Identification of heparin affin regulatory peptide domains with potential role on angiogenesis.
Heparin affin regulatory peptide (HARP) is a growth factor displaying high affinity for heparin. It is present in the extracellular matrix of many tissues, interacting with heparan sulfate and dermatan/chondroitin sulfate glycosaminoglycans. We have previously shown that HARP is implicated in the control of angiogenesis and its effects are mimicked, at least in part, by synthetic peptides that correspond to its N and C termini. In the present work, we show that HARP is cleaved by plasmin, leading to the production of five peptides that correspond to distinct domains of the molecule. Heparin, heparan sulfate and dermatan sulfate, at various HARP to glycosaminoglycan ratios, partially protect HARP from plasmin degradation. The molecules with higher affinity to HARP are the more protective, heparin being the most efficient. The peptides that are produced from cleavage of HARP by plasmin, affect in vivo and in vitro angiogenesis and modulate the angiogenic activity of vascular endothelial growth factor on human umbilical vein endothelial cells. Similar results were obtained in vitro with recombinant HARP peptides, identical to the peptides generated after treatment of HARP with plasmin. These results suggest that different regions of HARP may induce or inhibit angiogenesis.
Polykratis
Apostolos
A
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, GR 26504, Greece.
Delbé
Jean
J
Courty
José
J
Papadimitriou
Evangelia
E
Katsoris
Panagiotis
P
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D002642:Chick Embryo; D016207:Cytokines / Q000737:chemistry* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005341:Fibrinolysin / Q000378:metabolism; D006025:Glycosaminoglycans / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002352:Carrier Proteins; D016207:Cytokines; D006025:Glycosaminoglycans; D010446:Peptide Fragments; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C066845:pleiotrophin; D006493:Heparin; D005341:Fibrinolysin