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Relationship: 975

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

reduced production, VEGF leads to Impairment, Endothelial network

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Aryl hydrocarbon receptor activation leading to early life stage mortality, via reduced VEGF adjacent High Low Amani Farhat (send email) Open for citation & comment WPHA/WNT Endorsed

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
chicken Gallus gallus High NCBI
mammals mammals High NCBI
zebrafish Danio rerio High NCBI
Salmo salar Salmo salar High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Embryo High
Development High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

During vasculogenesis, angioblasts, which express vascular endothelial growth factor (VEGF) receptor 2 (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).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The importance of VEGF for endothelial network formation and integrity is clear (Ivnitski-Steele and Walker 2005); loss of a single VEGF-A allele results in defective vascularization and early embryonic lethality (Carmeliet et al. 1996; Ferrara et al. 1996).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Reduced secretion of VEGF is not the sole mechanism responsible for reduced coronary vasculogenesis as TCDD caused a dose-related reduction in tube outgrowth in vitro but all doses reduced VEGF-A secretion equally (Ivnitski-Steele et al. 2005).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The role of VEGF in vasculogenesis and angiogenesis (which include endothelial cell formation, migration and assemply) has been demostrated in chicken[4], zebrafish[8], Baltic salmon[9] and mammals[7].

References

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

1. Carmeliet, P., Ferreira, V., Breier, G., Pollefeyt, S., Kieckens, L., Gertsenstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Eberhardt, C., Declercq, C., Pawling, J., Moons, L., Collen, D., Risau, W., and Nagy, A. (1996). Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573), 435-439.

2. Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O'Shea, K. S., Powell-Braxton, L., Hillan, K. J., and Moore, M. W. (1996). Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380(6573), 439-442.

3. Ivnitski-Steele, I., and Walker, M. K. (2005). Inhibition of neovascularization by environmental agents. Cardiovasc. Toxicol. 5(2), 215-226.

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. Ivnitski-Steele, I. D., and Walker, M. K. (2003). Vascular endothelial growth factor rescues 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibition of coronary vasculogenesis. Birth Defects Res. A Clin Mol. Teratol. 67(7), 496-503.

6. Cecilia Y. Cheung (1997) Vascular Endothelial Growth Factor: Possible Role in Fetal Development and Placental Function. J Soc Gynecol Invest. 4: 169-77

7. 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.

8. 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.

9. Vuori, K.A.M., Soitamo, A., Vuorinen, P.J., and Nikinmaa, M. (2004) Baltic salmon (Salmo salar) yolk-sac fry mortality is associated with disturbances in the function of hypoxia-inducible transcription factor (HIF-1α) and consecutive gene expression. Aquatic Toxicology 68: 301–313