Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 645

with protein Tyr P phosphatase receptor PTPRb to signal via protein kinase-B to
stimulate nitric oxide synthase NOS3 (Fig. 10.4 )[ 1289 ].
The Ang1-TIE2 complex activates not only phosphoinositide 3-kinase, but also
survivin, or baculoviral inhibitor of apoptosis repeat-containing protein BIRC5,
whereas it inhibits caspase-9 and BCL2 antagonist of cell death (BAD), thus
preventing apoptosis. Moreover, sequestration of Src kinase by RhoA effector
Diaphanous stabilizes interendothelial junctions, as it prevents internalization me-
diated by Src kinase of vascular endothelial cadherin.

Angiopoietin-2

Synthesis of angiopoietin-2 is stimulated by hypoxia and VEGF, in particular, and
inhibited by Kruppel-like factor-2 [ 1289 ]. Autocrine angiopoietin-2 disrupts mature
vessels and initiates vessel regression. Angiopoietin-2 upregulated by hypoxia or
VEGF impedes the interaction between Ang1 and TIE2 receptor.
In endothelial cells, Ang2 is stored in Weibel-Palade bodies with von Willebrand
factor. Angiopoietin-2 storage level varies according to the vascular bed, thereby
influencing the degree of responsiveness of a given vascular bed to inflammatory or
angiogenic cytokines. Ang2 stores are much greater in cerebral microvessels than
in vasculature of skeletal muscles and heart. Secretagogue thrombin or vasopressin
can quickly liberate content of Weibel-Palade body to act on vessel permeability,
coagulation, and inflammation.
Angiopoietin-2 can activate TIE2 on some cells (agonist), whereas it blocks TIE2
activation on others (antagonist). Ang2 acts as a TIE2 agonist in lymphatic vessels,
but as an antagonist in blood vessels [ 1290 ]. Therefore, angiopoietin-2 promotes
angiogenesis according to the tissue and context. In addition, Ang2 produced and
stored by endothelial cells controls endothelial responsiveness to multiple factors,
such as vascular endothelial growth factor, histamine, bradykinin, and inflammatory
factors (e.g., tumor-necrosis factor-

α

).

TIE2 Receptor

Whereas VEGF and VEGFR2 intervene in the early stage of angiogenesis,
angiopoietin-1 and -2, TIE2 receptor, and PTPRb phosphatase operate in the later
stage of vessel remodeling. In particular, the Ang-TIE2 couple regulates tumor
vessel size [ 1291 ]. Phosphatase PTPRb reduces signaling from the Ang-TIE2
pathway.
VEGFR2 embryos fail to develop any blood vessel structures. Nevertheless,

murine embryonic stem (ES) cells, once implanted subcutaneously in mice, generate
teratomas, differentiate into epithelial, muscle, as well as endothelial cells within
teratomas that form occasional large-caliber blood vessels, even when they lack
VEGFR2 receptor [ 1291 ]. Increased TIE2 phosphorylation in PTPRb

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teratomas
demonstrates that PTPRb represses TIE2 activity in tumor angiogenesis [ 1291 ].

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