The soluble form of urokinase receptor promotes angiogenesis through its Ser88-Arg-Ser-Arg-Tyr92 chemotactic sequence

K. Bifulco, I. Longanesi-Cattani, M. Gala, G. Di Carluccio, M. T. Masucci, V. Pavone, L. Lista, C. Arra, M. P. Stoppelli, M. V. Carriero

Research output: Contribution to journalArticlepeer-review

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. Methods and 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 Ser88-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 αvβ3 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.

Original languageEnglish
Pages (from-to)2789-2799
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 2010

Keywords

  • Angiogenesis
  • Endothelial cell migration
  • Formyl-peptide receptor
  • Soluble urokinase receptor
  • Vitronectin receptor

ASJC Scopus subject areas

  • Hematology

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