Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 646

Ang2

(autocrine)

vessel destabilization

vessel caliber

cell migration

TIE2

Ang2

Src

Cadh5

WPB KLF2

FAK

Rho Dia

ANG2

APJ

TIE2 TIE2

FoxO1 GRB2

cell survival

Ang1

Abin2

PI3K

PI3K

VEGF

PTPRb

hypoxia

apelin

GRB4
GRB14

DOK2

HBEGF NOS3

PTPn11

GRB7

PKB

EC TIE2 EC TIE2

Ang1

(paracrine)

new vessel stabilization Ang2

cell migration

Ang1

SMC

Fig. 10.4 Ang-TIE signaling pathways in vascular cells (EC; Source: [ 1289 ]). Isotype Ang1
produced by mural cells such as smooth myocytes (SMC) stimulates receptor TIE2. In endothelial
cells, Ang2 synthesis is stimulated by forkhead box transcription factor FOxO1, VEGF, and
hypoxia, but is impeded by Kruppel-like factor KLF2. Angiopoietin-2 is stored in Weibel-Palade
bodies (WPB). Isoform Ang2 inhibits Ang1-TIE2 signaling to destabilize the resting endothelium,
but activates TIE2 in already hastened endothelium. Receptor TIE2 activation indeed primes
several signaling pathways. Activated TIE2 can recruit adaptors, such as growth factor receptor-
bound proteins GRB2, GRB4, GRB7, and GRB14, Dok-related docking protein Dok2, as well
as SH2 domain-containing Tyr phosphatase PTPn11 (SHP2) and mediator A20-binding inhibitor
of NF B Abin2. The dominant pathway corresponds to the PI3K-PKB axis that is responsible for

survival signals (inhibition of caspase-9 and BAD and activation of survivin. Secreted angiopoietin-
1 can bind to receptors TIE2 of adjacent cells, thus making trans-complexes into space between
adjacent endothelial cells. This complex associates with vascular endothelial phosphotyrosine
phosphatase (vePTP or PTPRb). Receptor TIE2 stimulates nitric oxide synthase NOS3, protein
kinase-B (PKB), RhoA GTPase and its effector Diaphanous that maintains interendothelial
stability by sequestering Src kinase, thus precluding Src-mediated VE-cadherin endocytosis.
Phosphoinositide 3-kinase also phosphorylates focal adhesion kinase (FAK) for cell migration.
Activated TIE2 upregulates endothelial heparin-binding EGF-like growth factor (HBEGF) and
hepatocyte growth factor (HGF) that favor SMC migration and recruitment to ECs. Last but not
least, PKB phosphorylates (inactivates) FOxO1 that targets the ANG2 gene (negative feedback
loop).

κ

TIE2 Receptor and Apelin
In endothelial cells, TIE2 activation generates apelin secretion [ 1292 ]. 67

Apelin

is a pleiotropic peptide that targets its cognate G-protein-coupled receptor

67 Apelin localizes preferentially in blood vessels. An immature peptide, preproapelin, is secreted
and cleaved by proteases to form apelin 13 , apelin 17 , and apelin 36 , among others. These isoforms