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

Blood. 2011 Sep 29;118(13):3743-55. Epub 2011 Jul 29. Endothelial progenitor cell-dependent angiogenesis requires localization of the full-length form of uPAR in caveolae. Margheri F, Chillà A, Laurenzana A, Serratì S, Mazzanti B, Saccardi R, Santosuosso M, Danza G, Sturli N, Rosati F, Magnelli L, Papucci L, Calorini L, Bianchini F, Del Rosso M, Fibbi G. Source Department of Experimental Pathology and Oncology, University of Florence Istituto Toscano Tumori, Florence, Italy. 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 colony-forming 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 caveolae-disrupting 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. PMID: 21803847 [PubMed - indexed for MEDLINE]