Complex receptor-ligand dynamics control the response of the VEGF system to protease injury.
BACKGROUND
Vascular homeostasis and response to injury are dependent on the coordinated activity of growth factors such as vascular endothelial growth factor-A (VEGF). VEGF signaling is mediated by VEGF receptors 1 (VEGFR1) and 2 (VEGFR2). VEGF also binds to extracellular matrix (ECM) and neuropilin (NP), a cell surface glycoprotein that enhances VEGF binding to VEGFR2 while inhibiting VEGF-VEGFR1 interactions. Proteases such as neutrophil elastase release VEGF bound to ECM; however, this results in proteolytic processing of VEGF to a smaller species termed VEGF fragment (VEGFf). We hypothesized that the generation and presence of VEGFf would have significant effects on the binding distribution of VEGF.


RESULTS
We show that VEGFf, unlike VEGF, does not bind ECM, fibronectin, or NP-1. Using computational simulations, we find that excess VEGFf can lead to increased binding of VEGF to VEGFR2 through VEGFf binding to VEGFR1 and subsequent liberation of NP-1. We show experimentally that VEGF-induced migration has a biphasic response to conversion of VEGF to VEGFf. Simulations suggest that a simple change in VEGFR1 or VEGFR2 complexes are unlikely to be responsible and that a more complex integration of signals is more likely involved.


CONCLUSIONS
These findings suggest that proteolytic damage at sites of tissue injury and inflammation has the potential to modulate the VEGF system through a complex process and highlight the need for quantitative analysis to reveal mechanisms of growth factor control.
Department of Chemical Engineering, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA. kfw@vt.edu
Kimberly
K
Forsten-Williams
Elma
E
Kurtagic
Matthew A
MA
Nugent
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D003198:Computer Simulation; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D039921:Neuropilins / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism / Q000502:physiology; D060066:Protein Interaction Maps; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D049490:Systems Biology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D005353:Fibronectins; D008024:Ligands; D039921:Neuropilins; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D010196:Pancreatic Elastase