Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 508

Table 9.19. Angiogenesis guidance pathways.

Pathway Ligand and receptor types

EPH-ephrin Ephrin ligands (transmembrane proteins)

Erythropoietin-producing hepatocyte receptor kinase

Netrin-DCC/Unc5 Secreted netrin-1/3/4/5

Deleted in colorectal carcinoma receptor
Unc5 receptor homologs

Netrin-NtnGR GPI-anchored netrin-G1/G2

Netrin-G single-pass transmembrane receptor

Notch-DLL Notch receptor (single-pass transmembrane heterodimer)

Notch-Jagged Delta-like ligands (membrane-bound and soluble proteins)

Jagged (membrane-bound and soluble proteins)

Slit-Roundabout single-pass transmembrane Robo1-Robo4 molecules

Secreted Slit ligands

guidance includes Delta-like ligand (DLL)-Notch, 71 EPH-ephrin, 72 netrin-Unc5, 73
and Slit-Roundabout pathways, 74

in addition to VEGF, Sprouty, and Hedgehog

(Sect. 10.2 ;Table 9.19 ).
Robo activated by Slit2 is expressed in stalk cells, but not in tip cells [ 892 ].
Receptor Robo1 is expressed by endothelial cells [ 936 ]. According to [ 892 ],
Robo4 suppresses the activity of vascular endothelial growth factor required in
angiogenesis (as it induces endothelial cell proliferation and migration, as well as
blood vessel wall permeability), hence stabilizing the endothelium. However, Robo4
can have a guidance role in developing vessels [ 935 ].

71 Notch receptor is a single-pass transmembrane heterodimeric receptor. It is composed of a large
extracellular subunit linked to a single-pass transmembrane subunit that has a short extracellular
and a small intracellular region. Membrane-bound proteins Delta-like ligands (DLL1 and DLL4)
and Jagged (Jagged-1-Jagged-2) are ligands for Notch receptors (endothelial Notch-1 and Notch-
4 and smooth muscle Notch-1 and Notch-3). Soluble DLL and Jagged proteins can also bind to
Notch receptors with similar or distinct binding affinities w.r.t. those of membrane-bound forms.
72 Ephrin ligands (ephrins; a portmanteau for EPH receptor-interacting protein) and erythropoietin-
producing hepatocyte receptor kinase (EPH) are both transmembrane proteins. Consequently,
EPH-epherin signaling can only occur via direct between-cell interaction.
73 Three secreted netrins (netrin-1 and netrin-3-netrin-4) and 2 GPI-anchored netrins (netrin-G1-
netrin-G2) exist. Receptors for the secreted netrins include Deleted in colorectal carcinoma protein
(DCC) and Unc5 homologs (Unc5a-Unc5d). The former is an attractant, whereas Unc5 homologs
and, in some cases, DCC are repellants. Netrin-G bind netrin-G single-pass transmembrane protein
(between-cell interaction). Netrins contribute to cell migration and regulate between-cell and cell-
matrix adhesion.
74 Members of the Roundabout family (Robo1-Robo4) are single-pass transmembrane cell adhe-
sion molecules that serve as receptors for secreted Slit ligands (Slit1-Slit3).