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Relationship: 2776

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

Oxidative Stress 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 adjacent Vinita Chauhan (send email) Under development: Not open for comment. Do not cite

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 High NCBI
pigs Sus scrofa Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
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
Not Otherwise Specified Low

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

Reactive oxygen species (ROS) are chemically active molecules produced normally from molecular oxygen during various cell processes (Beckhauser et al., 2016; Ray et al., 2012). While ROS play an important role in healthy functions such as cell signalling (Hughson et al., 2018; Knock & Ward, 2011; Soloviev & Kizub, 2018), the redox balance of biological systems is kept tightly controlled. When levels of ROS overwhelm antioxidant mechanisms, it results in redox imbalance and the onset of oxidative stress, a term used to describe imbalances in ROS and reactive nitrogen species (RNS) radical formation as well as antioxidants and ROS scavengers (Beckhauser et al., 2016; Elahi et al., 2009; Ray et al., 2012). Unchecked ROS, the most detrimental and well-studied free radicals, can go on to damage cellular components including lipids and membranes, proteins and nucleic acids and lead to progression of pathologies such as cancer, and atherosclerosis (Elahi et al., 2009; Knock & Ward, 2011; Nagane et al., 2021; Schiffrin, 2008). The oxidative stress response can arise from many sources, including exposure to radiation (Azzam et al., 2012; Soloviev & Kizub, 2018) where ROS can be generated through water radiolysis (Azzam et al., 2012). Upregulation of oxidoreductase enzymes can cause mitochondrial dysfunction, which can further exacerbate elevated ROS levels (Azzam et al., 2012; Soloviev & Kizub, 2018). Superoxide and peroxide, forms of ROS, can be measured to determine the relationship between radiation-induced oxidative stress and endothelial dysfunction.

Within the cardiovascular system, every vessel is lined with a single layer of endothelial cells (Augustin et al., 1994; Fishman, 1982). This endothelial layer plays a crucial role in the regulation of vascular homeostasis through controlling various factors such as vascular permeability, vasomotion, and immune response (Baran et al., 2021; Bonetti et al., 2003; Hughson et al., 2018; Slezak et al., 2017; Sylvester et al., 2018). Of the vascular wall components, the endothelium is also the most vulnerable to damage from ROS (Soloviev & Kizub, 2018). Endothelial cells normally exist in a quiescent state characterized by high nitric oxide (NO) bioavailability (Carmeliet & Jain, 2011), however can become activated as part of a normal host-defence response following tissue injury or oxidative stress (Deanfield et al., 2007; Krüger-Genge et al., 2019). Sustained activation leads to the pathological state of endothelial dysfunction which is defined by decreased NO bioavailability, increased vessel permeability, altered vasomotion, and a pro-thrombotic and inflammatory environment (Baran et al., 2021; Bonetti et al., 2003; Deanfield et al., 2007; Schiffrin, 2008).

Shifting redox balance towards oxidation is known to lead to various cardiac pathologies including endothelial dysfunction through various mechanisms (Hughson et al., 2018; Ramadan et al., 2020; Soloviev & Kizub, 2018). There are several ways through which imbalanced ROS can affect the endothelium function, including decreasing NO bioavailability through direct scavenging, which forms the RNS peroxynitrite (ONOO-), (Hatoum et al., 2006; Li et al., 2002; Schiffrin, 2008; Soloviev & Kizub, 2018; Venkatesulu et al., 2018) and impeding its production and diffusion (Schiffrin, 2008; Soloviev & Kizub, 2018). Additionally, elevated ROS contribute to introducing a pro-inflammatory and pro-thrombotic milieu characteristic of dysfunction (Hughson et al., 2018; Schiffrin, 2008; Slezak et al., 2017; Tapio, 2016; Venkatesulu et al., 2018). It is also linked to decreased vasomotion (Schiffrin, 2008; Soloviev & Kizub, 2018; Venkatesulu et al., 2018) and finally the onset of endothelial cell apoptosis and premature senescence (Borghini et al., 2013; Hughson et al., 2018; Tapio, 2016; Wang et al., 2016).

Evidence Collection Strategy

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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

Mechanisms for oxidative stress leading to endothelial dysfunction are outlined in various reviews on the topic (Hughson et al., 2018; Nagane et al., 2021; Slezak et al., 2017; Soloviev & Kizub, 2018; Venkatesulu et al., 2018; Wang et al., 2016) to stressors such as radiation.

Elevated ROS can lead to endothelial dysfunction by causing an imbalance of NO, specifically the decrease in NO bioavailability. Firstly, ROS can react with NO directly; if quenching outpaces NO production, it will cause reduced NO bioavailability underlying endothelial dysfunction (Hatoum et al., 2006; Li et al., 2002; Soloviev & Kizub, 2018). In particular, the superoxide anion (O-2) reacts with NO to form peroxynitrite, both reducing available NO and further accelerating NO degradation (Li et al., 2002; Soloviev & Kizub, 2018). In addition, superoxide and peroxynitrite can uncouple eNOS which produces more ROS instead of NO (Soloviev & Kizub, 2018). Peroxynitrite can cause cellular senescence as a part of endothelial dysfunction (Nagane et al., 2021). eNOS downregulation and subsequent drop in NO levels are caused in part by increased endothelin-1 (ET-1), a vasoconstrictor with enhanced secretion during an oxidative stress state (Marasciulo, Montagnani & Potenza, 2006; Ramadan et al., 2020). ROS is also involved in perturbing NO diffusion from the endothelial cells (Soloviev & Kizub, 2018). Overall, the decreased NO bioavailability causes reduced vasodilation and endothelial dysfunction (Soloviev & Kizub, 2018).

Oxidative stress also affects endothelial function through inhibition of endothelium-dependent vasodilation (Soloviev & Kizub, 2018; Venkatesulu et al., 2018). ROS in both endothelial cells and surrounding vascular smooth muscle cells (VSMCs) act as second messengers to many cellular pathways that mediate VSMC contractility and endothelial permeability and function, causing disruption to these endothelial functions (Hughson et al., 2018; Li et al., 2002; Ramadan et al., 2020; Soloviev & Kizub, 2018; Ungvari et al., 2013; Venkatesulu et al., 2018). Specifically, impaired endothelium-dependent vasomotion following radiation (Venkatesulu et al., 2018) was suggested to be due to the loss of PGF2α inhibition and therefore, vasoconstriction (Li et al., 2002).

Oxidative stress is also involved in inducing the pro-thrombotic and inflammatory environment of endothelial dysfunction. In the case of radiation induced endothelial injury, radiation type, fraction size used, and type of endothelial cell exposed all influence the resulting downstream endpoints (Venkatesulu et al., 2018). Possible changes to the endothelial milieu include alterations of cell adhesion molecule levels, creation of pro-thrombotic environment, endothelial cell apoptosis and inflammation (Hughson et al., 2018; Nagane et al., 2021; Slezak et al., 2017; Tapio, 2016; Venkatesulu et al., 2018). When induced by oxidative stress, NF-кB can target genes involved with the upregulation of prothrombotic markers associated with endothelial dysfunction (Slezak et al., 2017). Free radicals produced by macrophages have also been shown to stimulate TGF-β, thus accelerating the creation of a profibrotic milieu (Venkatesulu et al., 2018). Studies have also shown that transgenic mice overexpressing superoxide dismutase (SOD) have a twofold reduction in aortic lesions following X-ray exposure compared to control (Hughson et al., 2018). Overexpression of SOD also mitigates atherosclerotic plaque formation, further outlining the relationship between oxidative stress and the pathological environment of endothelial dysfunction (Tapio, 2016). ROS can also oxidize low-density lipoproteins (LDL) resulting in structural complications as oxidized LDL accumulates in blood circulation due to decreased cell uptake (Nagane et al., 2021; Slezak et al., 2017). Furthermore, endothelial cells can undergo morphological changes following oxidative injury, as the cells become enlarged, and form fibrin networks, showing increased levels of activated platelets and leukocytes with membrane protrusions and pseudopodial extensions, which are all indicative of an inflammatory and pro-thrombotic state (Li et al., 2002).

Furthermore, ROS can induce premature endothelial cell senescence, which in turn contributes to overall endothelial dysfunction (Hughson et al., 2018; Nagane et al., 2021; Tapio, 2016). In contrast to replicative senescence attributed to telomere dysfunction, oxidative stress is one of several injuries causing stress-induced premature senescence (Nagane et al., 2021). This is thought to occur through oxidative stress causing the induction of the p53/p21 pathway which regulates cell senescence (Borghini et al., 2013; Wang et al., 2016). Once senescent, the endothelial cells contribute to dysfunction in multiple ways. Firstly, senescence can stimulate a pro-inflammatory response and trigger apoptosis through decreased cell repair (Nagane et al., 2021; Ramadan et al., 2020). Additionally, senescent cells themselves are sources of ROS, furthering both genomic instability causing additional senescence in neighbouring cells and endothelial dysfunction itself (Tapio, 2016; Wang et al., 2016). Senescent cells also lack proper endothelial cell function, contributing to changing the environment to a dysfunctional one (Hughson et al., 2018; Tapio, 2016). This lack of function includes a decrease in NO production, increased monocyte adhesion, and loss of cell barrier integrity paired with increased levels of ET-1 (Hughson et al., 2018; Nagane et al., 2021; Tapio, 2016).

Finally, oxidative stress has been shown to lead to mitochondrial dysfunction and dysregulation, which is thought to play an important role in the development of endothelial dysfunction (Borghini et al., 2013; Hughson et al., 2018; Nagane et al., 2021; Slezak et al., 2017).

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

Work by Ramadan et al. (2020) explored the use of TAT-Gap19 to block endothelial intracellular communication in order to modulate radiation response of intercellular connexin proteins. Overall, TAT-Gap19 was shown to reduce ROS production and subsequent senescence (SA β-gal activity) and apoptosis (Annexin V and Caspase 3/7) markers. However, treatment with TAT-Gap19 led to an increase in SA β-gal in non-irradiated control at the 9-day point. Additionally, the 0.1 Gy irradiated group showed persistent SA β-gal activity at all time points studied, while the 5 Gy group demonstrated an unexpected decrease before day 14.

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

MnTBAP (a superoxide dismutase mimetic)

Treatment with MnTBAP after irradiation was able to reduce superoxide and peroxide levels and restore vasodilation ability

(Hatoum et al., 2006)

Drug

Tempol (a superoxide dismutase mimetic)

Treatment with tempol after irradiation was able to restore vasodilation ability

(Hatoum et al., 2006)

Drug

TAT-Gap19 (inhibitor of connexin 43 which is associated with atherogenesis and endothelial stiffness)

Treatment with TAT-Gap19 led to a decrease in ROS and SA β-gal levels after irradiation

(Ramadan et al., 2020)

Drug

hBMSCs (protect against vascular damage through antioxidant properties)

Treatment with hBMSCs after irradiation caused increased catalase and HO-1, as well as decreased oxidative damage and apoptosis

(Shen et al., 2018)

Drug

Oxp (can inhibit XO, a source of ROS)

Treatment with Oxp showed decreased XO activity and ROS production along with increased vasodilation after irradiation

(Soucy et al., 2007; Soucy et al., 2010; Soucy et al., 2011)

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

Dose concordance

Reference

Experiment Description

Result

Soucy et al. 2007

In vivo. Sprague-Dawley rats were whole-body irradiated with 137Cs gamma radiation at 50, 160 and 500 cGy. XO is a primary source of cardiac ROS and was used as a measure of oxidative stress. Vasodilation response to ACh was used to evaluate endothelial function.

At 500 cGy, XO activity was found to be 2-fold elevated compared to control, and there was also an increase in XO quantity. Simultaneously, there was endothelial dysfunction as seen with a ~30 percentage point decrease in vasodilation response to ACh.

Soucy et al. 2010

In vivo. In Sprague-Dawley rats were whole-body irradiated with 137Cs gamma radiation at 5 Gy. ROS were measured using dihydroethidium fluorescence. Aortic relaxation response to ACh was also measured.

After 5 Gy, ROS increased 1.7-fold and relaxation decreased 0.7-fold.

Soucy et al. 2011

In vivo. Wistar rats were exposed to 0.5 and 1 Gy doses of 56Fe-ion radiation. ROS production rates were evaluated using dihydroethidium fluorescence. ACh-induced vasodilation responses were measured.

Iron ion irradiation at 1 Gy produced a 1.75-fold increase in ROS levels. At 10-5 M ACh, aorta without irradiation relaxed by 87%, while aorta with 1 Gy irradiation had significantly lower relaxation of 76%.

Li et al. 2002

In vivo. Surgically exposed coronary arteries of yucatan pigs were irradiated with 20 Gy 32P β-irradiation. Oxidative stress was evaluated through superoxide production. Endothelial function was evaluated through endothelial-dependent vasomotor response and morphological changes.

Superoxide production increased 3.5-fold between the control and 20 Gy irradiated groups. Contractile response to KCl dropped over 50% in the irradiated group. Morphological changes were also observed, with irradiated arteries seeing enlarged endothelial cells, formation of fibrin networks, activated platelets, leukocytes exhibiting membrane protrusions and pseudopodial extensions all indicative of an inflammatory and pro-thrombotic state of endothelial dysfunction.

Shen et al. 2018

In vivo. Male mice were irradiated with 18 Gy X-rays. Oxidative stress was measured with 4-HNE and 3-NE oxidative damage markers and antioxidant enzymes catalase and HO-1, measured by immunohistological staining. Endothelial dysfunction was determined through apoptosis.

4-HNE showed a maximum increase of ~1.75-fold, and 3-NT showed a maximum increase of ~2.25-fold. a max increase of 1.75 fold in HO-1 and a max decrease of 0.37 fold in catalase. Apoptosis levels peaked at a ~5-fold increase above control levels.

Ramadan et al. 2020

In vitro. Telomerase-immortalized human Coronary Artery and Microvascular Endothelial cells (TICAE) and Telomerase Immortalized human Microvascular Endothelial cells (TIME) were exposed to X-rays (0.1 and 5 Gy). ROS production was measured using CM-H2DCFDA combined with Incucyte live cell imaging.

Endothelial dysfunction was evaluated through:

endothelial apoptosis

  • Annexin V and Caspase 3/7 marker levels
  • Dextran fluorescein dye uptake level by necrotic cells 

cell senescence

  • SA β-gal activity
  • IGFBP-7 and GDF-15 senescence marker levels

ROS production was increased in TIME cells after 0.1 and 5 Gy dose.

 

In both coronary and endothelial cells, apoptosis mainly occurred after 5 Gy radiation. With coronary cells demonstrating an increase in Annexin V and Caspase 3/7 markers and endothelial cells showing elevated Annexin V and membrane leakage. 

SA β-gal activity significantly increased for both 0.1 and 5 Gy doses. IGFBP-7 and GDF-15 levels were also elevated in both cell types; GDF-15 increasing at both 0.1 and 5 Gy doses, while IGFBP-7 only showed significant elevation at the 5 Gy dose. With the 0.1 Gy dose, there was a significant increase in SA β-gal activity of ~3-fold, while at 5 Gy the activity increased ~5-fold.

Endothelin-1 was found to be significantly elevated following 5 Gy irradiation in both cell types.

Ungvari et al. 2013

In vitro. Cerebral microvascular endothelial cells (CMVECs) from F344×BN rats were harvested and cultured. Following culture, cells were irradiated with 137Cs gamma radiation in doses between 2-8 Gy.

Oxidative stress was evaluated through cellular peroxide and superoxide production.

Endothelial dysfunction was evaluated through cell senescence via SA-β-gal presence, and apoptosis via caspase 3/7 maker and ratio of apoptotic:viable cells.

Oxidative stress increased in a dose-dependent manner following irradiation. Change of ROS became significant after 4 Gy at a ~1.5-fold increase and reached ~3-fold increase at the highest studied dose of 8 Gy. Mitochondrial oxidative stress also became significant after 4 Gy and increased linearly for a peak of a ~1.5-fold increase at 8 Gy.

Endothelial cell senescence and apoptosis were similarly found to increase in a dose dependent manner. With ~30% of cells being SA-β-gal positive after 8 Gy irradiation, signalling premature senescence. Ratio of dead cells peaked at 10% and Caspase 3/7 peaking at a ~5.5-fold change following 18h post irradiation.

Hatoum et al. 2006

In vivo. Effect of cumulative radiation doses on rat gut microvessels was studied. Rats were exposed to 1 to 9 fractions of 250 cGy for a total dose of up to 2250 cGy. Following exposure, the animals were euthanized, and submucosal vessels isolated.

Oxidative stress was measured through superoxide and peroxide levels.

Endothelial function was assessed through ACh vasodilation response.

After the final cumulative dose of 2250 cGy, superoxide was ~1.6-fold elevated and peroxides were ~1.7-fold elevated compared to non-irradiated controls. ROS levels increased sharply after the second dose, immediately preceding drop in ACh vasodilation response.

Max dilation dropped from 87% to 3% between pre-irradiation and post-final radiation dose. ACh response remained within control levels following doses 1 and 2, however following dose 3, response dropped below 30% for all remaining doses.

Delp et al. 2016

In vivo. The effects of HU and 1 Gy dose of 56Fe in vivo radiation on the gastrocnemius muscle feed arteries and coronary arteries of C57BL/6 mice was studied.

Xanthine oxidase (XO) levels were used as a measure of ROS production and therefore oxidative stress.

Endothelial function was evaluated through vasodilation response to ACh.

Following 2-week HU, there were no significant changes to XO levels or vasomotor response.

Following total body irradiation with 1 Gy, there was a ~2-fold increase in XO activity in both gastrocnemius muscle feed and coronary arteries. Vasodilation response subsequently decreased ~10 percentage points.

Combined HU and total body irradiation led to a ~2.25-fold increase in XO activity in both artery types and vasodilation response decrease of ~10 percentage points.

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

Shen et al. 2018

In vivo. Male mice were irradiated with 18 Gy X-rays. Immunohistochemical staining assessed oxidative stress using 4-HNE and 3-NE as markers for oxidative damage and antioxidant enzymes catalase and HO-1. Endothelial dysfunction was determined through apoptosis.

Exposure to 18 Gy showed increased 4-HNE and 3-NT levels. 4-HNE showed a maximum ~1.75-fold increase at 14-days post radiation, and 3-NT showed a maximum ~2.25-fold increase 7 days post radiation. HO-1 showed a similar trend with a maximum at day 7. Catalase decreased to 0.6 fold on day 3 and remained at this level on day 7, then slightly increased to day 84.

Apoptosis levels peaked at 7 days post-irradiation with a ~5-fold increase above control levels.

Ramadan et al. 2020

In vitro. TICAE and TIME cells were exposed to X-rays (0.1 and 5 Gy).

Oxidative stress was evaluated through intracellular ROS production.

Endothelial dysfunction was evaluated through:

endothelial apoptosis

  • Annexin V and Caspase 3/7 marker levels
  • Dextran fluorescein dye uptake level by necrotic cells 

cell senescence

  • SA β-gal activity
  • IGFBP-7 and GDF-15 senescence marker levels

Endothelin-1 levels

Highest oxidative stress response was observed for both doses at 45 minutes after irradiation followed by a decline at the 2- and 3-hour time points, but remaining elevated above non-irradiated control levels. Endothelial cells studied were found to produce more ROS than the compared coronary cells.

 

Caspase 3/7 and annexin V increased linearly until 100h.

SA β-gal activity significantly increased at 7 and 9 days. GDF-15 and IGFBP-7 were increased after 7 days.

Endothelin-1 was found to be significantly elevated after 7 days.

Ungvari et al. 2013

In vitro. Cerebral microvascular endothelial cells (CMVECs) from F344×BN rats were harvested and cultured. Following culture, cells were irradiated with 137Cs gamma radiation.

Oxidative stress was evaluated through cellular peroxide and superoxide production.

Endothelial dysfunction was evaluated through cell senescence via SA-β-gal presence, and apoptosis via caspase 3/7 maker and ratio of apoptotic:viable cells.

Superoxide and peroxide increased 1 day but not 14 days post-irradiation

With ~30% of cells being SA-β-gal positive after 8 Gy irradiation, measured 7 days post-irradiation. 24h after irradiation, 10% of cells were dead. Caspase 3/7 increased from 2 to 18h, peaking at a ~5.5-fold change following 18h post-irradiation but decreased at 24h.

Hatoum et al. 2006

In vivo. Effect of cumulative radiation doses on rat gut microvessels was studied. Rats were exposed to 1 to 9 cGy in 3 fractions per week on alternate days for 3 successive weeks for a total dose of up to 2250 cGy over a total time of 19 days.

Oxidative stress was measured through superoxide and peroxide levels from various fluorescent markers.

Endothelial function was assessed through ACh vasodilation response.

After 19 days, superoxide was ~1.6-fold elevated and peroxides were ~1.7-fold elevated compared to non-irradiated controls. ROS levels increased at day 5, at the same time as a drop in ACh vasodilation response.

Max dilation dropped from 87% to 3% between day 1 and day 19.

Known Feedforward/Feedback loops influencing this KER
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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 is derived from rat in-vivo and in-vitro models. Mice cell-derived studies were also available but less in-vivo evidence was available from this species. There was a low number of studies containing human or pig models to support this KER. Males have been studied more often than females. There are a few studies with unspecified lifestage of models, while the studies with a defined age typically used adult models.

References

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

References

Augustin, H. G., D. H. Kozian and R. C. Johnson (1994), “Differentiation of endothelial cells: Analysis of the constitutive and activated endothelial cell phenotypes”, BioEssays, Vol. 16/12, Wiley, Hoboken, https://doi.org/10.1002/bies.950161208.

Azzam, E. I., J. P. Jay-Gerin and D. Pain (2012), “Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury”, Cancer Letters, Vol. 327/1-2, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2011.12.012.

Baran, R. et al. (2021), “The Cardiovascular System in Space: Focus on In Vivo and In Vitro Studies”, Biomedicines, Vol. 10/1, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/biomedicines10010059.

Beckhauser, T. F., J. Francis-Oliveira and R. De Pasquale (2016), “Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity”, Journal of Experimental Neuroscience, Vol. 10, SAGE Publishing, Thousand Oaks, https://doi.org/10.4137/JEN.S39887.

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.

Borghini, A. et al. (2013), “Ionizing radiation and atherosclerosis: Current knowledge and future challenges”, Atherosclerosis, Vol. 230/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.atherosclerosis.2013.06.010.

Carmeliet, P., and R. K. Jain. (2011), “Molecular mechanisms and clinical applications of angiogenesis”, Nature, Vol. 473/7347, Nature Portfolio, London,  https://doi.org/10.1038/nature10144.

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.

Delp, M. D. et al. (2016), “Apollo Lunar Astronauts Show Higher Cardiovascular Disease Mortality: Possible Deep Space Radiation Effects on the Vascular Endothelium”, Scientific Reports, Vol. 316/23, Nature Portfolio, London, https://doi.org/10.1038/SREP29901.

Elahi, M. M., Y. X. Kong and B. M. Matata (2009), “Oxidative Stress as a Mediator of Cardiovascular Disease”, Oxidative Medicine and Cellular Longevity, Vol. 2/5, Hindawi, London, https://doi.org/10.4161/oxim.2.5.9441.

Fishman, A. P. (1982), “ENDOTHELIUM: A DISTRIBUTED ORGAN OF DIVERSE CAPABILITIES”, Annals of the New York Academy of Sciences, Vol. 401/1, Wiley-Blackwell, Hoboken, https://doi.org/10.1111/j.1749-6632.1982.tb25702.x.

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.

Knock, G. A. and J. P. T. Ward (2011), “Redox Regulation of Protein Kinases as a Modulator of Vascular Function”, Antioxidants & Redox Signaling, Vol. 15/6, Mary Ann Liebert, Larchmont, https://doi.org/10.1089/ars.2010.3614.

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.

Li, J. et al. (2002), “Endovascular irradiation impairs vascular functional responses in noninjured pig coronary arteries”, Cardiovascular Radiation Medicine, Vol. 3/3–4, Elsevier, Amsterdam, https://doi.org/10.1016/S1522-1865(03)00096-9.

Marasciulo, F., M. Montagnani and M. Potenza (2006), “Endothelin-1: The Yin and Yang on Vascular Function”, Current Medicinal Chemistry, Vol. 13/14, Bentham Science Publishers, Sharjah, https://doi.org/10.2174/092986706777441968.

Nagane, M. et al. (2021), “DNA damage response in vascular endothelial senescence: Implication for radiation-induced cardiovascular diseases”, Journal of Radiation Research, Vol. 62/4, Oxford University Press, Oxford, https://doi.org/10.1093/JRR/RRAB032.

Ramadan, R. et al. (2020), “Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage”, Frontiers in Pharmacology, Vol. 11, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphar.2020.00212.

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