Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 637

VEGFR

EC

SHC − GRB − SOS

TSP

PI3K

Shp

PKB

MAPK PIP2

NOS

PLC

VEGFR

catenins

DAG IP3

actinin

Vinc

VE cadherin

NOS3 actin

ERK PKC

MAPK RacGEF

Raf

FAK
Pax

Vinc

PI3K

talin

integrin VEGFR

ECM

Fig. 10.1 Vascular endothelial growth factor (VEGF) stimulates angiogenesis, particularly prolif-
eration of endothelial cells (EC; Source: [ 1257 ]). Factor VEGF binds to its receptors (VEGFR1-
VEGFR3). It then activates cell type-dependent signaling cascade via adaptors SHC and GRB,
cytosolic protein Tyr phosphatases PTPn6 and PTPn11, phospholipase PLC , phosphatidylinositol

3-kinase (PI3K), etc. Vascular endothelial (VE)-cadherins (cadherin-5) are involved in adherens
junctions between neighboring endothelial cells. They interact with catenins, and subsequently
with

γ

-actinin and vinculin (Vinc), and the actin cytoskeleton. Cadherin-5 acts with VEGFR2 to
control the PI3K-PKB pathway. Endothelial cells are linked to the extracellular matrix (ECM)
via integrins such as

α

3 -integrin and focal adhesion molecules, such as focal adhesion kinase
(FAK), talin, paxillin (Pax), and vinculin (Vinc).

α β V

kinase-C and -D (Vol. 4 - Chap. 5. Cytosolic Protein Ser/Thr Kinases), 46
phosphatidylinositol 3-kinase (Vol. 4 - Chap. 2. Signaling Lipids), and mitogen-
activated protein kinase (Vol. 4 - Chap. 6. Mitogen-Activated Protein Kinase
Modules).
Vascular endothelial growth factor-A binds to 2 receptor Tyr kinases on the
plasma membrane of endothelial cells: VEGFR1 47 and VEGFR2. 48 However,
VEGFa angiogenic effects are mainly mediated by VEGFR2 receptor. VEGFa Fac-
tor is required for chemotaxis and differentiation of endothelial precursors, as well
as endothelial cell proliferation, migration, and assembly into vascular structures

46 The PKD family includes PKD1 to PKD3. Kinases PKD1 and PKD3 are also called PKC

and

PKC , respectively. PKD1 is a class-2a HDAC export kinase.

47 Receptor VEGFR1 is implicated in chemotaxis and vascular permeability.
48 Receptor VEGFR2 is involved via protein kinase-B and mitogen-activated protein kinase in
endothelial cell proliferation and survival.

ν