Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 650

10.6.8 Regulators of Small GTPases

Angiogenesis is controlled by mechanical and chemical cues, i.e., physical interac-
tions between cells and extracellular matrix as well as soluble agonist and antagonist
regulators. A signaling pathway is sensitive to both extracellular matrix elasticity
and VEGF that targets VEGFR2 receptor.
Protein RhoGAP35 that inhibits small GTPase Rho is indeed regulated by growth
factors, matrix elasticity, and cytoskeletal distortion. It controls angiogenesis, as it
modulates the balance between 2 mutually antagonistic transcription factors GTF2i
and GATA2 that regulate expression of VEGFR2 [ 1305 ]. Mediator RhoGAP35
binds to GTF2i for cytosolic sequestration.

10.6.8.1 Regulators of G-Protein Signaling

Regulators of G-protein signaling shorten the duration of active G α q and

act on cell migration, proliferation, and mitogen-activated protein kinase activi-
ties [ 1306 ]. Subtype RGS4 inhibits MAPKs and VEGFR2 expression [ 1307 ]. Other
stimulators of G-protein-coupled receptors (thrombin, angiotensin-2, endothelin-1,
prokineticin-1 and -2, etc.) are also implicated.
Tumoral angiogenesis leads to aberrant vasculature. Tumor vasculature is in fact
characterized by dilated and fragile vessels, intensive vessel sprouting, and loss
of hierarchical architecture. Protein RGS5 causes abnormal vessel morphology in
tumors, as RGS5 loss leads to pericyte maturation and vascular structure normal-
ization [ 1344 ]. Altered tumor vasculature prevents migration of immunocytes into
tumor parenchyma. Vascular normalization that results from RGS5 loss promotes
immune destruction.

α i and G

10.6.9 Phosphoinositide 3-Kinase and Phospholipase-C

Angiogenesis is characterized by stabilization and destabilization stages, selecting
the vessel able to develop for suitable perfusion. Angiogenesis can be regulated
at the level of plasmalemmal lipids. Enzyme PI3K c1α generates the lipid sec-
ond messengers phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol
(3,4,5)-trisphosphate that localize to the inner leaflet of the plasma membrane.
Kinase PI3K c1α regulates angiogenesis in the developing embryo and fetus as well
as pathological situations.
Phosphatidylinositol (4,5)-bisphosphate coordinates the phases of angiogenesis.
The angiogenic program is driven by phosphoinositide 3-kinase and antagonist
phospholipase-C

. The former promotes tube formation, the latter tube regres-
sion [ 1309 ]. Both substances compete for their common substrate, phosphatidyli-
nositol (4,5)-bisphosphate. Enzyme PLC

γ

γ controls tube formation by reducing the