Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 652

Reduced concentrations of thrombospondin Tsp1 and Tsp2 shift the PKB activity
toward increased angiogenesis. 71
The zinc-binding matrix metallopeptidase, a disintegrin and metallopeptidase
with thrombospondin-1 motif ADAMTS1, modulates angiogenesis, cleaving
matrix-bound thrombospondins TSp1 and Tsp2, and thereby releasing anti-
angiogenic polypeptidic fragments [ 1317 ]. Enzyme ADAMTS1 mainly targets
Tsp1 of the endothelial basement membrane. 72
Protein kinase-B phosphorylates actin-binding protein girdin to promote VEGF-
dependent migration of endothelial cells and tube formation [ 1318 ]. 73 Both PKB1
and PKB2 isoforms phosphorylate girdin. However PKB2 concentration is very low
in human umbilical vein endothelial cells. Girdin is required in cell-cell and cell-
matrix adhesion, as well as in phosphorylation of other PKB substrates, such as
NOS3 and GSK3 , and in activation of small GTPases. Girdin is highly

expressed in endothelial cells of capillaries in both normal and tumoral tissues.
The PKB-girdin axis mediates VEGF-dependent cell migration, tube formation, and
microvessel remodeling, as well as microvessel sprouting in postnatal angiogenesis.
Girdin is localized on the actin stress fibers, especially at junctions between the actin
filaments, but weakly found on cortical actin filaments. In large blood vessels, girdin
is produced by smooth myocytes, but not endothelial cells. In hemangiomas, girdin
is synthesized in both immature endothelial cells and mural cells. Phosphorylated
girdin is located at the leading edge of migrating cells.

α and - β

10.6.11 Cyclooxygenases and Prostaglandins

Cyclooxygenase-2 favors expression of angiogenic factors such as VEGF and
FGF2. It can inhibit endothelial cell apoptosis, stimulating intracellular anti-
apoptotic pathways.
Cyclooxygenase-2

has a pro-angiogenic activity owing to its metabolite

prostaglandin-E2. A pathway crosstalk exists between prostaglandin-E2 and

transforming growth factor- in tumor angiogenesis [ 1319 ]. Prostaglandin-E2

activates the ALK5-SMAD3 pathway to induce neovascularization. This activated
pathway releases active TGF

β

β from its latent form using clustered mt1MMP

metallopeptidases.

71 Thrombospondins are involved not only in endothelial cell proliferation and apoptosis, but also
in collagen assembly and maintenance of vascular integrity. Thrombospondin-2 controls the level
of matrix metallopeptidase MMP2 [ 1316 ].
72 Substrates of ADAMTS1 also include aggrecan, versican, and nidogen. It is associated with
catalytic modifiers such as fibulin-1. Moreover, ADAMTS1 has a non-catalytic function, as it
sequesters VEGF factor.
73 Girdin is also known as Akt (PKB) phosphorylation enhancer (APE), G α -interacting vesicle-
associated protein (GIV), and Hook-related protein-1 (HkRP1). Kinase PKB phosphorylates girdin
to regulate its subcellular location and fibroblast migration.