This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
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 ligand production, ligand binding, receptor tyrosine kinase activity, or crosstalk with angiogenic chemokines, cytokines and growth factors.
How It Is Measured or Detected
Analysis of basal VEGFR-2 expression under different physiological and toxicological contexts can be determined by standard array-based to define regulation of the angiogenic transcriptome, as well as targeted non-array methods to characterize cell-specific profiles during in vivo and in vitro development [Dumont et al. 1995; Abbott et al. 2000; Drake et al. 2007; Murakami et al. 2011]. In addition, the ontogenetic profile of VEGFR-1 and VEGFR-2 expression can be mapped in reporter zebrafish embryos whereby the EGFP gene is expressed under specific control of Flk or Flt gene regulatory elements [Shirinifard et al. 2013; Tal et al. 2014]. Zebrafish possess 72 orthologs for 70% of human genes and 86% of 1318 human drug targets. Transgenic zebrafish that express EGFP in developing blood vessels are: (1) fit for purpose of visualizing blood vessel formation during early development; (2) localize and quantitate regional effects of chemicals on a phenotypic readout of angiogenic vessel formation; (3) assess the reproducibility of vascular disruption across species; and (4) evaluation of the half-maximal inhibitory concentration (AC50) from a concentration-response curve.