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Abstract
Elastase released from neutrophils as part of the innate immune system has been implicated in chronic diseases such as emphysema and cardiovascular disease. We have previously shown that neutrophil elastase targets vascular endothelial growth factor-A (VEGF) for partial degradation to generate a fragment of VEGF (VEGFf) that has distinct activities. Namely, VEGFf binds to VEGF receptor 1 but not to VEGF receptor 2 and shows altered signaling compared to intact VEGF. In the present study we investigated the chemotactic function of VEGF and VEGFf released from cells by neutrophil elastase. We found that endothelial cells migrated in response to intact VEGF but not VEGFf whereas RAW 264.7 macrophages/monocytes and embryonic endothelial progenitor cells were stimulated to migrate by either VEGF or VEGFf. To investigate the role of elastase-mediated release of VEGF from cells/extracellular matrices, a co-culture system was established. High or low VEGF producing cells were co-cultured with macrophages, endothelial or endothelial progenitor cells and treated with neutrophil elastase. Elastase treatment stimulated macrophage and endothelial progenitor cell migration with the response being greater with the high VEGF expressing cells. However, elastase treatment led to decreased endothelial cell migration due to VEGF cleavage to VEGF fragment. These findings suggest that the tissue response to NE-mediated injury might involve the generation of diffusible VEGF fragments that stimulate inflammatory cell recruitment.
Highlights
The development and progression of pulmonary emphysema is characterized by tissue destruction, uncontrolled elastase activity, alveolar apoptosis, reduced alveolar capillary density and altered extracellular matrix (ECM) mechanics [1,2,3,4,5]
We have previously found that vascular endothelial growth factor-A (VEGF) is a substrate for neutrophil elastase (NE) cleavage leading to the generation of a VEGF fragment (VEGFf) that shows altered activity
Chemotaxis is a critical component of wound healing and inflammation, and VEGF has been shown to possess this activity for a variety of cell types including monocytes and endothelial cells
Summary
The development and progression of pulmonary emphysema is characterized by tissue destruction, uncontrolled elastase activity, alveolar apoptosis, reduced alveolar capillary density and altered extracellular matrix (ECM) mechanics [1,2,3,4,5]. We have previously found that VEGF is a substrate for neutrophil elastase (NE) cleavage leading to the generation of a VEGF fragment (VEGFf) that shows altered activity. It binds VEGFR1 and has lost the ability to bind to VEGFR2, the VEGF co-receptor, neuropilin (Nrp1), and fibronectin and heparan sulfate in the ECM [14, 15]. NE has been implicated in the generation of emphysema and has been shown to participate in pathologies such as arthritis, aneurysms, atherosclerosis and other chronic conditions related to alterations in structural tissues In all these diseases there is a significant vascular component associated with endothelial cell dysfunction. VEGF release from extracellular matrices might regulate inflammatory and progenitor cell recruitment and activity, modulating inflammatory response and potentially mediating tissue repair
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