In vivo angiogenic activity of urokinase: Role of endogenous fibroblast growth factor-2

Domenico Ribatti, Daria Leali, Angelo Vacca, Roberta Giuliani, Anna Gualandris, Luisa Roncali, Maria Luisa Nolli, Marco Presta

Research output: Contribution to journalArticlepeer-review

Abstract

In vitro experimental evidences suggest that the proteolytic degradation of the extracellular matrix (ECM) by activation of the urokinase-type plasminogen activator (uPA)/plasmin system may affect growth factor activity and bioavailability. However, no direct in vivo observations were available to support this hypothesis. Here we demonstrate that endothelial GM 7373 cells overexpressing human uPA (uPA-R5 cells) cause the release of 125I-labeled fibroblast growth factor-2 (FGF2) from endothelial ECM in a plasmin-dependent manner. Accordingly, uPA-R5 cells are angiogenic in vivo when applied on the top of the chorioallantoic membrane (CAM) of the chick embryo. In contrast, mock-transfected Neo2 cells are unable to release ECM-bound 125I-FGF2 and are poorly angiogenic. Neovascularization elicited by uPA-R5 cells is significantly reduced by neutralizing anti-FGF2 antibodies to values similar to those observed in Neo2 cell-treated CAMs. Accordingly, purified human uPA stimulates neovascularization of the CAM in the absence of an inflammatory response. The angiogenic activity of uPA is significantly inhibited by neutralizing anti-FGF2 antibodies or by pretreatment with phenylmethylsulfonyl fluoride. The non-catalytic, receptor-binding aminoterminal fragment of uPA is instead non angiogenic. Taken together, the data indicate that uPA is able to induce angiogenesis in vivo via a plasmin-dependent degradation of ECM that causes the mobilization of stored endogenous FGF2.

Original languageEnglish
Pages (from-to)4213-4221
Number of pages9
JournalJournal of Cell Science
Volume112
Issue number23
Publication statusPublished - 1999

Keywords

  • Angiogenesis
  • Chick embryo
  • Extracellular matrix
  • FGF
  • Fibrinolysis
  • Urokinase

ASJC Scopus subject areas

  • Cell Biology

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