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Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors

Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular... Vascular endothelial growth factor (VEGF) is a critical mediator of blood vessel formation during development and in pathological conditions. In this study, we demonstrate that VEGF bioavailability is regulated extracellularly by matrix metalloproteinases (MMPs) through intramolecular processing. Specifically, we show that a subset of MMPs can cleave matrix-bound isoforms of VEGF, releasing soluble fragments. We have mapped the region of MMP processing, have generated recombinant forms that mimic MMP-cleaved and MMP-resistant VEGF, and have explored their biological impact in tumors. Although all forms induced similar VEGF receptor 2 phosphorylation levels, the angiogenic outcomes were distinct. MMP-cleaved VEGF promoted the capillary dilation of existent vessels but mediated a marginal neovascular response within the tumor. In contrast, MMP-resistant VEGF supported extensive growth of thin vessels with multiple and frequent branch points. Our findings support the view that matrix-bound VEGF and nontethered VEGF provide different signaling outcomes. These findings reveal a novel aspect in the regulation of extracellular VEGF that holds significance for vascular patterning. Footnotes Abbreviations used in this paper: CAM, chorioallantoic membrane; HEK, human embryonic kidney; MALDI-TOF MS, matrix-assisted laser desorption time-of-flight MS; MMP, matrix metalloproteinase; μLC/MS n , capillary and microcapillary nano–liquid chromatography MS; μLC/MS/MS, microcapillary reverse-phase HPLC nano-electrospray tandem MS; MS, mass spectrometry; PAE, porcine aortic endothelial; PAE-VEGFR2, PAE cells expressing VEGFR2; PECAM, platelet/endothelial cell adhesion molecule 1; TIMP, tissue inhibitor of MPs; VEGFR2, VEGF receptor 2. Submitted: 20 September 2004 Accepted: 4 March 2005 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Cell Biology Rockefeller University Press

Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors

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References (54)

Publisher
Rockefeller University Press
Copyright
© 2005 Rockefeller University Press
ISSN
0021-9525
eISSN
1540-8140
DOI
10.1083/jcb.200409115
pmid
15911882
Publisher site
See Article on Publisher Site

Abstract

Vascular endothelial growth factor (VEGF) is a critical mediator of blood vessel formation during development and in pathological conditions. In this study, we demonstrate that VEGF bioavailability is regulated extracellularly by matrix metalloproteinases (MMPs) through intramolecular processing. Specifically, we show that a subset of MMPs can cleave matrix-bound isoforms of VEGF, releasing soluble fragments. We have mapped the region of MMP processing, have generated recombinant forms that mimic MMP-cleaved and MMP-resistant VEGF, and have explored their biological impact in tumors. Although all forms induced similar VEGF receptor 2 phosphorylation levels, the angiogenic outcomes were distinct. MMP-cleaved VEGF promoted the capillary dilation of existent vessels but mediated a marginal neovascular response within the tumor. In contrast, MMP-resistant VEGF supported extensive growth of thin vessels with multiple and frequent branch points. Our findings support the view that matrix-bound VEGF and nontethered VEGF provide different signaling outcomes. These findings reveal a novel aspect in the regulation of extracellular VEGF that holds significance for vascular patterning. Footnotes Abbreviations used in this paper: CAM, chorioallantoic membrane; HEK, human embryonic kidney; MALDI-TOF MS, matrix-assisted laser desorption time-of-flight MS; MMP, matrix metalloproteinase; μLC/MS n , capillary and microcapillary nano–liquid chromatography MS; μLC/MS/MS, microcapillary reverse-phase HPLC nano-electrospray tandem MS; MS, mass spectrometry; PAE, porcine aortic endothelial; PAE-VEGFR2, PAE cells expressing VEGFR2; PECAM, platelet/endothelial cell adhesion molecule 1; TIMP, tissue inhibitor of MPs; VEGFR2, VEGF receptor 2. Submitted: 20 September 2004 Accepted: 4 March 2005

Journal

The Journal of Cell Biology – Rockefeller University Press

Published: May 23, 2005

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