Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Aryl hydrocarbon receptor activation leading to embryolethality via cardiotoxicty||KE||Moderate|
Level of Biological Organization
How this Key Event works
During vasculogenesis, angioblasts, which express vascular endothelial growth factor (VEGF) receptor 2 (a.k.a. fetal liver kinase; Flk-1), are stimulated to proliferate and differentiate into endothelial cells by VEGF-A. These endothelial cells then assemble into patent capillary tubes via stimulation of VEGF receptor 1 (fms-like tyrosine kinase; Flt-1) by VEGF-A. The endothelial cells then are activated by angiogenic stimuli (such as basic fibroblast growth factor and VEGF-A) to migrate and proliferate, producing new capillary sprouts (Ivnitski-Steele and Walker 2005). Ftl-1 can also act as a decoy receptor to sequester VEGF-A from Flk-1; there is even an alternatively spliced form of this receptor1 (sFlt1) that is secreted (i.e. not membrane bound) and functions primarily as a decoy (Zygmunt et al. 2011).
One potent stimulus of the angiogenic process is tissue hypoxia; insufficient oxygen being delivered to the proliferating tissue leads to the stabilization of the transcription factor hypoxia inducible factor 1α (HIF-1α). Accumulation of HIF-1α leads to the transcriptional induction of angiogenic signaling factors and their receptors, including VEGF-A and flk-1, and the stimulation of angiogenesis (Ivnitski-Steele and Walker 2005).
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
VEGF-A protein can be measured by enzyme-linked immunosorbent assay, as described in Ivnitski-Steele et al. (2005).
Evidence Supporting Taxonomic Applicability
1. Ivnitski-Steele, I., and Walker, M. K. (2005). Inhibition of neovascularization by environmental agents. Cardiovasc. Toxicol. 5(2), 215-226.
2. Ivnitski-Steele, I. D., Friggens, M., Chavez, M., and Walker, M. K. (2005). 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibition of coronary vasculogenesis is mediated, in part, by reduced responsiveness to endogenous angiogenic stimuli, including vascular endothelial growth factor A (VEGF-A). Birth Defects Res. A Clin Mol. Teratol. 73(6), 440-446.
3. Zygmunt, T., Gay, C. M., Blondelle, J., Singh, M. K., Flaherty, K. M., Means, P. C., Herwig, L., Krudewig, A., Belting, H. G., Affolter, M., Epstein, J. A., and Torres-Vazquez, J. (2011). Semaphorin-PlexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1. Dev. Cell 21(2), 301-314.