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Relationship: 974

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 dimerization, ARNT/HIF1-alpha leads to reduced production, VEGF

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 Moderate Moderate Amani Farhat (send email) Open for citation & comment WPHA/WNT Endorsed
AhR activation leading to preeclampsia adjacent Sabrina Tait (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 Do not cite Under Development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 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
mouse Mus musculus 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
During development and at adulthood 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

Dimerization between AHR nuclear translocator (ARNT) and hypoxia inducible factor 1 alpha (HIF-1α) forms a transcription factor complex (HIF-1) that binds to hypoxia response enhancer sequences on DNA to activate the expression of angiogenic factors including vascular endothelial growth factor (VEGF) (Fong 2009). The HIF-1 complex binds to the VEGF gene promoter, then recruits additional transcriptional factors such as P-CREB and P-STAT3, to the promoter and initiates VEGF transcription (Ahluwalia and Tarnawski 2012).  In the absence of HIF-1, VEGF expression and secretion is diminished.

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 transcriptional control of VEGF by HIF-1 is well understood (Ahluwalia and Tarnawski 2012; Fong 2009)

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
  • ARNT knock-out in mice (effectively null for HIF-1) show disrupted angiogenesis and reduced VEGF expression (Maltepe et al. 1997); however, HIF-1α null mice (also effectively null for HIF-1) show disrupted angiogenesis with a slight increase in VEGF expression (Compernolle et al. 2003).  This may indicate that alternate, compensatory mechanisms for transcriptional regulation of VEGF exist, which are HIF-1α-independent but ARNT dependent.
  • There is also the potential for HIF-1-independent regulation of VEGF, as illustrated in an ARNT-deficient mutant cell line (Hepa1 C4) in which VEGF expression was only partially abrogated (Gassmann et al. 1997).
  • It has been reported that the AHR/ARNT heterodimer binds to estrogen response elements, with mediation of the estrogen receptor (ER), and activates transcription of VEGF-A (Ohtake et al. 2003). The potential involvement of AHR in opposing regulatory cascades (directly inducing VEGF through ER and indirectly suppressing it by ARNT sequestration) also helps explain conflicting results found in the literature.

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

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Transcriptional regulation of VEGF by the HIF-1 complex has been demonstrated in chicken embryos (Cheung 1997; Ivnitski-Steele et al. 2004),  Baltic salmon (Vuori et al. 2004), mice (Maltepe et al. 1997) and rats (Levy et al.1995).  This KER is likely applicable in general to birds, fish and mammals based on the conserved nature of the VEGF gene (Masabumi Shibuya 2002).

References

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

1. 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.

2. Cheung, C. Y. (1997). Vascular endothelial growth factor: possible role in fetal development and placental function. J Soc. Gynecol. Investig. 4(4), 169-177.

3. Fong, G. H. (2009). Regulation of angiogenesis by oxygen sensing mechanisms. J Mol. Med. (Berl) 87(6), 549-560.

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., Sanchez, A., and Walker, M. K. (2004). 2,3,7,8-tetrachlorodibenzo-p-dioxin reduces myocardial hypoxia and vascular endothelial growth factor expression during chick embryo development. Birth Defects Res. A Clin. Mol. Teratol. 70(2), 51-58.

6. Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., and Semenza, G. L. (1998). Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 12(2), 149-162.

7. Maltepe, E., Schmidt, J. V., Baunoch, D., Bradfield, C. A., and Simon, M. C. (1997). Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386(6623), 403-407.

8. Roman, A. C., Carvajal-Gonzalez, J. M., Rico-Leo, E. M., and Fernandez-Salguero, P. M. (2009). Dioxin receptor deficiency impairs angiogenesis by a mechanism involving VEGF-A depletion in the endothelium and transforming growth factor-beta overexpression in the stroma. J Biol. Chem 284(37), 25135-25148.

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

10. Maltepe, E., Achmidt, J.V., Baunoch, D, Bradfield, C.A., ad Simon, M.C. (1997) Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386 (6623). p.403 - 407.

11. Levy, A. P., Levy, N. S., Wegner, S., and Goldberg, M. A. (1995). Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J. Biol. Chem. 270(22), 13333-13340.

12. Compernolle, V., Brusselmans, K., Franco, D., Moorman, A., Dewerchin, M., Collen, D., and Carmeliet, P. (2003). Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1alpha. Cardiovasc. Res. 60(3), 569-579.

13. Gassmann, M., Kvietikova, I., Rolfs, A., and Wenger, R. H. (1997). Oxygen- and dioxin-regulated gene expression in mouse hepatoma cells. Kidney Int. 51(2), 567-574.

14. Ohtake, F., Takeyama, K., Matsumoto, T., Kitagawa, H., Yamamoto, Y., Nohara, K., Tohyama, C., Krust, A., Mimura, J., Chambon, P., Yanagisawa, J., Fujii-Kuriyama, Y., and Kato, S. (2003). Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423(6939), 545-550.

15. Masabumi Shibuya (2002) Vascular Endothelial Growth Factor Receptor Family Genes: When Did the Three Genes Phylogenetically Segregate? Biol. Chem., 383: 1573 – 1579