors for growth factors. They are implicated in angiogenesis. Syndecans are
implicated in communication between endothelial and smooth muscle cells aimed
at ensuring proper structure and function of blood vessels and their maintenance.
These mural cell types communicate via, at least partly, Notch-3 and syndecan-2
plasmalemmal receptors. The latter is produced in smooth myocytes upon contact
with endothelial cells and Notch activation in smooth myocytes [
1248
]. Both Notch-
2 and -3 contribute to the upregulation of syndecan-2. In particular, syndecan-2
interacts with Notch-3 and regulates expression of several Notch-3 target genes
(only in coculture conditions). Conversely, expression of syndecan-2 in smooth
myocytes needs Notch-2 and Notch-3 proteins.
10.6.4.2
Wnt
The Wnt-
Ctn pathway favors DLL4 expression in the vasculature. Conversely,
the DLL4-Notch complex activates Wnt in stalk cells. In addition, Notch pro-
motes vascular stability via Notch-regulated ankyrin repeat-containing protein
(NRARP) [
886
]. Agent NRARP limits Notch activity, but stimulates Wnt signaling
to stabilize stalk cells.
The planar cell polarity mode of Wnt signaling participates in endothelial cell
proliferation and angiogenesis. On the other hand, Disheveled-associated activator
of morphogenesis DAAM1 that operates as a formin to cause actin polymerization
and especially microtubule stabilization precludes endothelial cell proliferation and
migration [
1249
].
Retinal myeloid cells (macrophages) produce Wnt ligands to suppress retinal
(postnatal) angiogenesis via the non-canonical Wnt-VEGFR1 pathway [
1250
].
β
44
A.k.a. pre-adipocyte factor-1 (PreF1). It precludes differentiation into adipocytes, neuroen-
docrine cells, osteoblasts, myocytes, and hematopoietic cells.
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