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Relationship: 2779

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 Altered, Nitric Oxide Levels

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 High 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 High NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

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

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate
Juvenile 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

Deposition of energy from irradiation can affect nitric oxide (NO), a diffusible signaling molecule responsible for vasodilation (Dong et al., 2020; Mitchell et al., 2019; Soloviev & Kizub, 2019; Wang, Boerma & Zhou, 2016). NO activity is regulated by nitric oxide synthase (NOS) enzymes, which can be affected by NOS protein concentrations and cofactors tetrahydobiopterin (BH4), nicotinamide adenine dinucleotide phosphate (NADPH) and Ca2+ (Luiking, Engelen & Deutz, 2010). The deposition of energy can alter certain pathways involving NO and therefore indirectly alter NO levels. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway, the RhoA/Rho kinase (ROCK) pathway, the renin-angiotensin-aldosterone system (RAAS), and the acidic sphingomyelinase/ceramide pathway can influence NO levels (Hemmings & Restuccia 2012; Millatt, Abdel-Rahman & Siragy, 1999; Nagane et al., 2021; Soloviev & Kizub, 2019; Yao et al., 2010). 

Deposition of energy can alter NO levels through radiolysis and the direct formation of reactive oxygen species (ROS) (Azzam, Jay-Gerin & Pain, 2013). An increase in ROS and reactive nitrogen species (RNS) can influence NO levels; however, the involvement of RNS in NO production has not been strongly demonstrated in literature (Nagane et al., 2021). ROS acts as a modulator for the relationship between energy deposition leading to altered NO levels. Following ionizing radiation (IR) exposure, there are various enzymes and immune cells involved with indirectly increasing ROS, thereby influencing NO levels (Powers & Jackson, 2008; Soloviev & Kizub, 2019; Vargas-Mendoza et al., 2021).  

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: High

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 and altered NO levels is well-supported by reviews in the literature and mechanistic understanding. NO is a diffusible molecule produced by endothelial cells (Soloviev & Kizub, 2019; Wang, Boerma & Zhou, 2016). The enzyme NOS produces NO and can be used as a proxy to measure NO levels. eNOS and iNOS are common endpoints for assessing NO levels. Changes in eNOS phosphorylation (p-eNOS) can also indicate NO levels, with phosphorylation at serine 1177 increasing eNOS activity and phosphorylation at threonine 495 decreasing eNOS activity (Nagane et al., 2021). The deposition of energy from IR can indirectly lead to changes in NO levels through various pathways (Nagane et al., 2021; Soloviev & Kizub, 2019). 

NO levels can be altered by deposition of energy through ROS. ROS can be produced directly through the radiolysis of water or indirectly through the mitochondrial electron transport chain (ETC) and various enzymes and immune cells (Azzam, Jay-Gerin & Pain, 2013; Powers & Jackson, 2008; Soloviev & Kizub, 2019; Vargas-Mendoza et al., 2021). NO bioavailability is reduced through the molecule’s reaction with ROS that produces peroxynitrite, or oxidation of the NOS cofactor BH4. This uncouples NOS causing it to produce ROS instead of NO, further driving down NO bioavailability (Forrester et al., 2019; Soloviev & Kizub, 2019). NO can also increase as a result of deposition of energy through activation of iNOS during oxidative stress (Nathan & Xie, 1994). However, this additional NO reacts with ROS to form peroxynitrite (Nagane et al., 2021; Soloviev & Kizub, 2019). The reaction of ROS with NO produces the RNS peroxynitrite, which can also further oxidize BH4 and uncouple NOS, resulting in further NO reduction (Soloviev & Kizub, 2019). 

Deposition of energy can also alter NO levels by activating signaling pathways involved in NO regulation. Under normal conditions, the PI3K/Akt pathway can activate NOS through phosphorylation (Hemmings & Restuccia 2012; Nagane et al., 2021). The RhoA/ROCK pathway prevents both the expression and phosphorylation of NOS (Yao et al., 2010). Furthermore, the RAAS pathway can increase the production of ROS through NADPH oxidase (NOX), which causes decreased NO (Nguyen Dinh Cat et al., 2013). Additionally, the RAAS pathway can activate NOS as a countermeasure for vasoconstriction (Millatt, Abdel-Rahman & Siragy, 1999). Lastly, the acidic sphingomyelinase/ceramide pathway can also activate NOX, resulting in lower NO levels (Soloviev & Kizub, 2019). Deposition of energy from IR can change these pathways through oxidative stress and changes in protein expression, which results in altered NO levels (Schmidt-Ullrich et al., 2000).

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
  • Due to the high reactivity of NO, it can be difficult to directly measure it (Luiking, Engelen & Deutz, 2010). The inconsistencies in NO levels may be attributed to the challenges in measuring NO, such as its availability in cell (Azimzadeh et al., 2017; Hirakawa et al., 2002; Hong et al., 2013; Sakata et al., 2015; Sonveaux et al., 2003), serum (Abdel-Magied & Shedid,. 2019; Azimzadeh et al. 2015; Ohta et al., 2007) or tissue (Abdel-Magied & Shedid, 2019; Baker et al., 2009; Fuji et al., 2016; Hamada et al., 2020), its homeostasis with ROS, and its relationship to nitrosylation as accumulated damage and whether p-eNOS/eNOS is being measured.

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

References

Drug 

ZnO-NPs (Zinc oxide nanoparticles that act as antioxidants) 

Treatment with ZnO-NPs after irradiation returned nitrite/nitrate levels closer to control 

Abdel-Magied & Shedid, 2019 

Drug 

Fenofibrate (PPARα agonist) 

Treatment with Fenofibrate eliminated the radiation-induced decrease in NO levels. 

Azimzadeh et al., 2021 

Drug 

Atorvastatin 

Treatment significantly increased eNOS levels 

Sadhukhan et al., 2020 

Drug 

Gamma tocotrienol 

Treatment eliminated the radiation-induced decrease in eNOS levels. 

Sadhukhan et al., 2020 

Drug 

Geranylgeranyl transferase I inhibitor 298 

Treatment eliminated the radiation-induced decrease in eNOS levels. 

Sadhukhan et al., 2020 

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

Dose Concordance 

Reference 

Experiment Description 

Result 

Azimzadeh et al., 2015 

In vivo. 10-week-old mice were exposed to X-ray irradiation at either 8 or 16 Gy. Cardiac levels of NO, eNOS and p-eNOS were determined. Protein levels were measured using immunoblotting, and NO was measured using an ELISA assay. 

p-eNOS decreased 0.6-fold after 8 Gy and 0.2-fold after 16 Gy. NO decreased 0.3-fold after 8 Gy and 0.2-fold after 16 Gy. eNOS levels did not change. 

Azimzadeh et al., 2017 

In vitro. HCAECs were irradiated with 0.5 Gy X-ray irradiation over 1 minute. Phosphorylated and total eNOS levels were determined using immunoblotting, and NO levels were determined using ELISA assay. Measurements were taken after 1, 7, and 14 days. 

p-eNOS/total eNOS was 0.7-fold lower than control and NO was 0.8-fold lower than control after 14 days. 

Hong et al., 2013 

In vitro. HUVECs were irradiated with 4 Gy X-rays (2.7 Gy/min) and amounts of eNOS, iNOS and nitrotyrosine (a biomarker for peroxynitrite) were determined by western blot. Measurements were taken after 1.5, 3, and 6 hours. 

In 4 Gy irradiated HUVECs, iNOS was increased 6.6-fold and nitrotyrosine was increased 6.4-fold after 6 h. eNOS expression did not change. 

Fuji et al., 2016 

In vivo. eNOS levels in the smooth muscle layer of 4-week-old rat pulmonary arteries were determined using immunohistochemical staining after irradiation (dose not specified). A 6.5 GeV electron beam was converted into monochromatic X-rays. Measurements were taken after 2 weeks. 

eNOS levels decreased 0.6-fold compared to control. 

Abdel-Magied & Shedid, 2019 

In vivo. Adult male rats were irradiated with 8 Gy 137Cs gamma irradiation (0.4092 Gy/min). Serum and heart total NOx was determined with a NOx assay kit. Measurements were taken after 14 days. 

Cardiac and serum NOx increased 2 and 1.8-fold after exposure to 8 Gy, respectively. 

Hamada et al., 2022 

In vivo. 8-week-old mice were irradiated with 5 Gy 260 kVp X-rays at 0.5 Gy/min delivered in 25 or 100 daily fractions over 42 or 152 days, respectively, or delivered as an acute single dose. As well, chronic 137Cs gamma rays (<1.4 mGy/h for 153 days) were delivered in another regimen. eNOS levels were determined by immunofluorescence. 

At 6 months after the start of irradiation, eNOS decreased 0.3-fold, 0.4-fold, and 0.4-fold following single dose irradiation, 25 fraction regimens, and 100 fraction regimens, respectively. eNOS also decreased 0.8-fold after chronic gamma ray irradiation. At 12 months after the start of irradiation, eNOS decreased 0.7-fold, 0.8-fold and 0.8-fold following acute, 25 fraction and 100 fraction regimens, respectively.  

Hamada et al., 2020 

In vivo. 8-week-old male mice were irradiated by 5 Gy 137Cs gamma rays (0.5 Gy/min). Immunofluorescence was used to determine eNOS levels. Measurements were taken after 1, 3, and 6 months. 

6 months post-irradiation of 5 Gy, eNOS decreased by 0.3- fold. 

Baker et al., 2009 

In vivo. Male rats were irradiated with 10 Gy X-rays (1.95 Gy/min). Western blotting was used to determine eNOS and iNOS. NOx content was determined using ozone chemiluminescence. Measurements were taken after 120 days. 

Rats exposed to 10 Gy of TBI experienced a 27% decrease in eNOS, a 29% decrease in iNOS protein, and a 20% decrease in NOx (index of NO activity). 

Sonveaux et al., 2003 

In vitro. Levels of eNOS and p-eNOS after X-ray irradiation of BAECs and HUVECs were measured with immunoblotting at various doses (0.86 Gy/min). eNOS mRNA was also measured with RT-qPCR before and after 2 Gy-irradiated human tumour cells. 

Compared to controls, 24 h after irradiation, eNOS increased 1.3-fold after 2 Gy (not significant), 2.1-fold after 4 Gy (not significant), 3-fold after 6 and 8 Gy, 4.3-fold after 10 Gy and 3.4-fold after 20 Gy. Compared to controls, 24 h after irradiation, p-eNOS increased 1.2-fold after 2 Gy and 1.7-fold after 6 Gy. eNOS increased in human tumor cells in every patient after 2 Gy irradiation. 

Hirakawa et al., 2002 

In vitro. BAECs were irradiated with X-rays at various doses. eNOS and iNOS were measured with semiquantitative RT-PCR and western blot. NO was measured through DAF-2, a NO-sensitive fluorescent dye after treatment with L-arginine. 

eNOS expression did not significantly change from 1-60 Gy. iNOS expression did not occur in non-irradiated samples, but increased to 6% of GAPDH expression after 1 Gy, 26% after 2 Gy and remained around 40% of GAPDH expression from 10-60 Gy. NO increased a maximum of 5.2-fold 12h after 2 Gy irradiation. 

Sakata et al., 2015 

In vitro. HUVECs were irradiated with various doses of X-rays. eNOS, p-eNOS (Ser1177 & Thr495), iNOS, citrulline (produced by NOS with NO) and NOx levels were measured with western blots for proteins and various assay kits for molecules. 

For maximum changes after 10 Gy, eNOS expression did not significantly change, p-eNOS (Ser1177) increased 1.8-fold, p-eNOS (Thr495) decreased 0.3-fold, iNOS showed a non-significant 1.4-fold increase and citrulline increased 1.3-fold. NOx increased consistently from 1-20 Gy and showed a maximum 10-fold increase after 10 Gy. 

Ohta et al., 2007 

In vivo. Levels of nitrate in mouse serum were measured by Griess assay after a whole-body X-ray irradiation of 6-week-old mice using various doses from 19.6 to 31.5 Gy. 

Serum nitrate concentrations increased about 2-fold from 0-31.5 Gy. 

Hamada et al., 2021 

In vivo. Either acute or chronic doses of X-rays and 137Cs gamma rays were given to 8-week-old B6J mice, to a total 5 Gy dose. X-rays were given as a single acute dose, 25 fractions of 0.2 Gy/fraction spread over 42 days or 100 fractions of 0.05 Gy/fraction spread over 153 days all given at 0.5 Gy/min. Gamma rays were given as a single acute dose at 0.5 Gy/min or chronically at <1.4 mGy/h for 153 days. eNOS was measured through immunofluorescence. 

All regimens of X-rays and acute gamma rays led to a 0.3- to 0.4-fold decrease in eNOS levels. Chronic gamma rays led to a 0.8-fold (nonsignificant) decrease in eNOS levels. 

Azimzadeh et al., 2021 

In vivo. 8-week-old male C57BL/6J were irradiated with an acute dose of 16 Gy X-rays. eNOS activity and NO were measured using fluorometric and Griess assays, respectively. 

16 Gy resulted in a decrease in eNOS activity to 73% in heart tissue. NO levels decreased to 63% in serum. 

Sadhukhan et al., 2020 

In vitro. HUVECs were irradiated with various regimens and doses of 137Cs gamma radiation. eNOS levels were determined by western blot. Fractionated doses were separated by 24 h. 

At 5 doses of 2 Gy, eNOS decreased 0.2-fold. At 5 doses of 2.5 Gy, eNOS decreased 0.3-fold. At a single dose of 10 Gy, eNOS decreased 0.8-fold. At a single dose of 12 Gy, eNOS decreased 0.7-fold. 

Dias et al., 2018 

In vitro. HAoECs were irradiated with various regimens of 60Co gamma radiation. Acute radiation was given at 1 Gy/min, while chronic radiation was given at 6 mGy/h eNOS mRNA level was determined using qPCR. Each dose was measured at different times after irradiation. 

An acute dose of 0.05 Gy led to a 0.6-fold decrease in eNOS while the chronic dose led to a 1.6-fold increase. At 0.5 Gy, the acute dose did not significantly change eNOS, while the chronic dose increased it 1.6-fold. Acute 1 Gy caused eNOS to decrease 0.5-fold without significant changes chronically. Acute 2 Gy caused a 0.3-fold decrease in eNOS without significant changes chronically. 

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 

Azimzadeh et al., 2017 

In vitro. HCAECs were irradiated with 0.5 Gy X-ray irradiation over 1 minute. Phosphorylated and total eNOS levels were determined using immunoblotting, and NO levels were determined using ELISA assay. Measurements were taken after 1, 7 or 14 days. 

1 day after 0.5 Gy irradiation, p-eNOS/total eNOS was 0.8-fold lower than control and NO did not change. After 7 days, p-eNOS/total eNOS was 0.6-fold lower than control and NO was 0.8-fold lower than control. After 14 days, p-eNOS/total eNOS was 0.7-fold lower than control and NO was 0.8-fold lower than control. 

Hong et al., 2013 

In vitro. HUVECs were irradiated with 4 Gy X-rays (2.7 Gy/min) and amounts of iNOS and nitrotyrosine (a biomarker for peroxynitrite) were determined by western blot at various times over 6 hours. 

1.5 h after 4 Gy irradiation, iNOS 1.9-fold higher than control and nitrotyrosine did not change. After 3 h, iNOS was 2.8-fold higher than control and nitrotyrosine did not change. After 6 h, iNOS was 6.6-fold higher than control and nitrotyrosine was 6.3-fold higher than control. 

Hamada et al., 2020 

In vivo. 8-week-old male mice were irradiated by 5 Gy 137Cs gamma rays (0.5 Gy/min). Immunofluorescence was used to determine eNOS levels. Measurements were taken after 1, 3 and 6 months. 

eNOS levels decreased 0.5-fold at 1-month post-irradiation, 0.4-fold at 3 months post-irradiation and a maximal fold decrease of 0.3-fold 6 months post-irradiation. 

Sonveaux et al., 2003 

In vitro. Level of eNOS after X-ray irradiation of BAECs and HUVECs was measured with immunoblotting at various times. 

At 6 Gy, eNOS did not significantly change 1-6 h post-irradiation, but increased 1.8-fold after 12 h, 2-fold after 24 h and 1.5-fold after 48 h. 

Hirakawa et al., 2002 

In vitro. BAECs were irradiated with 2 Gy X-rays at various times. eNOS and iNOS were measured with semiquantitative RT-PCR and western blotting. NO was measured through DAF-2, a NO-sensitive fluorescent dye after treatment with L-arginine. 

eNOS expression did not significantly change from 0-120 h post-irradiation. iNOS expression did not occur in non-irradiated samples but increased to a maximum 26% of GAPDH expression 6 h post-irradiation, and slowly decreased to 16% after 120 h. Similarly, NO increased a maximum of 5.2-fold after 12 h, while NO levels slowly returned after 120 h. 

Sakata et al., 2015 

In vitro. HUVECs were irradiated with 10 Gy X-rays at various times. eNOS, p-eNOS (Ser1177 & Thr495), iNOS, citrulline (produced by NOS with NO) and NOx levels were measured with western blots for proteins and various assay kits for molecules. 

eNOS expression did not significantly change over 72 h, p-eNOS (Ser1177) increased 1.8-fold over 72 h, p-eNOS (Thr495) decreased 0.3-fold after 6 h and returned to initial levels after 72 h, iNOS did not change other than a nonsignificant 1.4-fold increased after 24 h. Citrulline increased 1.3-fold after 6 h and remained the same for 72 h. NOx increased 3.7-fold after 6 h and 5-fold after 72 h. 

Ohta et al., 2007 

In vivo. Levels of nitrate in mouse serum were measured by Griess assay at various times after a whole-body 26 Gy X-ray irradiation of 6-week-old mice. 

Serum nitrate concentration showed a maximum increase of 2.1-fold after 3 h, followed by a return to pre-irradiation levels at 12 h and 24 h post-irradiation. 

Sadhukhan et al., 2020 

In vitro. HUVECs were irradiated with various regimens and doses of 137Cs gamma radiation. eNOS levels were determined by western blot 4 and 24 h after irradiation. Fractionated doses were separated by 24 h. 

After the 10 Gy doses, eNOS was lowest at 4 h, but after 12 Gy it was the same at both 4 and 24 h. 

Dias et al., 2018 

In vitro. HAoECs were irradiated with various regimens of 60Co gamma radiation. Acute radiation was given at 1 Gy/min, while chronic radiation was given at 6 mGy/h. eNOS mRNA level was determined using qPCR up to 16 days after irradiation. Each timepoint used a different dose.

An acute dose of 0.05 Gy led to a 0.6-fold decrease in eNOS while the chronic dose led to a 1.6-fold increase 1 day post-irradiation. At 0.5 Gy, the acute dose did not significantly change eNOS, while the chronic dose increased it 1.6-fold 4 days post-irradiation. Acute 1 Gy caused eNOS to decrease 0.5-fold without significant changes chronically 8 days post-irradiation. Acute 2 Gy caused a 0.3-fold decrease in eNOS without significant changes chronically 16 days post-irradiation. 

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 evidence comes from in vitro human cell-derived models. The relationship has been shown in vivo in mice and rats, with considerable evidence in mice. The relationship has been shown in vivo in males and is likely in females. Most in vivo studies indicate adult or adolescent animal models used. In addition, the relationship is also likely in preadolescent animals.

References

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

Abdel-Magied, N. and S. M. Shedid (2019), “Impact of zinc oxide nanoparticles on thioredoxin-interacting protein and asymmetric dimethylarginine as biochemical indicators of cardiovascular disorders in gamma-irradiated rats”, Environmental Toxicology, Vol. 35, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/tox.22879.

Azimzadeh, O. et al. (2021), “Activation of PPARα by feno fibrate attenuates the effect of local heart high dose irradiation on the mouse cardiac proteome”, Biomedicines, Vol. 9/12, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/biomedicines9121845.

Azimzadeh, O. et al. (2017), “Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways”, International Journal of Radiation Biology, Vol. 93/9, Informa, London, https://doi.org/10.1080/09553002.2017.1339332.

Azimzadeh, O. et al. (2015), “Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction”, Journal of Proteome Research, Vol. 14/2, American Chemical Society, Washington, https://doi.org/10.1021/pr501141b.

Azzam, E. I., J. P. Jay-Gerin and D. Pain (2012), “Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury”, Cancer Letters, Vol. 327, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2011.12.012.

Baker, J. E. et al. (2009), “10 Gy total body irradiation increases risk of coronary sclerosis, degeneration of heart structure and function in a rat model”, International Journal of Radiation Biology, Vol. 85/12, Informa, London, https://doi.org/10.3109/09553000903264473

Dias, J. et al. (2018), “Gamma Low- Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate–Dependent Manner”, Dose-Response, Vol. 16/1, SAGE Publications, Thousand Oaks, https://doi.org/10.1177/1559325818755238.

Dong, S. et al. (2020), “Oxidative stress: A critical hint in ionizing radiation induced pyroptosis”,  Radiation Medicine and Protection, Vol. 1/4, National Institute of Radiological Protection, https://doi.org/10.1016/j.radmp.2020.10.001.

Forrester, S. J. et al. (2018), “Reactive Oxygen Species in Metabolic and Inflammatory Signaling”, Circulation Research, Vol. 122/6, Lippincot Williams & Wilkins, Philadelphia, https://doi.org/10.1161/CIRCRESAHA.117.311401.

Fuji, S. et al. (2016), “Association between endothelial function and micro-vascular remodeling measured by synchrotron radiation pulmonary micro-angiography in pulmonary arterial hypertension”, General Thoracic and Cardiovascular Surgery, Vol. 64, Springer, New York, https://doi.org/10.1007/s11748-016-0684-6.

Hamada, N. et al. (2022), “Temporal Changes in Sparing and Enhancing Dose Protraction Effects of Ionizing Irradiation for Aortic Damage in Wild-Type Mice”, Cancers, Vol. 14/14, MDPI, Basel, https://doi.org/10.3390/cancers14143319

Hamada, N. et al. (2021), “Vascular damage in the aorta of wild-type mice exposed to ionizing radiation: Sparing and enhancing effects of dose protraction”, Cancers, Vol.13/21, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/cancers13215344.

Hamada, N. et al. (2020), “Ionizing Irradiation Induces Vascular Damage in the Aorta of Wild-Type Mice”, Cancers, Vol. 12/10, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/CANCERS12103030.

Hemmings, B. A. and D. F. Restuccia (2012). “PI3K-PKB/Akt Pathway”, Cold Spring Harbor Perspectives in Biology, Vol. 4/9, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, https://doi.org/10.1101/CSHPERSPECT.A011189.

Hirakawa, M. et al. (2002), “Tumor Cell Apoptosis by Irradiation-induced Nitric Oxide Production in Vascular Endothelium”, Cancer Research, Vol. 62/5, American Association for Cancer Research, Philadelphia, pp. 1450–1457.

Hong, C. W. et al. (2013), “Involvement of inducible nitric oxide synthase in radiation-induced vascular endothelial damage”, Journal of Radiation Research, Vol. 54/6, Oxford University Press, Oxford, https://doi.org/10.1093/JRR/RRT066.

Ježek, P. and L. Hlavatá (2005), “Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism”, The International Journal of Biochemistry & Cell Biology, Vol. 37/12, Elsevier, Amsterdam,    https://doi.org/10.1016/j.biocel.2005.05.013.

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

Luiking, Y. C., M. P. Engelen and N. E. Deutz (2010), “Regulation of nitric oxide production in health and disease”, Current Opinion in Clinical Nutrition and Metabolic Care, Vol. 13/1, Lippincott Williams and Wilkins Ltd, Philadelphia, https://doi.org/10.1097/MCO.0b013e328332f99d.

Millatt, L. J., E. M. Abdel-Rahman and H. M. Siragy (1999), “Angiotensin II and nitric oxide: a question of balance”, Regulatory Peptides, Vol. 81/1-3, Elsevier, Amsterdam, https://doi.org/10.1016/S0167-0115(99)00027-0.

Mitchell, A. et al. (2019), “Cardiovascular effects of space radiation: implications for future human deep space exploration”, European Journal of Preventive Cardiology Vol. 26/16, SAGE Publishing, Thousand Oaks, https://doi.org/10.1177/2047487319831497.

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