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Relationship: 2777

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

Increased pro-inflammatory mediators 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 Do not cite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 Low 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 Low
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

Activated endothelial cells can then lead to overexpression of pro-inflammatory mediators, including the cytokines tumor necrosis factor-α (TNF-α), interleukin 1 beta and 6 (IL-1β, IL-6), chemokines monocyte chemoattractant protein 1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) (Venkatesulu et al., 2018). An increase in pro-inflammatory mediators, can lead to inflammatory response which can disrupt cellular homeostasis and if persistent can lead to eventual endothelial dysfunction (Korpela & Liu, 2014). Normally, an inflammatory response provides a protective effect to the endothelium but if prolonged (over months) it can exhaust this protective inflammatory effect, as a result, endothelial cells may become senescent or apoptotic, leading to endothelial dysfunction (Deanfield et al., 2007; Bonetti et al., 2003, Wang et al., 2016; Hughson et al., 2018; Ramadan 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

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 biological plausibility surrounding the connection between increased pro-inflammatory mediators leading to increase in endothelial dysfunction is well-supported by literature this has been demonstrated in animal studies and human cell models (Shen et al., 2018; Chang et al., 2017; Baselet et al., 2017; Ramadan et al., 2020; Ungvari et al., 2013). Inflammation can initially provide a protective effect to the endothelium, but chronic inflammation can exhaust this protective inflammatory effect resulting in loss of endothelial integrity and resident cells becoming senescent or apoptotic, 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. These changes lead to endothelial dysfunction, which also affects dysregulation of vasodilation (Wang et al., 2016; Hughson et al., 2018; Ramadan et al., 2021). The inflammatory response is regulated by a balance between pro-inflammatory mediators and anti-inflammatory mediators, and specific cytokine profiles are dependent on parameters of the stressor/exposure/insult (Wang et al., 2019). The pro-inflammatory cytokines TNF and IL-1 play a critical role by triggering a cytokine cascade, which initiates an inflammatory response to promote healing and restore tissue function. TNF is able to induce apoptotic cell death, which is implicated in endothelial dysfunction. Nuclear factor kappa B (NF-кB) is also activated, which targets multiple genes coding for vascular cell adhesion proteins (VCAM), ICAM, and IL-1, as well as prothrombotic markers (Slezak et al., 2017). NF-кB mediates a pro-survival and pro-inflammatory state. Inflammation persisting for months leads to prolonged chronic inflammation which causes an ineffective healing process, further worsened by a decrease in endothelium-dependent relaxation. This causes endothelial dysfunction, making vasculature more vulnerable to damage from non-laminar flow (Sylvester et al., 2018). Senescent cells also have a pro-inflammatory secretory phenotype, which further contributes to negative effects on the endothelium. Increased pro-inflammatory mediators may be due to increased expression but may also be attributed to increased permeability of the endothelium as seen after irradiation in animal models, which results in increased transmigration of inflammatory cells into the endothelium and can lead to eventual dysfunction (Hughson et al., 2018).

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 of the evidence for this relationship comes from in vitro studies; further work is needed to determine the certainty of the relationship at the tissue level.
  • Although studies often measure pro-inflammatory mediators at a few specific time points, chronic inflammation is what contributes to endothelial dysfunction. More human studies should examine the temporal concordance of this relationship to identify whether the inflammation is chronic.

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

TAT-Gap19 (connexin 43 hemichannel blocker)

Attenuated the radiation-induced increase of many pro-inflammatory mediators.

(Ramadan et al., 2020)

Media

Mesenchymal stem cell conditioned media

The increase in various pro-inflammatory mediators was reduced.

(Chang et al., 2017)

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. Human telomerase immortalized coronary artery endothelial cells (TICAE) were irradiated with X-rays in the range of 0.05-2 Gy at a dose rate of 0.50 Gy/min.

Inflammatory markers IL6 and CCL2 were measured with a multiplex bead array. SA β-gal activity (marker for endothelial cell senescence) was measured with absorbance at 570 nm.

Pro-inflammatory mediators CCL2 and IL-6 show a slight but insignificant increase at 0.05 and 0.1 Gy. SA-β-gal, a marker for endothelial dysfunction, increased 1.25-fold after 0.05 Gy and 1.5-fold after 0.1 Gy. IL-6 and CCL2 increased 2-fold after 0.5 Gy, while SA-β-gal had a 1.5-fold increase. After 2 Gy IL-6 increased 3-fold, CCL2 increased 4-fold and SA-β-gal had a 1.5-fold increase.

Shen et al., 2018

In vivo. Male mice were irradiated with 18 Gy of X-rays. Endpoints were assessed in the aorta. Inflammatory markers TNF-α, and ICAM-1 were measured with immunohistological staining. Aortic apoptosis was measured with TUNEL staining.

TNF-α and ICAM-1 increased 2-fold following irradiation. Apoptosis, a marker of endothelial dysfunction, increased 5-fold.

Chang et al., 2017

In vivo and in vitro. Mice and human endothelial cells were irradiated with 10 Gy of X-rays at a dose rate of 1.5 Gy/min. Pro-inflammatory markers IL-1α, IL-6 and TNF-α were measured with commercial ELISA kits for the in vivo study. IL-8 was measured in the in vitro study. HUVEC apoptosis (as a sign of endothelial dysfunction) was analyzed with flow cytometry.

Following 10 Gy, IL-8 increased 4-fold following irradiation. IL-1α, IL-6, and TNF-α were also increased but significance was not indicated. Apoptosis increased 5-fold.

Ungvari et al., 2013

In vitro. Primary rat endothelial cells were irradiated with 2-8 Gy of gamma rays. Concentration of inflammatory markers IL-6, IL-1α, MCP-1 and IL-1β were measured with a magnetic multiplex bead array. Percentage of SA-β-gal positive cells (marker for endothelial cell senescence) was measured with a histological staining kit.

After 6 Gy, IL-6 secretion increased 1.75-fold, IL-1α increased 1.6-fold, MCP-1 increased 1.4-fold, and IL-1β increased 1.6-fold. SA-β-gal positive cells increased from 0% at control to ~30% (n.s.)

Ramadan et al., 2020

In vitro. Human endothelial cells were irradiated with either 0.1 or 5 Gy of X-rays at a dose rate of 0.5 Gy/min. . Pro-inflammatory mediators were determined by cytokine detection, including MCP-1, IL-8, IL-1β, VCAM-1, IL-6, PECAM-1, TNF-α, CRP, E-selectin, and ICAM-1. SA-β-gal activity as a marker for endothelial cell senescence was measured.

At 5 Gy, MCP-1 increased 4-fold, IL-1β increased 1.5-fold, IL-8 and VCAM-1 increased 2-fold, and IL-6 increased 3-fold. SA-β-gal activity increased by 1.5-fold in TICAE cells.

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

Baselet et al., 2017

In vitro. Human telomerase immortalized coronary artery endothelial cells (TICAE) were irradiated with X-rays in the range of 0.05-2 Gy at a dose rate of 0.50 Gy/min.

Inflammatory markers IL6 and CCL2 were measured with a multiplex bead array. SA β-gal activity (marker for endothelial cell senescence) was measured with absorbance at 570 nm.

At 1-day post-irradiation, IL6 increased to 1.5-fold and at 2 days, CCL2 had increased to 4-fold over the control. At 14 days post-irradiation, SA-β-gal had a maximum increase of 1.5-fold.

Ramadan et al., 2020

In vitro. Human endothelial cells were irradiated with 5 Gy of X-rays at a dose rate of 0.5 Gy/min. Pro-inflammatory mediators were determined by cytokine detection, including MCP-1, IL-8, IL-1β, VCAM-1, IL-6, PECAM-1, TNF-α, CRP, E-selectin, and ICAM-1. SA-β-gal activity as a marker for endothelial cell senescence was measured.

Pro-inflammatory mediators were significantly increased as soon as 24 hours post-irradiation. After 7 days MCP-1 increased 4-fold, IL-1β increased 1.5-fold, IL-8 and VCAM-1 increased 2-fold, and IL-6 increased 3-fold. SA-β-gal activity increased by 1.5-fold.

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

Pro-inflammatory mediators can induce endothelial cell senescence and subsequent endothelial dysfunction. Senescent endothelial cells can secrete many pro-inflammatory cytokines and chemokines, contributing to further senescence of other endothelial cells and further endothelial dysfunction (Hughson et al., 2018; Wang et al., 2016).

Domain of Applicability

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The majority of the evidence is derived from in vitro studies, and a single in vivo study in male pre-adolescent mice.

References

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

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.

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.

Chang, P. Y. et al. (2017), “MSC-derived cytokines repair radiation-induced intra-villi microvascular injury”, Oncotarget, Vol. 8/50, Impact Journals, Buffalo, https://doi.org/10.18632/oncotarget.21236.

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.

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.

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.

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.

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.

Slezak, J. et al. (2017), “Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury”, Canadian journal of physiology and pharmacology, Vol. 95/10, Canadian Science Publishing, Ottawa, https://doi.org/10.1139/cjpp-2017-0121.

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.

Soloviev, A. I. and I.V. Kizub (2019), “Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction”, Biochemical pharmacology, Vol. 159, Elsevier, Amsterdam, https://doi.org/10.1016/j.bcp.2018.11.019.

Ungvari, Z. et al. (2013), “Ionizing Radiation Promotes the Acquisition of a Senescence-Associated Secretory Phenotype and Impairs Angiogenic Capacity in Cerebromicrovascular Endothelial Cells: Role of Increased DNA Damage and Decreased DNA Repair Capacity in Microvascular Radiosensitivity”, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 68/12, Oxford University Press, Oxford, https://doi.org/10.1093/gerona/glt057.

Venkatesulu, B. P. et al. (2018), “Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms”, JACC: Basic to translational science, Vol. 3/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.jacbts.2018.01.014.

Wang, H. et al. (2019), “Radiation-induced heart disease: a review of classification, mechanism and prevention”, International Journal of Biological Sciences, Vol. 15/10, Ivyspring International Publisher, Sydney, https://doi.org/10.7150/ijbs.35460.

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