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Relationship: 2780

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

Energy Deposition leads to Increase, Endothelial Dysfunction

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
Deposition of energy leads to vascular remodeling non-adjacent Moderate Low Vinita Chauhan (send email) Open for citation & comment

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
human Homo sapiens Low NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI
rabbit Oryctolagus cuniculus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male Moderate
Female Moderate
Unspecific Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate
Juvenile Low
Not Otherwise Specified Moderate

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

Energy deposition can lead to ionization events that can directly interact with molecules within the cell and can subsequently lead to biological changes such as the formation of free radicals and the initiation of DNA damage repair mechanisms. Different radiation types have different physical properties and as a result the biological effects on cells may differ. Dose and dose rate of the deposited energy also play a role as these factors affect the amount and rate of energy deposited (Donaubauer et al., 2020). Repeated or prolonged exposure to radiation can exhaust the protective effect of the endothelium and lead to endothelial dysfunction (Baselet et al., 2019). Consequently, cells within the vascular endothelium may lose their integrity and become senescent or apoptotic via alterations to signaling pathways related to cell survival, leading to dysregulation of vasodilation and eventual endothelial dysfunction (Deanfield et al., 2007; Bonetti et al., 2003). Activation of the endothelium, consisting of inflammation, proliferation, thrombosis and low nitric oxide, occurs as a normal response to pathological conditions and oxidative stress from deposited energy (Krüger-Genge et al., 2019).

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

The strategy for collating the evidence on radiation stressors to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall weight of evidence: Moderate

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 biological plausibility surrounding the connection between deposition of energy leading to endothelial dysfunction is well-supported by reviews in the literature and mechanistic understanding. The impact on endothelial dysfunction from deposited energy onto cells may vary with the radiation source and associated parameters of dose, dose rate, and type, which can influence the amount of energy absorbed, among other factors such as tissue type. 

Radiation types such as gamma rays, X-rays, and charged particles at doses ranging from 0.05-18 Gy and dose rates as low as 2.4 mGy/h induce endothelial dysfunction through an increase in cellular markers of apoptosis and cellular senescence in human cell and animal models as well as diminished relaxation response of vessels in animal models (Yentrepalli et al., 2013a; Yentrepalli et al., 2013b; Soucy et al., 2011; On et al., 2001; Hatoum et al., 2006; Soucy et al., 2010; Soloviev et al., 2003; Baselet et al., 2017; Shen et al., 2017). Following irradiation, endothelial cells may lose their integrity and become senescent or apoptotic via alterations to signaling pathways related to cell survival, leading to endothelial dysfunction (Deanfield et al., 2007; Bonetti et al., 2003). Senescent endothelial cells show changes in cell morphology, cell-cycle arrest, and increased senescence-associated β-galactosidase (SA-β-gal) staining. They also have a pro-inflammatory secretory phenotype, which further contributes to negative effects. These changes lead to endothelial dysfunction, which results in dysregulation of vasodilation (Wang et al., 2016; Hughson et al., 2018; Ramadan et al., 2021). Prolonged chronic inflammation following irradiation causes an ineffective healing process, further worsened by a decrease in endothelium-dependent relaxation. This leads to endothelial dysfunction, making the vasculature more vulnerable to damage from non-laminar flow (Sylvester et al., 2018). Since the endothelium is largely responsible for controlling fluid flow, dysfunctions in the endothelium can lead to fluid imbalance, blood pressure changes, and blood clot formation (Konukoglu & Uzun, 2017; Korpela & Liu, 2014; Verma et al., 2003). 

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

Much evidence for this relationship comes from high dose studies (>2 Gy); further work is needed at varying doses and dose rates to better understand the relationship. 

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

Modulating factor 

Details 

Effects on the KER 

Reference

Drug 

Oxypurinol (Oxp) (a xanthine oxidase inhibitor) 

Treatment led to increased endothelial relaxation response to ACh after irradiation. 

(Soucy et al., 2011) 

Drug 

Vitamin C 

Treatment increased the relaxation response to ACh after irradiation. 

(On et al., 2001) 

Drug 

MnTBAP 

Treatment restored vasodilation ability after irradiation. 

(Hatoum et al., 2006) 

Drug 

Tempol 

Treatment restored vasodilation ability after irradiation. 

(Hatoum et al., 2006) 

Drug 

Human bone marrow stem cells 

Both low and high doses decreased apoptosis after irradiation. 

(Shen et al., 2018) 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Dose Concordance  

Reference 

Experiment Description 

Result 

Baselet et al., 2017   

In vitro. X-ray radiation was delivered to human endothelial cells at a dose rate of 0.5 Gy/min for total doses of 0.05, 0.1, 0.5 and 2 Gy. SA-β-gal activity was used as a marker for senescence and endothelial dysfunction and was measured 14 days post exposure.  

SA-β-gal activity for all radiation doses was significantly elevated above the non-irradiated control and increased with an increase in radiation dose. At the highest dose of 2 Gy, there was a 1.7-fold increase compared to control.  

Soucy et al., 2011   

In vivo. 3-4 months-old rats were whole body irradiated with 0.5 or 1 Gy of 56Fe ions before their aortas were harvested and the endothelium dependent vasodilation response to ACh was evaluated at 4 months post-irradiation.  

A 0.5 Gy dose did not show significant changes to maximum relaxation response to ACh compared to non-irradiated control.  

Following a 1 Gy dose there was a 0.8-fold decrease in maximum relaxation response to ACh compared to non-irradiated control.  

Soucy et al., 2010  

In vivo. 4-months-old rats were irradiated with 5 Gy of 137Cs, and the endothelium dependent vasodilation response to ACh of harvested aortas was evaluated.  

There was a 0.6-fold decrease in maximum relaxation response to ACh in the aorta compared to the non-irradiated control.  

Soloviev et al., 2003  

In vivo. The endothelium dependent vasorelaxation response to ACh of aortas from rabbits exposed to 6 Gy of 60Co whole body irradiation was evaluated 9 days post exposure. Furthermore, endothelium dependent relaxation response following exposure to 1, 2, and 4 Gy on the 7th day post exposure were also evaluated.  

9 days after exposure to 6 Gy, there was a 0.5-fold decrease in maximum relaxation response to ACh.  

At 7 days post irradiation, maximum relaxation response to ACh decreased with an increase in radiation dose, with 60% maximum relaxation at 0 Gy dropping down to 30% after 4 Gy.  

Shen et al., 2018  

In vivo. 18 Gy of X-ray radiation was delivered to 8-week-old mice. Apoptosis was evaluated using TUNEL assays at 3-, 7-, 14-, 28- and 84-days post irradiation.  

Apoptosis levels in 18 Gy irradiated groups were significantly elevated above sham irradiated control at all time points tested. The difference peaked 7-days post irradiation at a 5-fold increase compared to control.  

Hatoum et al., 2006  

In vivo. Rats were whole body irradiated with up to 2250 cGy via 9 fractions of 250 cGy X-rays at a dose rate of 243 cGy/min. Endothelium dependent vasodilation response to ACh of harvested submucosal vessels was evaluated at various radiation doses.

After the final dose (total 22.5 Gy) there was a 0.03-fold decrease in maximum relaxation response to ACh in irradiated rat microvessels compared to non-irradiated controls.  

Following dose 1 and 2 (250 cGy and 500 cGy total dose), maximum dilation remained similar to non-irradiated control (~90% maximum dilation). However, following the third dose (750 cGy total), maximum dilation dropped below 10% and remained significantly below non-irradiated control levels for all remaining doses tested.  

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

Time Concordance

Reference 

Experiment Description 

Result 

Yentrapalli et al., 2013a   

In vitro. Chronic gamma irradiation (137Cs) was delivered to human umbilical vein endothelial cells (HUVECs) at a dose rate of 1.4 mGy/h or 2.4 mGy/h. SA-β-gal activity was used as a marker for premature endothelial cell senescence and was evaluated at 1-, 3-, 6-, 10- and 12-weeks post irradiation.  

Between 1 to 6 weeks post irradiation no significant differences were observed between either of the irradiated groups and the sham irradiated control.  

At the 10- and 12-week time points, the 1.4 mGy/h exposure continued to show no significant changes from control, while the 2.4 mGy/h group showed a 1.7-fold increase at 10-weeks and 1.9-fold increase at 12-weeks.   

Yentrapalli et al., 2013b   

In vitro. Chronic gamma (137Cs) of HUVECs at a dose rate of 4.1 mGy/h for up to 6 weeks for final doses of 0.69, 2.07 and 4.13 Gy. SA-β-gal activity was used as a marker for premature endothelial cell senescence and was evaluated at 1-, 3- and 6-weeks post exposure.  

No significant changes in SA-β-gal activity were observed between irradiated and sham irradiated groups in the first week.  

SA-β-gal activity was significantly elevated in irradiated HUVECs at the 3- and 6-week timepoints, showing a 2-fold and 3-fold elevation above control respectively.   

Soucy et al., 2011   

In vivo. 3-4 months-old rats were whole body irradiated with 0.5 or 1 Gy of 56Fe ions before their aortas were harvested and the endothelium dependent vasodilation response to ACh was evaluated.  

At 4 months post radiation there was a 0.8-fold decrease in maximum relaxation response to ACh with a return to control levels by 6 months. 

Soloviev et al., 2003   

In vivo. The maximum endothelium dependent vasorelaxation response to ACh of aortas from rabbits having been whole body irradiated to 6 Gy 60Co gamma-rays was evaluated 9- and 30-days post exposure. 

At both 9- and 30-days post-irradiation there was a ~0.5-fold decrease in maximum relaxation response to ACh compared to non-irradiated control. There was no significant difference in maximum relaxation between the 9- and 30-day timepoints.  

Shen et al., 2018  

In vivo. 18 Gy of X-ray radiation was delivered to 8-week-old mice with apoptosis levels being measured for up to 84 days post-irradiation in the aorta. 

There was a significant increase of 3-fold in apoptosis as soon as 3 days post-irradiation with a peak of 7-fold after 7 days. There was a gradual return to a 3-fold increase by 84 days. 

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

Not identified. 

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 evidence for the taxonomic applicability to humans is low as the majority of the evidence is from in vitro human-derived cells. The relationship is supported by both sexes of mouse, rat, and rabbit models. The in vivo studies were mostly undertaken in adolescent or adult rats and mice. In addition, the relationship is likely at any life stage.

References

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

Baselet, B. et al. (2019), “Pathological effects of ionizing radiation: endothelial activation and dysfunction”, Cellular and Molecular Life Science, Vol. 76, Springer, New York, https://doi.org/10.1007/s00018-018-2956-z.

Baselet, B. et al. (2017), “Functional Gene Analysis Reveals Cell Cycle Changes and Inflammation in Endothelial Cells Irradiated with a Single X-ray Dose”, Frontiers in pharmacology, Vol. 8, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphar.2017.00213

Boerma, M. et al. (2015), “Space radiation and cardiovascular disease risk”, World Journal of Cardiology, Vol. 7/12, Baishideng Publishing Group, Pleasanton, https://doi.org/10.4330/wjc.v7.i12.882

Bonetti, P. O., L. O. Lerman and A. Lerman (2003), “Endothelial dysfunction: a marker of atherosclerotic risk”, Arteriosclerosis, thrombosis, and vascular biology, Vol. 23/2, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.atv.0000051384.43104.fc

Deanfield, J. E., J. P. Halcox and T. J. Rabelink (2007), “Endothelial Function and Dysfunction”, Circulation, Vol. 115/10, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/CIRCULATIONAHA.106.652859.

Donaubauer, A. J. et al. (2020), “The Influence of Radiation on Bone and Bone Cells-Differential Effects on Osteoclasts and Osteoblasts”, International journal of molecular sciences, Vol. 21/7, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms21176377.

Finch, W., K. Shamsa, M. S. Lee (2014), “Cardiovascular complications of radiation exposure”, Reviews in Cardiovascular Medicine, Vol. 15/3, IMR Press, https://doi.org/10.3909/ricm0689

Hatoum, O. A. et al. (2006), “Radiation Induces Endothelial Dysfunction in Murine Intestinal Arterioles via Enhanced Production of Reactive Oxygen Species”, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26/2, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.ATV.0000198399.40584.8c

Hughson, R.L., A. Helm and M. Durante (2018), “Heart in space: Effect of the extraterrestrial environment on the cardiovascular system”, Nature Reviews Cardiology, Vol. 15/3, Nature Portfolio, London, https://doi.org/10.1038/nrcardio.2017.157.

Konukoglu, D., and H. Uzun (2017), “Endothelial Dysfunction and Hypertension”, Advances in experimental medicine and biology, Vol. 956, Springer, New York, https://doi.org/10.1007/5584_2016_90.

Korpela, E., and S. K. Liu (2014), “Endothelial perturbations and therapeutic strategies in normal tissue radiation damage”, Radiation oncology, Vol. 9, BioMed Central, London, https://doi.org/10.1186/s13014-014-0266-7.

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, Vol. 98/12. https://doi.org/10.1080/09553002.2022.2110306

Krüger-Genge, A. et al. (2019), “Vascular Endothelial Cell Biology: An Update”, International Journal of Molecular Sciences, Vol. 20/18, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/IJMS20184411.

On, Y. K. et al. (2001), “Vitamin C prevents radiation-induced endothelium-dependent vasomotor dysfunction and de-endothelialization by inhibiting oxidative damage in the rat”, Clinical and experimental pharmacology & physiology, Vol. 28/10, Wiley-Blackwell, Hoboken, https://doi.org/10.1046/j.1440-1681.2001.03528.x.

Ramadan, R. et al. (2021), “The role of connexin proteins and their channels in radiation-induced atherosclerosis”, Cellular and molecular life sciences: CMLS, Vol. 78/7, Springer, New York, https://doi.org/10.1007/s00018-020-03716-3.

Shen, Y. et al. (2018), “Transplantation of bone marrow mesenchymal stem cells prevents radiation-induced artery injury by suppressing oxidative stress and inflammation”, Oxidative Medicine and Cellular Longevity, Vol. 2018, Hindawi, London, https://doi.org/10.1155/2018/5942916.

Soloviev, A. I. et al. (2003), “Mechanisms of endothelial dysfunction after ionized radiation: selective impairment of the nitric oxide component of endothelium-dependent vasodilation”, British journal of pharmacology, Vol. 138/5, Wiley, https://doi.org/10.1038/sj.bjp.0705079

Soucy, K. G. et al. (2011), “HZE 56Fe-Ion Irradiation Induces Endothelial Dysfunction in Rat Aorta: Role of Xanthine Oxidase”, Radiation Research, Vol. 176/4, Radiation Research Society, Bozeman, https://doi.org/10.1667/RR2598.1.

Soucy, K. G. et al. (2010), “Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta”, Journal of Applied Physiology, Vol. 108/5, American Physiological Society, Rockville, https://doi.org/10.1152/japplphysiol.00946.2009.

Sylvester, C. B. et al. (2018), “Radiation-Induced Cardiovascular Disease: Mechanisms and Importance of Linear Energy Transfer”, Frontiers in Cardiovascular Medicine, Vol. 5, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fcvm.2018.00005.

Verma, S., M. R. Buchanan and T. J. Anderson (2003), “Endothelial function testing as a biomarker of vascular disease”, Circulation, Vol. 108/17, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.CIR.0000089191.72957.ED.

Wang, Y., M. Boerma and D. Zhou (2016), “Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases”, Radiation research, Vol. 186/2, Radiation Research Society, Bozeman, https://doi.org/10.1667/RR14445.1.  

Yentrapalli, R. et al. (2013a), “The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation”, PloS one, Vol. 8/8, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0070024.

Yentrapalli, R. et al. (2013b), “Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation”, Proteomics, Vol. 13/7, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/pmic.201200463.