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Cardiovasc Res. 2012 Apr 1;94(1):125-35. doi: 10.1093/cvr/cvs017. Epub 2012 Jan 26.

VEGF-induced endothelial cell migration requires urokinase receptor (uPAR)-dependent integrin redistribution.

Author information

1
Institute of Vascular Biology and Thrombosis Research, Vienna A-1090, Austria.

Abstract

AIMS:

Vascular endothelial growth factor (VEGF)-initiated angiogenesis requires coordinated proteolytic degradation of extracellular matrix provided by the urokinase plasminogen activator/urokinase receptor (uPA/uPAR) system and regulation of cell migration provided by integrin-matrix interaction. In this study, we investigated the mechanisms underlying the uPAR-dependent modulation of VEGF-induced endothelial migration.

METHODS AND RESULTS:

We used flow cytometry to quantify integrins at the cell surface. Stimulation of human and murine endothelial cells with VEGF resulted in internalization of α5β1-integrins. Micropatterning and immunocytochemistry revealed co-clustering of uPAR and α5β1-integrins and retrieval via clathrin-coated vesicles. It was also contingent on receptors of the low-density lipoprotein receptor (LDL-R) family. VEGF-induced integrin redistribution was inhibited by elimination of uPAR from the endothelial cell surface or by inhibitory peptides that block the uPAR-integrin interaction. Under these conditions, the migratory response of endothelial cells upon VEGF stimulation was impaired both in vitro and in vivo.

CONCLUSIONS:

The observations indicate that uPAR is an essential component of the network through which VEGF controls endothelial cell migration. uPAR is a bottleneck through which the VEGF-induced signal must be funnelled for both focused proteolytic activity at the leading edge and for redistribution of integrins.

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PMID:
22287577
PMCID:
PMC6176909
DOI:
10.1093/cvr/cvs017
[Indexed for MEDLINE]
Free PMC Article

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