Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 633

The VEGF and Notch pathways are coupled. Signaling triggered by VEGFa
provokes DLL4 production prominently in tip cells of endothelial sprouts. Notch
ligand DLL4 induced by VEGF in tip cells activates Notch in adjacent endothelial
cells, where it suppresses the expression of VEGFR receptors, thereby restraining
excessive endothelial sprouting. In fact, expression of DLL4 in endothelial cells is
controlled by VEGF that promotes Notch signaling to suppress the formation of
additional tip cells [ 1240 , 1241 ].
Notch signaling primed by DLL4 hence acts as a negative regulator of VEGF-
induced angiogenesis. Blockade of interaction between DLL4 and Notch receptor
prevents Notch signaling and inhibits angiogenesis in tumors resistant to VEGF
inhibitors [ 1242 , 1243 ]. 42 The DLL4-Notch pathway intervenes during active
vascularization rather than during vessel maintenance [ 1243 ]. Ligand DLL4 is
upregulated in tumor rather than in normal vessels [ 1242 ].
Sprouting blood vessels are organized with leader tip and follower stalk cells.
Competition between endothelial cells for the tip position is regulated by gly-
cosylation of Notch receptors and by the antagonism of Notch ligands Jag1 and
DLL4 [ 1244 ]. In mice, whereas sprouting of endothelial tip cells is inhibited by the
binding of Notch receptor to its ligand DLL4, the Notch ligand Jagged-1 is a potent
angiogenic activator in cells that possess the Fringe family of glycosyltransferases.
Notch glycosylation enhances DLL4-Notch signaling, whereas Jagged-1 has a weak
signaling capacity.
Cerebral cavernous malformation protein CCM1 stabilizes endothelial junc-
tions and keeps endothelium quiescent, thus acting as an anti-angiogenic sub-
stance [ 1245 ]. 43 It primes the inhibitory DLL4-Notch signaling to prevent endothe-
lial cell proliferation, migration, apoptosis, and lumenogenesis. It then promotes
PKB phosphorylation, but represses that of ERK kinases.
In arteries, in which Notch is more active, DLL4 was strongly expressed and
VEGFR3 concentration is low. On the other hand, VEGFR2 lodges in both arteries
and veins. In retinal tip cells, DLL4 expression is only weakly modulated by
VEGFR2 signaling. Therefore, VEGFR2 is not essential for DLL4 expression in tip
cells [ 1246 ]. Moreover, activated Notch is a potent inhibitor of VEGFR3 synthesis,
but not of VEGFR2 expression. Receptor VEGFR2 is indeed not or only weakly
regulated by Notch [ 1246 ]. Activity of VEGFR3 is pro-angiogenic in endothelial
42 Tumor growth rate is not correlated with tumor vascular density. Tumor perfusion could be
improved by vasculature pruning. Repression of DLL4 results in excessive angiogenesis. Normally,
endothelial cell stimulation by multiple growth factors leads to cell proliferation with controlled
degradation of the extracellular matrix and migration using various chemoattractants and adhesion
molecules. Endothelial cells then form a central lumen and mature into a functional vessel.
Neutralized DLL4 leads to defective cell fate and impairs formation of tubular structures by
endothelial cells. Most tumor vessels are not functional; they are either not perfused or convey
a reduced blood flow.
43 Protein CCM1 is produced in astrocytes and endothelial cells. It complexes with CCM2 and
CCM3, as well as lipids and components of the cytoskeleton, cell junctions, and signal transduction
pathways.