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Key Event Title
reduced production, VEGF
|Level of Biological Organization|
|angioblastic mesenchymal cell|
Key Event Components
|gene expression||vascular endothelial growth factor A||decreased|
|abnormal protein level||vascular endothelial growth factor A||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|AHR activation to ELS mortality, via VEGF||KeyEvent||Arthur Author (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|AhR activation leading to preeclampsia||KeyEvent||Agnes Aggy (send email)||Under development: Not open for comment. Do not cite||Under Development|
Key Event Description
Vascular endothelial growth factors (VEGFs) are a family of homodimeric glycoproteins that stimulate vasculogenesis and angiogenesis in various tissues. They play vital roles in fetal development and increased oxygen supply in response to tissue injury and hypoxic stress[1,2]. VEGFs signal through cell surface receptor tyrosine kinases: VEGFR-1, VEGFR-2 and VEGFR-3 (Figure 1), which play critical roles in haematopoietic cell development, vascular endothelial cell development and lymphatic endothelial cell development, respectively. The mammalian VEGF-A family has been extensively studied, and includes multiple splice variants, with VEGF165 being the most abundantly expressed.
Figure 1: VEGF family members and their respective receptors (Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain. Retrieved 24/05/2017)
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 protein can be measured by enzyme-linked immunosorbent assay (Ivnitski-Steele et al. (2005), immunihistochemistry or western blot (Li et al. 2016).
VEGF gene expression, which is directly correlated with protein levels, can be measured by quantitative real-time polymerase chain reaction (QPCR) (Medford et al. 2009).
Domain of Applicability
VEGF proteins have been isolated and characterized in multiple species including mammals[1,2,4], chicken, Japanese quail, Xenopus laevis and zebrafish[4,5,7]; VEGF165 in particular is highly conserved among species with >95% homology between the human transcript and bovine, ovine and murine variants. The avian and amphibian VEGF proteins are highly homologous to the mammalian VEGFs, wheres the fish homologue is less similar. Invertebrates, such as C. elegans and Drosophila also contain a VEGFR-like receptor.
1. Cecilia Y. Cheung (1997) Vascular Endothelial Growth Factor: Possible Role in Fetal Development and Placental Function. J Soc Gynecol Invest. 4: 169-77
2. Ahluwalia, A., and Tarnawski, A. S. (2012). Critical role of hypoxia sensor--HIF-1alpha in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr. Med. Chem. 19(1), 90-97.
3. Holmes, K., Roberts, O. L., Thomas, A. M., and Cross, M. J. (2007). Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 19(10), 2003-2012.
4. 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.
5. Zhu, D., Fang Y., Gao, K., Shen, J., Zhong, T.P., and Li, F. (2017) Vegfa Impacts Early Myocardium Development in Zebrafish. Int J Mol Sci. 18(2): 444.
6. Eichmann, A., Marcelle, C., Breant, C., and Le Douarin, N.M. (1996). Molecular cloning of Quek 1 and 2, two quail vascular endothelial growth factor (VEGF) receptor-like molecules. Gene 174, 3–8.
7. Masabumi Shibuya (2002) Vascular Endothelial Growth Factor Receptor Family Genes: When Did the Three Genes Phylogenetically Segregate? Biol. Chem., 383: 1573 – 1579.
8. Li, X.; Liu, X.; Guo, H.; Zhao, Z.; Li, Y.S. and Chen, G. (2016) The significance of the increased expression of phosphorylated MeCP2 in the membranes from patients with proliferative diabetic retinopathy. Scientific Reports, volume 6, Article number: 32850. 10.1038/srep32850
9. Medford, A. R., Douglas, S. K., Godinho, S. I., Uppington, K. M., Armstrong, L., Gillespie, K. M., van Zyl, B., Tetley, T.D., Ibrahim, N.B.N. and Millar, A. B. (2009). Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury. Respiratory Research, 10(1), 27. http://doi.org/10.1186/1465-9921-10-27