Key Event Title
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
Vascular endothelial growth factor A (VEGF-A) is a soluble protein that acts directly on endothelial cells through two receptor tyrosine kinases: VEGFR-1 (Flt-1) and VEGFR-2 (KDR). The former is a decoy receptor that traps VEGF-A into corridors preventing interaction with the active receptor, VEGFR-2. When liganded, VEGFR-2 induces endothelial proliferation, survival, and vascular permeability. The specific MIE considered here is disruption of VEGFR-2 or other transcriptional regulators leading to a change in VEGF-A response. This would include a change in the local production of VEGF-A, an increase in the decoy receptor (VEGFR-1), or a drop in the expression or activity of VEGFR-2.Chemical effects may commence at VEGF receptors (VEGFRs) by influencing local VEGF-A ligand production, ligand binding, receptor tyrosine kinase activity, or crosstalk with angiogenic chemokines, cytokines and growth factors.
VEGF-A can be trapped in the extracellular milieu by binding to components in the extracellular matrix (ECM) or by the decoy receptor, VEGFR-1. VEGFR-1 binds VEGF-A with 10-fold greater affinity than does VEGFR-2. VEGF-A can be liberated by ECM breakdown during morphogenetic remodeling of tissues or upon stimulation of matrix metalloproteinase (MMP) production during chemical injury. These events can positively or negatively regulate the local bioavailability of VEGF-A to its cognate receptor (VEGF-A).
How It Is Measured or Detected
Proximity Ligation Assays have been used to identify small molecule inhibitors of VEGF-A binding to its receptors [Gustafsdottir et al. 2008]. This assay is: (1) fit for the purpose of monitoring the formation and inhibition of VEGF-A–receptor complexes; (2) defines chemical disruption of VEGF-A direct binding to its receptors (VEGFR-1, VEGFR-2); (3) correlates well with results obtained by measuring receptor phosphorylation (VEGFR-2); and (4) allows evaluation of the half-maximal inhibitory concentration (AC50) from a concentration-response curve.
Domain of Applicability
Gustafsdottir SM, Wennstrom S, Fredriksson S, Schallmeiner E, Hamilton AD, Sebti SM, et al. Use of proximity ligation to screen for inhibitors of interactions between vascular endothelial growth factor A and its receptors. Clinical chemistry. 2008;54(7):1218-25.