Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 636

10.6.5.1 Vascular Endothelial Growth Factors

Vascular endothelial growth factors regulate the initial stages of blood vessel
formation. Later, they are also implicated in association with other activators, such
as angiopoietins, fibroblast (FGF), insulin-like (IGF), and transforming (TGF

β )

growth factors, as well as TNF , apelin, ephrin, and Notch. Most of these factors

act on other cell types and complement or coordinate VEGF signaling rather than
operating as independent regulators of angiogenesis.
In the absence of TGF

α

1, VEGF favors endothelial cell survival via VEGFR2
and P38MAPK [ 1255 ]. In the presence of TGF

β

1, VEGF promotes cell apoptosis.
During angiogenesis, apoptosis is required for pruning the forming vascular net-
work. Factor TGF

β

1 promotes the expression of FGF2 by endothelial cell, which
upregulates the expression of VEGF and acts via ERK1 and ERK2 kinases.
Vascular endothelial growth factor is a potent mitogen for endothelial cells
derived from arteries, veins, and lymphatics [ 1256 ]. Moreover, VEGF stimulates
cardiomyocytes. Factor VEGF exerts its angiogenic effects via its cognate VEGFR
receptors (Fig. 10.1 ). Endothelial cells activated by VEGFa, assemble, and form
tubes.
Vascular endothelial growth factors also act on the development of the nervous
system 45 and protect nerve cells under stress conditions, as a neurotrophic and
angiogenic factor.
Vascular endothelial growth factor-A also acts on pericytes in coordination with
other growth factors such as the platelet-derived growth factor-BB homodimer
secreted by endothelial cells [ 1259 ].

β

VEGF Receptors

Receptor Tyr kinase signaling, especially VEGFR and angiopoietin receptors
TIE1 and TIE2, is regulated by Tyr phosphatases, such as receptor protein Tyr
phosphatase PTPRb. Phosphatase PTPRb dephosphorylates TIE2 and cadherin-5,
but not VEGFR2 receptor. It is expressed in both arterial (more strongly) and
venous endothelium in embryos [ 1260 ]. It is highly produced in the developing
outflow tract of the heart and developing heart valves. Although PTPRb does
not intervene in early stages of vasculogenesis, it mediates suitable remodeling
of vascular plexi into large vessels and branched vascular networks by pruning,
coalescence, sprouting, and intussusception. Phosphatase PTPRb is also synthesized
in adults in the vasculature and heart valves.
Binding of VEGF to its receptors induces receptor dimerization and autophos-
phorylation. This process then activates several downstream kinases: protein

45 In vitro, VEGF is implicated in the survival, proliferation, and migration of Schwann cells,
astrocytes, and microglia [ 1258 ]. In vivo, VEGF is required for migration of certain motoneurons.