Collagen XVIII/endostatin structure and functional role in angiogenesis

The angiogenesis inhibitor endostatin is a 20 LDA C-terminal fragment of co llagen XVIII, a proteoglycan/collagen found in vessel walls and basement me mbranes, The endostatin fragment was originally identified in conditioned m edia from a murine endothelial tumor cell line. Endostatin inhibits endothe lial cell migration in vitro and appears to be highly effective in murine i n vivo studies. The molecular mechanisms behind the Inhibition of angiogene sis have not yet been elucidated. Studies of the crystal structure of endos tatin have shown a compact globular fold, with one face particularly rich i n arginine residues acting as a heparin-binding epitope, It was initially s uggested that zinc binding was essential for the antiangiogenic mechanism b ut later studies indicate that zinc has a structural rather than a function al role in endostatin. The generation of endostatin or endostatin-like coll agen XVIII fragments is catalyzed by. proteolytic enzymes, including cathep sin L and matrix metalloproteases, that cleave peptide bonds within the pro tease-sensitive hinge region of the C-terminal domain. The processing of co llagen XVIII to endostatin may represent a local control mechanism for the regulation of angiogenesis.