Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 648

kinase, protein kinase B, and nitric oxide synthase-3 [ 1295 ]. It heightens synthesis
of vascular endothelial growth factor and VEGFR2 receptor.

10.6.6.3 Sphingosine 1-Phosphate

Sphingosine 1-phosphate released by platelets during blood clotting is a selec-
tive chemoattractant for endothelial cells. It favors angiogenesis during heal-
ing [ 1296 ]. It activates S1P 1 receptor and 3 subtypes of G-protein-coupled receptors
(Vol. 3 - Chap. 7. G-Protein-Coupled Receptors) on endothelial cells to regulate
angiogenesis.
Sphingosine 1-phosphate is also secreted by endothelial cells. Receptor

PDGFR can cooperate with sphingosine 1-phosphate receptors (S1P 1 -S1P 5 ).

Receptors S1P 1 to S1P 3 serve to recruit mural cells (pericytes and vascular smooth
myocytes). Receptor S1P 1 favors localization of N-cadherins in contact zones
between endothelial and mural cells [ 1184 ].

β

10.6.6.4 Vasohibins

Whereas angiogenic factors, such as VEGF and FGF2, support vascular endothelial
cell proliferation and organization into tubular networks, angiogenesis inhibitors
restrain vessel formation. Angiogenesis inhibitors include angiostatin, endostatin,
prolactin, serpin-F1, thrombospondins, and chemokines CXCL4 and CXCL10, as
well as vasohibins. The latter functions in a negative feedback loop to repress
VEGF- and FGF2-primed angiogenesis.
Vasohibin actually ensures an autocrine negative feedback, as it impedes their
migration and proliferation [ 1297 ]. On the other hand, it does not influence the
migration of smooth myocytes and fibroblasts.
Vasohibin is also produced by hematopoietic stem cells, but not hematopoietic
progenitors or mature hematopoietic cells from adult bone marrow [ 1298 ]. Vaso-
hibin production is stimulated by VEGF and FGF2 in a time- and concentration-
dependent manner. The secreted protein antagonizes the angiogenic effects of
VEGF. Vasohibin synthesis is attenuated by hypoxia, TNF [ 1299 ].

Vasohibin-1, but not most angiogenesis inhibitors, is synthesized by endothe-
lial cells. An alternately spliced isoform lacks C-terminal half of the molecule
(VasH1 Δ

α ,IL1 β , and Ifn γ

CT

) that suppresses FGF2-induced angiogenesis and mediates heparin bind-
ing [ 1299 , 1301 ]. Moreover, various vasohibin forms with distinct molecular weights
result from proteolytic cleavage in the extracellular milieu. At least 2 cleaving sites
exist in the N-terminus. The N-terminal truncated form (VasH1 Δ

NT

) not only retains
its inhibition on angiogenesis, but also has strong affinity to heparin [ 1301 ].
Another

VEGF-inducible, endothelium-derived inhibitor of angiogenesis,

vasohibin-2, or vasohibin-like protein [ 1300 ], is produced preferentially in