title: An IP-10 (CXCL10)-derived peptide inhibits angiogenesis.
abstract: Angiogenesis plays a critical role in processes such as organ development, wound healing, and tumor growth. It requires well-orchestrated integration of soluble and matrix factors and timely recognition of such signals to regulate this process. Previous work has shown that newly forming vessels express the chemokine receptor CXC receptor 3 (CXCR3) and, activation by its ligand IP-10 (CXCL10), both inhibits development of new vasculature and causes regression of newly formed vessels. To identify and develop new therapeutic agents to limit or reverse pathological angiogenesis, we identified a 21 amino acid fragment of IP-10, spanning the α-helical domain residues 77-98, that mimic the actions of the whole IP-10 molecule on endothelial cells. Treatment of the endothelial cells with the 22 amino acid fragment referred to as IP-10p significantly inhibited VEGF-induced endothelial motility and tube formation in vitro, properties critical for angiogenesis. Using a Matrigel plug assay in vivo, we demonstrate that IP-10p both prevented vessel formation and induced involution of nascent vessels. CXCR3 neutralizing antibody was able to block the inhibitory effects of the IP-10p, demonstrating specificity of the peptide. Inhibition of endothelial function by IP-10p was similar to that described for IP-10, secondary to CXCR3-mediated increase in cAMP production, activation of PKA inhibiting cell migration, and inhibition of VEGF-mediated m-calpain activation. IP-10p provides a novel therapeutic agent that inhibits endothelial cell function thus, allowing for the modulation of angiogenesis.
authors: Tuskegee University, Center for Cancer Research, Tuskegee, Alabama, United States of America. cey4@pitt.edu
authors: Cecelia C
authors: CC
authors: Yates-Binder
authors: Margaret
authors: M
authors: Rodgers
authors: Jesse
authors: J
authors: Jaynes
authors: Alan
authors: A
authors: Wells
authors: Richard J
authors: RJ
authors: Bodnar
authors: Timothy
authors: T
authors: Turner
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000737:chemistry*; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D054367:Receptors, CXCR3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D057134:Antibodies, Neutralizing; D054357:Chemokine CXCL10; D010455:Peptides; D054367:Receptors, CXCR3; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases