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

Autor: 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
Rok vydání: 2010
Předmět:
Zdroj: Journal of thrombosis and haemostasis : JTH. 8(12)
ISSN: 1538-7836
Popis: 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.To investigate whether Su-PAR may trigger endothelial cell signaling leading to new vessel formation through its chemotactic Ser⁸⁸ -Arg-Ser-Arg-Tyr⁹² sequence.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.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.
Databáze: OpenAIRE
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