Key Event Title
Key Event Component
|gene expression||vascular endothelial growth factor A||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Aryl hydrocarbon receptor activation leading to embryolethality via cardiotoxicty||KeyEvent|
Level of Biological Organization
|angioblastic mesenchymal cell|
Life Stage Applicability
How This Key Event Works
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-A protein can be measured by enzyme-linked immunosorbent assay, as described in Ivnitski-Steele et al. (2005).
Evidence Supporting Taxonomic Applicability
VEGF proteins have been isolated and charachterized in multiple species including mammals, birds and fish[1,2,4,5]; VEGF165 in particular is highly conserved among species with >95% homology between the human transcript and bovine, ovine and murine variants.
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.