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Event: 948

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

reduced production, VEGF

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
angioblastic mesenchymal cell

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
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

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
chicken	Gallus gallus	High	NCBI
mammals	mammals	High	NCBI
Japanese quail	Coturnix japonica	High	NCBI
zebrafish	Danio rerio	High	NCBI
Xenopus laevis	Xenopus laevis	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Embryo	High
Development	High
Adult	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Vascular endothelial growth factors (VEGFs) are a family of homodimeric glycoproteins that stimulate vasculogenesis and angiogenesis in various tissues^[1]. 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^[3]. The mammalian VEGF-A family has been extensively studied, and includes multiple splice variants, with VEGF₁₆₅ being the most abundantly expressed^[1].

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

VEGF proteins have been isolated and characterized in multiple species including mammals^[1,2,4], chicken^[4], Japanese quail^[6], Xenopus laevis^[7] 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^[1]. The avian and amphibian VEGF proteins are highly homologous to the mammalian VEGFs, wheres the fish homologue is less similar^[7]. Invertebrates, such as C. elegans and Drosophila also contain a VEGFR-like receptor^[7].

References

List of the literature that was cited for this KE description. More help

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