Biochemical Activities of TSP1 That Could Influence Angiogenesis

Several biochemical activities of the TSP-1 protein have been defined in vitro that could ultimately impinge on angiogenesis in vivo. Proteolysis is essential for angiogenesis, and TSP-1 has been shown to bind and inactivate the serine proteases, neutrophil elastase and cathepsin G, which are found at sites of inflammation or injury (74). Cathe-psin G is also present in new vessels forming in glioblastomas and prostate carcinomas (75). TSP-1 also binds to, and may inhibit the activity of, urokinase plasminogen activator and plasmin (74), which clearly play important roles in extracellular matrix degradation by endothelial cells, as well as by tumor and stroma (76).

TSP-1 could also modulate angiogenesis through its ability to activate TGF-p. In vitro, TGF-P stimulates endothelial cell migration at picomolar concentrations; at nanomolar concentrations, it inhibits endothelial cell migration (14), as well as endothelial cell growth, proteolysis, and tube formation (77-79). TSP-1 binds and activates latent TFG-P in vitro, and such activation can contribute to a portion of TSP-1's ability to inhibit the mitogenesis of cultured endothelial cells (31). Because cultured endothelial cells produce latent TGF-p, its activation by TSP-1 can be hard to avoid. However, using neutralizing antibodies for TGF-P or TSP family members unable to activate the cytokine, the ability of TSP-1 to inhibit endothelial cell migration (14), mitogenesis (32) and apoptosis (52a) have been shown to occur independently of the activation of latent TGF-p.

TSP-1 can also play a significant role in the activation of TGF-P in vivo (79a). It is doubtful that this activation contributes to the ability of TSP-1 to inhibit neovascularization, because, when tested in vivo, TGF-p always appears to induce, rather than inhibit, angiogenesis (78,80), probably because of its proinflammatory activity, and TSP-1 can block angiogenesis induced in the cornea by TGF-P (15).

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