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

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.

Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

“…MMP19 was reported to efficiently cleave VEGF into smaller fragments. 33 However, the reduced expression of VEGF in the conditioned media with WT MMP19 in this study was not likely due to the cleaving activity of the MMP19 on VEGF, since no small fragments were detected in conditioned media of WT MMP19 clones. Instead, MMP19 may down-regulate VEGF secretion by retaining VEGF in the ECM.…”

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

“…This finding was initially unexpected, as the PDGF-DD(GFD) more potently transformed NIH/3T3 cells in vitro. However, considering that altered pericellular retention and/or matrix interactions are important determinants for the physiological action of many other growth factors (LaRochelle et al, 1991;Ostman et al, 1991;Carmeliet et al, 1999;Grunstein et al, 2000;Lindblom et al, 2003;Lee et al, 2005), this could be a likely mechanism for controlling the function of PDGF-DD as well. In line with this, one could speculate that the observed differences in foci morphology induced by the two PDGF-DD forms are due to different spatial distribution, especially as we have previously shown that smaller and unevenly shaped foci can be formed from NIH/3T3 cells overexpressing matrix-bound PDGF-BB (Li et al, 2003).…”

Matrix metalloproteinases and the regulation of tissue remodelling

“…Uncleaved VEGF is enriched in at least one MMP9-mutant postnatal tissue, the hypertrophic chondrocyte zone 38 , which indicates that VEGF is an important downstream effector, and possibly a substrate, of MMP9. Truncated VEGF has different effects on tumour blood vessels than does uncleavable VEGF; truncated VEGF increases vessel diameter, whereas uncleavable VEGF increases vessel sprouting 64 . Mmp9-null mice display defective post-embryonic neovasculature, suggesting that in wild-type mice, postnatal blood vessels respond differently to cleaved and uncleaved forms of VEGF.…”

“…d | MMPs can activate or modify the action of latent signalling molecules, resulting in diverse cellular consequences. For example, cleavage of vascular endothelial growth factor (VEGF) by MMPs changes angiogenic outcome by modifying the binding and diffusion properties of VEGF 64 . e | MMPs can deactivate or modify the action of active signalling molecules, resulting in changes in proliferation, cell death, differentiation or cell motility.…”