API

Event: 304

Key Event Title

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Decreased, VegfR2

Short name

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Decreased, VegfR2

Key Event Component

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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Level of Biological Organization

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Taxonomic Applicability

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Sex Applicability

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How This Key Event Works

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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

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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.


Evidence Supporting Taxonomic Applicability

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References

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