Schematic representation of elastase-mediated VEGFf generation, release and recruitment of circulating cells to the injured tissue.

<p>VEGF is stored in the extracellular matrix (ECM). Neutrophils are the first innate immune cells to be recruited to the site of injury and secrete proteases (e.g. neutrophil elastase). Neutrophil elastase is able to modulate VEGF dynamics within ECM by degrading fibronectin (FN) and heparan sulfate proteoglycan (HSPGs) binding sites in the ECM as well as by directly cleaving VEGF and releasing VEGFf to act on surrounding cells [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145115#pone.0145115.ref014" target="_blank">14</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145115#pone.0145115.ref015" target="_blank">15</a>]. The extent of proteolytic injury would dictate the ratio of intact and cleaved VEGF being released. As such, endothelial tissue repair would be promoted through VEGF/VEGFf acting on neighboring endothelial cells and circulating endothelial progenitor cells, promoting neo/angiogenesis. In the event of extensive proteolytic injury, the majority of released VEGF might be the more diffusible VEGFf, preferentially binding to VEGFR1 on macrophage/monocytic cells, leading to their recruitment, propagation of the inflammatory response and excessive proteolytic tissue degradation. This schematic representation is simplified and is not intended to exclude the possibility that other proteases (e.g., MMPs) may also influence VEGF release during tissue injury and inflammation.