Endothelial progenitor cell - Dependent angiogenesis requires localization of the full-length form of uPAR in caveolae

Francesca Margheri, Anastasia Chillà, Anna Laurenzana, Simona Serratì, Benedetta Mazzanti, Riccardo Saccardi, Michela Santosuosso, Giovanna Danza, Niccolò Sturli, Fabiana Rosati, Lucia Magnelli, Laura Papucci, Lido Calorini, Francesca Bianchini, Mario Del Rosso, Gabriella Fibbi

Research output: Contribution to journalArticlepeer-review

Abstract

Endothelial urokinase-type plasminogen activator receptor (uPAR) is thought to provide a regulatory mechanism in angiogenesis. Here we studied the proangiogenic role of uPAR in endothelial colonyforming cells (ECFCs), a cell population identified in human umbilical blood that embodies all of the properties of an endothelial progenitor cell matched with a high proliferative rate. By using caveolaedisrupting agents and by caveolin-1 silencing, we have shown that the angiogenic properties of ECFCs depend on caveolae integrity and on the presence of full-length uPAR in such specialized membrane invaginations. Inhibition of uPAR expression by antisense oligonucleotides promoted caveolae disruption, suggesting that uPAR is an inducer of caveolae organization. Vascular endothelial growth factor (VEGF) promoted accumulation of uPAR in ECFC caveolae in its undegraded form. We also demonstrated that VEGF-dependent ERK phosphorylation required integrity of caveolae as well as caveolar uPAR expression. VEGF activity depends on inhibition of ECFC MMP12 production, which results in impairment of MMP12-dependent uPAR truncation. Further, MMP12 overexpression in ECFC inhibited vascularization in vitro and in vivo. Our data suggest that intratumor homing of ECFCs suitably engineered to overexpress MMP12 could have the chance to control uPAR-dependent activities required for tumor angiogenesis and malignant cells spreading.

Original languageEnglish
Pages (from-to)3743-3755
Number of pages13
JournalBlood
Volume118
Issue number13
DOIs
Publication statusPublished - Sep 29 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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