title: The soluble form of urokinase receptor promotes angiogenesis through its Ser⁸⁸-Arg-Ser-Arg-Tyr⁹² chemotactic sequence.
abstract: BACKGROUND
  The urokinase plasminogen activator receptor (u-PAR) focuses the proteolytic activity of the urokinase plasminogen activator (u-PA) on the endothelial cell surface, thus promoting angiogenesis in a protease-dependent manner. The u-PAR may exist in a glycophosphatidylinositol-anchored and in a soluble form (soluble u-PAR [Su-PAR]), both including the chemotactic Ser⁸⁸ -Arg-Ser-Arg-Tyr⁹² internal sequence.
  
  
  OBJECTIVE
  To investigate whether Su-PAR may trigger endothelial cell signaling leading to new vessel formation through its chemotactic Ser⁸⁸ -Arg-Ser-Arg-Tyr⁹² sequence.
  
  
  RESULTS
  In this study, the formation of vascular-like structures by human umbilical vein endothelial cells was assessed by using a matrigel basement membrane preparation. First, we found that Su-PAR protein promotes the formation of cord-like structures, and that this ability is retained by the isolated Ser(88) -Arg-Ser-Arg-Tyr⁹² chemotactic sequence, the maximal effect being reached at 10 nmol L⁻¹ SRSRY peptide (SRSRY). This effect is mediated by the α(v) β₃ vitronectin receptor, is independent of u-PA proteolytic activity, and involves the internalization of the G-protein-coupled formyl-peptide receptor in endothelial cells. Furthermore, exposure of human saphenous vein rings to Su-PAR or SRSRY leads to a remarkable degree of sprouting. Finally, we show that Su-PAR and SRSRY promote a marked response in angioreactors implanted into the dorsal flank of nude mice, retaining 91% and 66%, respectively, of the angiogenic response generated by a mixture of vascular endothelial growth factor and fibroblast growth factor type 2.
  
  
  CONCLUSIONS
  Our results show a new protease-independent activity of Su-PAR that stimulates in vivo angiogenesis through its Ser⁸⁸ -Arg-Ser-Arg-Tyr⁹² chemotactic sequence.
authors.affiliation: Department of Experimental Oncology, National Cancer Institute of Naples, Naples, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Bifulco
authors.forename: I
authors.initials: I
authors.lastname: Longanesi-Cattani
authors.forename: M
authors.initials: M
authors.lastname: Gala
authors.forename: G
authors.initials: G
authors.lastname: DI Carluccio
authors.forename: M T
authors.initials: MT
authors.lastname: Masucci
authors.forename: V
authors.initials: V
authors.lastname: Pavone
authors.forename: L
authors.initials: L
authors.lastname: Lista
authors.forename: C
authors.initials: C
authors.lastname: Arra
authors.forename: M P
authors.initials: MP
authors.lastname: Stoppelli
authors.forename: M V
authors.initials: MV
authors.lastname: Carriero
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002633:Chemotaxis; D018920:Coculture Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D012995:Solubility
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator