Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 624

Like Sema3a, Sema3f influences vessel formation via neuropilin-1. Dimer
Sema3e that targets plexin-D1 is a chemorepellant of endothelial cells [ 1212 ].
Agent Sema3e controls endothelial cell positioning and patterning of the developing
vasculature. One the other hand, catabolized Sema3e can act as a chemoattractant.

Semaphorin-4 Isoforms

Semaphorin-4A, an activator of T-cell-mediated immunity, is also expressed in
endothelial cells. Semaphorin-4A hinders endothelial cell migration and division
stimulated by vascular endothelial growth factor, thus preventing angiogenesis in
vivo [ 1213 ]. Semaphorin-4A uses different receptors according to the cell type.
It targets plexin-D1 in endothelial cells with a lower affinity for plexin-D1 than
Sema3e.
As an activator of T-cell-mediated immunity, Sema4a connects to T-cell im-
munoglobulin and mucin domain-containing protein TIMD2 in T lymphocytes.
Semaphorin-4A also binds to Plexin-B1. It uses PI3K effectors in the VEGF-
VEGFR2 pathway. It suppresses PKB phosphorylation and production of Rac GTP
that promotes endothelial cell motility.
Semaphorin-4D induces endothelial cell proliferation and tubule formation via
plexin-B1 [ 1214 ]. Plexin-B1 activates HGFR receptor protein Tyr kinase.

10.6.1.2 Netrins

Netrins (sanskrit netr: scout) are secreted matrix-binding proteins that yield migra-
tion signals for axon guidance and motion of other cells in the developing central
nervous system. Axon-guidance functions are mediated by 2 families of receptors:
(1) Uncoordinated-5 (Unc5) receptor family and (2) Deleted in colorectal cancer
(DCC) family that includes neogenin subclass and belongs to the immunoglobulin
superfamily. Netrins provide attractive or repulsive signals by interacting with DCC
and Unc5 receptors or Unc5-DCC heterodimers, respectively.
Calcium influx via plasmalemmal Ca 2 + channels and from cytoplasmic stores
is required. High and low cAMP-to-cGMP ratios favor attraction and repulsion, re-
spectively. Netrins also regulate cell adhesion, motility, proliferation, differentiation,
and survival in other biological tissues. 31
Netrins are guidance cues for vascular endothelial and smooth muscle cells
during angiogenesis. Netrin receptor Unc5b in endothelial tip cells and develop-
ing capillaries mediates repulsion. Integrin-

α 3 β 1 operate as netrin-1
receptors in endothelial cells [ 1215 ]. Activated integrins recruit and phosphorylate
adaptor SHC that, in association with the GRB-SOS complex, activates Ras, then

α 6 β 4 and -

31 Netrin-1 is particularly expressed in the developing lungs, pancreas, and mammary gland.