Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 606

Table 10.1. Endothelial sprouting ( Part 1 ); Source: [ 886 ]; DLL: Delta-like ligand; EC:
endothelial cell; ECM: extracellular matrix; MMP: matrix metallopeptidase; Nrp: neuropilin;
Robo: Roundabout homolog; S1P: sphingosine 1-phosphate; Sema: semaphorin (Sema, Ig,
transmembrane, and short cytoplasmic domain); TIE: Tyr kinase with Ig and EGF homology
domains (angiopoietin receptor); Unc5b: Uncoordinated-5B homolog; VEGF: vascular endothelial
growth factor; VEGFR: VEGF receptor). Endothelial cells produce platelet-derived growth factor
PDGFb, transforming growth factor TGF 1, angiopoietin-2 (Ang2), S1P and S1P receptor S1P 1 ,

TIE2 receptor, and VEGFR1 to VEGFR3 receptors. Mural cells synthesize angiopoietin-1 (Ang1),
S1P, activin receptor-like kinase ALK5, which heteromerizes with T

β

R2 receptor, and PDGFb.
Signaling via VEGFR2, VEGFR3, or VEGFR2-VEGFR3 heterodimers is pro-angiogenic. Cleaved
VEGFc and VEGFd interact with VEGFR2; VEGFa connects to VEGFR1 and soluble VEGFR1 S
(secreted extracellular domain) that then limit VEGFa availability. Vascular endothelial growth
factor VEGFa and Ang2 support mural cell detachment and vessel destabilization. Receptor TIE2
tethers to matrix-associated Ang1 at adhesion sites between endothelial cells and matrix, thereby
assisting migration. On the other hand, at EC-EC adhesions, the PTPRb-TIE2-Ang1-TIE2-
PTPRb complex between apposed cells. In addition, Ang2 antagonizes Ang1 activity on TIE2 to
foster angiogenesis. Ephrin-B2 links to VEGFR2 or VEGFR3 and promotes their internalization,
thereby enhancing angiogenesis. Tip cell selection is associated with inhibition of tip cell formation
laterally and migration of tip cells followed by stalk cells during sprout elongation with repression
of tip cell fate in stalk cells. Tip and stalk cells can exchange their respective positions during
sprouting elongation. The Robo4-Unc5b complex impedes VEGFR signaling. Endothelial cell
migration continues in a given direction until anastomosis.

β

Event Factors

Tip cell VEGFa/c, VEGFR2/3

selection Ang2

Inhibition of DLL4-Notch,

tip cell fate Robo4, Wnt,

in adjacent VEGFR1

endothelial cells

Tip cell Ang1-TIE2 (EC-ECM adhesion sites)

migration VEGFa/c/d-VEGFR2, VEGFc/d-VEGFR3/VEGFR2-VEGFR3

Sprout Cadherin-5 extraction from cell junctions

elongation MMP (matrix degradation)

Tip cell Ephrin-B2-EPHb4, Ephrin-B2-EPHb4-VEGFR2/3,

guidance VEGFa/c-Nrp1/2-VEGFR2/3, Sema3e-plexin-D1,

Slit2-Robo4, Robo4-Unc5b, netrin-Unc5b

Tip cells contains a higher Delta-like (Notch) ligand DLL4 concentration with
respect to stalk cells (Table 10.3 ). Messenger Notch, in turn, determines VEGFR
concentration. As a feedback, VEGFR controls DLL4 expression. Endothelial
tip cells are activated and guided by an extracellular VEGFa gradient. Activated
Notch signaling in stalk cells impedes VEGFR, thereby repressing tip cells and
maintaining the hierarchical organization of sprouting tip and stalk cells. The
VEGF-VEGFR-DLL4-Notch-VEGFR feedback loop assigns position of endothe-
lial cells to tip or stalk cells. However, tip cells can shift to stalk cells and conversely