Decreased, VegfR2

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.

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.