Oncothanin, a Peptide from the α 3 Chain of Type IV Collagen, Modifies Endothelial Cell Function and Inhibits Angiogenesis

Previous reports from our laboratory have shown that basement membrane (BM) collagen from anterior lens capsule type IV collagen (ALC-COL IV) and peptides from the noncollagenous domain of the α 3(IV) chain, corresponding to residues 185-203 and 179-208, inhibit tumor cell proliferation, specifically through the interaction of the -SNS- tripeptide (residues 189-191) with the CD47/αv β3 integrin receptor complex. Data presented here demonstrate that the α 3(IV)185-203 and the α 3(IV)179-208 peptides, designated as oncothanin, regulate endothelial cell (EC) proliferation, adhesion, and motility that ultimately influence angiogenesis. The data also indicate that oncothanin, when used as a chemoattractant, greatly enhanced EC chemotaxis. In contrast, pretreatment of EC with oncothanin inhibited chemotaxis toward several different chemoattractants. When oncothanin was used as a substrate, it enhanced EC adhesion that was inhibited when pretreated with same. Analysis of angiogenesis by EC differentiation (tube formation), aortic ring microvessel formation, and the chorioallantoic membrane assay demonstrate that oncothanin, but not the control medium or peptides, inhibits angiogenesis. In the EC differentiation assay, oncothanin completely inhibited tube formation at 25 μ g/ml, whereas peptides with comparable sequences, lacking the -SNS- sequence, from ALC-COL IV NC1 domains α 1 and α 2 chains failed to inhibit tube formation. The data support the hypothesis that ALC-COL IV and oncothanin inhibit angiogenesis by modulation of EC function.