Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 621

Fibulin-3 stimulates production of vascular endothelial growth factor, hence
angiogenesis [ 1202 ]. Moreover, fibulin-3 hinders tumor cell apoptosis.
Fibulin-4 is an elastic fiber-associated protein that is required for formation
of elastic fibers, especially in arteries, lungs, and skin. It regulates tropoelastin
expression [ 1203 ].
Fibulin-5 that interacts with integrins is expressed in developing arteries. Its
expression is reinduced in injured vessels and atherosclerosis in intimal smooth
muscle and endothelial cells [ 1204 ].

10.5.5 Thrombospondins

Vessel formation requires a tuned balance between various interacting stimu-
latory and inhibitory signals. Thrombospondin inhibits blood vessel formation.
Thrombospondin-1 binds to integrins, matrix metallopeptidase-2, transforming
growth factor TGF β 1, proteoglycans, and fibronectin.

10.5.6 Matrix Metallopeptidases

Remodeling of the extracellular matrix by various molecules, especially extracellu-
lar and membrane-bound matrix metallopeptidases, is required during angiogenesis.
The type of cleavage of matrix components can lead to opposite effects. Proteolysis
of collagen-4 and -18, as well as plasminogen, releases angiogenesis inhibitors,
whereas cleavage of collagen-4 by MMP9 stimulates migration of endothelial cells
and angiogenesis.

10.5.7 Transglutaminase and Carboxypeptidases

Angiogenesis requires localized destabilization of the extracellular matrix.
Afterward, transglutaminase-2 is downregulated in endothelial cells during capillary
morphogenesis to secondarily stabilize the underlying basement membrane [ 923 ].
Glutamate carboxypeptidase-2 25 expressed in endothelial cells, contributes to the re-
modeling of the extracellular matrix for angiogenesis. Glutamate carboxypeptidase-
2 acts on

β

1 -integrin and leads to activation of P21-activated kinase PAK1 [ 1205 ].
It also interacts with actin-binding filamin-A, leading to phosphorylation of

25 Transmembrane

glutamate carboxypeptidase-2 is also named prostate-specific membrane

antigen.