Endorepellin, a Novel Inhibitor of Angiogenesis Derived from the C Terminus of Perlecan

• Published in: The Journal of biological chemistry 2003-02, Vol.278 (6), p.4238-4249
• Main Authors: Mongiat, Maurizio, Sweeney, Shawn M., San Antonio, James D., Fu, Jian, Iozzo, Renato V.
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Base Sequence; Cell Line; Collagen - pharmacology; Collagen Type XVIII; DNA Primers; Endostatins; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Heparan Sulfate Proteoglycans - chemistry; Heparan Sulfate Proteoglycans - isolation & purification; Heparan Sulfate Proteoglycans - pharmacology; Humans; Peptide Fragments - chemistry; Peptide Fragments - isolation & purification; Peptide Fragments - pharmacology; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; Recombinant Proteins - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M210445200

Perlecan, a ubiquitous basement membrane heparan sulfate proteoglycan, plays key roles in blood vessel growth and structural integrity. We discovered that the C terminus of perlecan potently inhibited four aspects of angiogenesis: endothelial cell migration, collagen-induced endothelial tube morphogenesis, and blood vessel growth in the chorioallantoic membrane and in Matrigel plug assays. The C terminus of perlecan was active at nanomolar concentrations and blocked endothelial cell adhesion to fibronectin and type I collagen, without directly binding to either protein; henceforth we have named it “endorepellin.” We also found that endothelial cells possess a significant number of high affinity (Kd of 11 nm) binding sites for endorepellin and that endorepellin binds endostatin and counteracts its anti-angiogenic effects. Thus, endorepellin represents a novel anti-angiogenic product, which may retard tumor neovascularization and hence tumor growth in vivo.