Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 638

(sprouting and tube formation) and remodeling. Different VEGFa isoforms regulate
blood vessel growth and patterning.
Factor VEGFb binds to VEGFR1. 49 Receptor VEGFR1 mediates the recruitment
of implicated bone marrow-derived cells. It is also involved in activation of matrix
metallopeptidases [ 1261 ] and paracrine release of growth factors from endothelial
cells [ 1262 ].

VEGF Signaling

Signaling triggered by VEGF leads to activation of numerous genes, such as those
encoding regulator of calcineurin (PP3) RCan2 50 and NR4a1 nuclear receptor.
Histone deacetylase HDAC7 controls endothelial function by repressing MEF2-
dependent and -independent genes. Activated PKD phosphorylates HDAC7, hence
creating docking sites for 14-3-3 proteins. Enzyme PKD thus promotes HDAC7
nuclear export to activate VEGF-responsive genes in endothelial cells [ 1263 ].
In cultured endothelial cells, VEGFa stimulates the synthesis of various
molecules involved in different angiogenesis stages, such as urokinase-type (uPA)
and tissue-type (tPA) plasminogen activators, uPA receptor (uPAR), as well as
plasminogen activator inhibitor-1 and

α V β 5 -integrins. Factor VEGFa
also activates collagenase for a subsequent environmental degradation to prepare
the ground for angiogenesis. Because VEGF promotes the expression of urokinase
receptor in endothelial cells, it favors uPA-uPAR interaction that mediates cellular
invasion and tissue remodeling.
In addition, VEGF provokes VCAM1 and ICAM1 production by endothelial
cells. Factor VEGF increases vascular permeability with possible plasma protein
leakage and formation of a fibrin gel used as a substrate by endothelial cells. Agent
VEGF stimulates hexose transport in endothelial cells for increased energy demands
during proliferation.
In endothelial cells, G proteins, particularly G

α V β 3 -and

α 11 , interact with and
mediate intracellular signaling stimulated by VEGFR2 [ 1264 ].
Activation of VEGFR2 by VEGF stimulates the ERK and P38MAPK pathways.
Vascular endothelial growth factor-A induces endothelial cell migration after actin
filament assembly and stress fiber formation [ 1265 ], via a P38MAPK pathway,
activated by MAP2K3 and MAP2K6 enzymes.
MAPK-activated protein kinase MAPKAPK2, a downstream kinase of
the P38MAPK cascade stimulated by VEGFa, phosphorylates heat shock
protein HSP27, an actin-binding protein that, in its non-phosphorylated form,
precludes actin polymerization; phosphorylated HSP27 released from capped
actin filaments stimulates actin polymerization [ 1266 ]. Kinase MAPKAPK2 also

α q and G

49 Growth factors VEGFb and PlGF are selective ligands of VEGFR1 (Vol. 3 - Chap. 8. Receptor
Kinases).
50 A.k.a. calcipressin-2 [(Cps2).