Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan.
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 (K(d) 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.
Mongiat
Maurizio
M
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Sweeney
Shawn M
SM
San Antonio
James D
JD
Fu
Jian
J
Iozzo
Renato V
RV
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D003094:Collagen / Q000494:pharmacology; D043170:Collagen Type XVIII; D017931:DNA Primers; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D043170:Collagen Type XVIII; D017931:DNA Primers; D043169:Endostatins; D019812:Heparan Sulfate Proteoglycans; D010446:Peptide Fragments; D011994:Recombinant Proteins; C071927:perlecan; D003094:Collagen