Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 651

level of PI(4,5)P 2 that is targeted by protein kinase-C to produce diacylglycerol and
inositol trisphosphate, and inhibits protein Tyr kinases.
Only activity of class-1A catalytic subunit PI3K c1α that is preferentially induced
by receptor protein Tyr kinase ligands such as VEGFa in endothelial cells is essential
for vascular development [ 1310 ]. 69
About 50 PI3K effectors that contain pleckstrin homology (PH) domains specifi-
cally bind to PI(3,4,5)P 3 . These effectors are regulated by PI(3,4,5)P 3 that causes
translocation to the plasma membrane and/or a conformational change. Many
PI(3,4,5)P 3 -binding proteins are regulators of small guanosine triphosphatases of
the RHO and ARF superfamilies.
Dual GTPase-activating protein ARAP3 is a PI(3,4,5)P 3 - and Rap-activated
stimulator for RhoA and ARF6 GTPases that is required for sprouting angiogenesis
that depends on cell migration [ 1311 ]. Recruitment of ARAP3 to the plasma
membrane as well as its ArfGAP activity depends on PI(3,4,5)P 3 produced by
PI3K c1α . Both ARF6 and RhoA GTPases regulate cell motility.

10.6.10 Protein Kinase-B

Protein kinase-B regulates vascular permeability and angiogenesis by fine-tuning
of signaling pathways in endothelial cells, including pro- and anti-angiogenic
signalings [ 1312 ]. Kinase PKB has various roles at different stages of angiogenesis.
Coronary angiogenesis is enhanced during the acute phase of adaptive car-
diac growth, implicating myocardial VEGF and angiopoietin-2 [ 1313 ]. 70 On the
other hand, neovascularization is reduced during maladaptive remodeling. Indeed,
sustained PKB signaling causes microvascular malformations [ 1314 ]. Chronic
PKB activation precludes PI3K activity (PI3K-dependent effectors are required for
full cardioprotection) [ 1315 ]. Short-term PKB activity mediates hypoxia-induced
expression of VEGF, whereas its prolonged activation decreases VEGF level.
Protein kinase-B1 is required for migration and integrin-mediated adhesion of
endothelial cells. Protein kinase-B is also necessary in pericyte recruitment for
vessel maturation.
Protein kinase-B targets endothelial nitric oxide synthase. The NOS3 pathway is
implicated in vascular maturation. Protein kinase-B also controls the expression of
thrombospondins Tsp1 and Tsp2, inhibitors of angiogenesis, by endothelial cells.

69 In endothelial cells, PI3K c1β

operates downstream from liganded G-protein-coupled receptors

such as CXCR4 α -chemokine receptor. In these cells, PI3K c1δ is expressed at low concentration.

Catalytic subunits of class-1A PI3K isoforms PI3K c1α and PI3K c1β are ubiquitous, whereas

PI3K c1δ is only enriched in leukocytes.
70 This transient signaling is associated with normal microvascular development, acute PKB
activation of myristoylated PKB (PKB M ) being cardioprotective.