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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, generated recombinant forms that mimic MMP-cleaved and MMP-resistant VEGF, and explored their biological impact in tumors. Although all forms induced similar VEGF receptor 2 (VEGFR2) phosphorylation levels, the angiogenic outcomes and impact on tumor growth were distinct. MMP-cleaved VEGF promoted 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. Interestingly, MMP-resistant VEGF tumors grew faster and bigger, while MMP-cleaved VEGF tumors grew slower, smaller and macrospically pale. Our findings support the view that matrix-bound VEGF and non-tethered VEGF provide different signaling outcomes and, extracellular VEGF processing offers an important mode for regulation in soluble versus bound VEGF levels in addition to splicing events.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual summary rept. 16 Apr 2002-14 Apr 2005 |
| Pages: |
26 |
| Report Date: |
19 OCT 2005 |
| Contract Number: |
DAMD170210328 |
| Report Number: |
A871834 |
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