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Relationship: 2785

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 Occurrence, Abnormal Vascular Remodeling

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Energy Deposition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Occurrence, Abnormal Vascular Remodeling

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 abnormal vascular remodeling	non-adjacent	High	Low	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed

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	High	NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Juvenile	Moderate
Adult	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Deposition of energy can trigger vascular remodeling through many pathways (Tapio, 2016) including changes to vessel structure and blood flow (Patel, 2020; Sylvester et al., 2018). Pro-inflammatory mediators can be increased, which can result in a low level of inflammation causing intimal thickening (Sylvester et al., 2018). Deposition of energy can generate reactive oxygen species (ROS) and highly reactive radicals sparsely from low- linear energy transfer (LET) radiation and densely from high-LET radiation, which can cause endothelial dysfunction and subsequent vascular remodeling (Boerma et al., 2015; Hughson, Helm & Durante, 2017; Slezak et al., 2017; Soloviev & Kizub, 2019; Sylvester et al., 2018). Increased production of ROS changes the bioavailability of nitric oxide (NO), a diffusible molecule responsible for vasodilation, which leads to inhibited vasomotion and cellular senescence as components of endothelial dysfunction (Patel, 2020; Soloviev & Kizub, 2019). Changes in the expression or activity of proteins in many signaling pathways can lead to endothelial dysfunction (Schmidt-Ullrich et al., 2000; Tapio, 2016). In addition, the increased pro-inflammatory mediators can lead to endothelial dysfunction and therefore, vascular remodeling (Tapio, 2016). Another possible vascular remodeling change is age accelerated atherosclerosis (EPRI, 2020; Hamada et al., 2014). Studies using varying LET, delivered at acute and chronic dose-rates, have shown remodeling of the vasculature (reviewed in Tapio, 2016).

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 suggesting that deposition of energy leads to abnormal vascular remodeling is well-supported by reviews and mechanistic studies published in the literature. Vascular remodeling may occur due to aging and diet (Zieman, Melenovsky & Kass, 2005). However, the deposition of energy from ionizing radiation (IR) can accelerate vascular remodeling in the form of accelerated atherosclerosis (Boerma et al., 2015; Boerma et al., 2016; EPRI, 2020; Hamada et al., 2014; Hughson, Helm & Durante, 2017; Mitchell et al., 2019; Sylvester et al., 2018), which can be demonstrated by arterial thickening or the amount of oxidized low-density lipoprotein (oxLDL) (Poznyak et al., 2021). Remodeling normally allows adaptation to long-term hemodynamic changes but can also contribute to vascular diseases (Gibbons & Dzau, 1994). Various short-term post-spaceflight studies have shown vascular remodeling after deposition of energy from space IR (Patel, 2020).

Under physiological conditions, the body maintains a balance of ROS and NO levels. IR generates ROS that can react with NO and reduce its bioavailability, causing endothelial dysfunction and vascular stiffness (Patel, 2020). Similarly, signaling pathways can cause vascular remodeling through endothelial dysfunction and altered NO (Tapio, 2016). Increased ROS or altered signaling can cause a prolonged inflammatory response; this has been observed in animal models exposed to high-LET radiation (Hughson, Helm & Durante, 2017; Sylvester et al., 2018; Tapio, 2016). The low level of inflammation results in intimal thickening and inhibits tissue and vessel recovery (Sylvester et al., 2018). Microvascular injury and inflammation may cause angiogenesis, which prevents vascular resistance (Slezak et al., 2017). However, depending on the source, radiation may have different effects on angiogenesis (Grabham & Sharma, 2013). An increase in pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), secreted as a consequence of photon irradiation can promote angiogenesis. Exposure to low-LET protons and high-LET heavy ion radiation can disturb angiogenesis due to decreased VEGF secretion and tubule formation (Grabham & Sharma, 2013; Sylvester et al., 2018). Matrix metalloproteinases (MPPs) are involved in remodeling of the extracellular matrix (ECM) and can affect various pathological processes after irradiation (Slezak et al., 2017). Following radiation, existing collagen in the heart may be remodeled, which indicates ECM remodeling (Shen et al., 2018; Sridharan et al., 2020; Zieman, Melenovsky & Kass, 2005). Thus, many mechanisms exist via which the deposition of energy can lead to abnormal vascular remodeling; these are generally well understood and described in the literature, leading to a strong weight of evidence for the biological plausibility of this KER.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

There is moderate empirical evidence supporting the connection between deposition of energy leading to abnormal vascular remodeling. The evidence was gathered from studies using in vivo rat and mouse models, as well as in vitro models of human vessels and ex vivo human vessel biopsies (Grabham et al., 2011; Hamada et al., 2020; Hamada et al., 2021; Hamada et al., 2022; Russel et al., 2009; Sarkozy et al., 2019; Shen et al., 2018; Soucy et al., 2007; Soucy et al., 2010; Soucy et al., 2011; Sridharan et al., 2020; Yu et al., 2011). The models used stressors such as iron ions (56Fe) (Soucy et al., 2011; Yu et al., 2011), gamma rays (Hamada et al., 2020; Hamada et al., 2021; Hamada et al., 2022; Soucy et al., 2007; Soucy et al., 2010), X-rays (Hamada et al., 2021; Hamada et al., 2022; Shen et al., 2018), electrons (Sarkozy et al., 2019), protons and oxygen ions (16O) (Sridharan et al., 2020). Vascular stiffness measured by pulse wave velocity (PWV) and vascular composition (Hamada et al., 2020; Hamada et al., 2021; Hamada et al., 2022; Shen et al., 2018; Soucy et al., 2007; Soucy et al., 2010; Soucy et al., 2011; Sridharan et al., 2020), vessel thickness/diameter measured directly (Sarkozy et al., 2019; Shen et al., 2018; Soucy et al., 2011; Sridharan et al., 2020; Yu et al., 2011) and other morphological changes (Hamada et al., 2020; Hamada et al., 2021; Hamada et al., 2022) were used as endpoints for vascular remodeling.

Dose Concordance

PWV is often measured to determine vascular stiffness and therefore remodeling, where PWV is quadratically proportional to Young's modulus (measure of a material’s stiffness) (Pereira, Correia & Cardoso, 2015; Soucy et al., 2011). The PWV of irradiated rats increased with an increase in radiation dose. Across several studies, 0.5, 1, 1.6, and 5 Gy doses were tested, with responses of 1.1 to 1.2-fold changes to PWV (Soucy et al., 2007, 2010, 2011). PWV is also quadratically proportional to the vessel diameter and inversely quadratically proportional to the vessel wall thickness. However, Soucy et al. (2011) found no significant change in the aortic wall thickness:lumen diameter ratio, indicating the change in PWV was due to changes in vessel composition and not geometric remodeling. Collagen composition in the membrane was also measured to determine vascular composition and therefore remodeling, with increased collagen indicating stiffness (Zieman, Melenovsky & Kass, 2005). Collagen accumulation increased 1.4-fold after 18 Gy X-ray irradiation (Shen et al., 2018) and 1.5-fold after various regiments of 5 Gy X-rays (Hamada et al., 2021; Hamada et al., 2022) in mice. Following 12 months of 16O exposure, the tissue content of collagen type III peptide increased 2.3-fold and 2-fold at 0.05 Gy and 0.25 Gy, respectively (Sridharan et al, 2020). VE-cadherin, a marker for adherens junctions, decreased 0.2- to 0.3-fold in mice after various regimens of 5 Gy gamma and X-rays, with a high decrease in the acute and fractionated doses and no change after chronic gamma rays (Hamada et al., 2022; Hamada et al., 2021; Hamada et al., 2020). oxLDL increased in mice after X-ray irradiation at both 8 and 16 Gy; however, the increase was not greater at 16 Gy relative to 8 Gy (Azimzadeh et al., 2015).

Vessel thickness was also measured in various studies. Aortic thickness increased 1.4-fold after 18 Gy X-ray irradiation of mice (Shen et al., 2018). Iron ion irradiation on apolipoprotein E (apoE)-deficient mice, a model for atherosclerosis, at both 2 and 5 Gy showed a 1.4-fold increase in carotid artery intima thickness compared to sham-irradiated apoE-deficient mice (Yu et al., 2011). Markers of vascular remodeling, anterior and inferior wall thicknesses in systole (AWTs and IWTs) and diastole (AWTd and IWTd) were measured after a high dose of 50 Gy electrons. AWTs increased 1.3-fold, IWTs increased 1.1-fold, AWTd increased 1.5-fold and IWTd increased 1.2-fold (Sarkozy et al., 2019). In turn, patients having undergone radiation treatment for head and neck or breast cancer with radiation doses totaling 66 Gy and 49 Gy, respectively, observed increased intima-media ratios (IMR) of 1.5- and 1.4-fold, respectively (Russel et al., 2009). Mice that did not show endothelial detachments before irradiation showed high frequencies of detachments after acute doses of 5 Gy gamma and X-rays (Hamada et al., 2020; Hamada et al., 2021). Vascular permeability was also significantly increased after 5 Gy gamma rays in mice (Hamada et al., 2020).

Radiation type can affect the nature of vascular remodeling following exposure. A study using 3D vessel models of endothelial cells in a gel matrix showed that high-LET iron-ions reduces vessel length in both mature and developing vessels after only 0.8 Gy. In contrast, low-LET protons only inhibited growth in developing vessels at 0.8 Gy and required a dose of 3.2 Gy to affect mature vessels. γ radiation required a dose of 0.8 Gy to inhibit vessel growth and 6.4 Gy for any significant breakdown of mature vessels (Grabham et al., 2011).

Time Concordance

In rats irradiated with 5 Gy gamma rays, PWV as a measure of arterial stiffness increased from 3.9 m/s before irradiation to around 4.5 m/s after 1 day, 1 week and 2 weeks (Soucy et al., 2007). Under the same conditions, PWV increased from 4.1 m/s before irradiation to 4.6 m/s after 1 day, 4.9 m/s after 1 week, and 4.8 after 2 weeks in a separate study by the same authors (Soucy et al., 2010). Using 1 Gy iron ions instead, PWV increased by 0.5 m/s both 4 months and 8 months post-irradiation (Soucy et al., 2011). Mice irradiated with 18 Gy X-rays showed significantly increased aortic thickness 1.4-fold after 7 days and 1.3-fold after 14 and 28 days, while collagen accumulation increased 1.4-fold after 14, 28 and 84 days (Shen et al., 2018). ApoE-deficient mice that were irradiated with both 2 and 5 Gy iron ions showed a 1.4-fold increase in carotid artery intima thickness after 13 weeks compared to controls (Yu et al., 2011). Mice irradiated with 8 and 16 Gy of X-rays showed increased oxLDL levels at 16 weeks post-irradiation (Azimzadeh et al., 2015). Ventricular posterior wall thickness decreased at 3- and 5-months post-irradiation, and PWV increased at 12 months post-irradiation with 16O irradiation (Sridharan et al., 2020). The results suggest that 16O irradiation may lead to long-term vascular dysfunction in rats similar to iron ions in the studies by Soucy et al. (2011) and Yu et al. (2011). Collagen type III increased 2.4-fold after 12 months of 0.5 Gy proton irradiation (Sridharan et al., 2020). CD2, CD4 and CD8 markers for the T-protein lymphocytes that are thought to be involved with promoting hypertension and microvascular remodeling increased in rat hearts 6 months after a 0.1 Gy dose of 16O, and 12 months after a single 0.5 Gy dose of 16O (Sridharan et al., 2020). Mice irradiated with 5 Gy gamma rays showed increased endothelial detachments, increased vascular permeability and VE-cadherin expression at 1, 3 and 6 months after irradiation (Hamada et al., 2020; Hamada et al., 2021). VE-cadherin was also increased 12 months after irradiation, but endothelial detachments were no longer present (Hamada et al., 2022).

Essentiality

Vascular remodeling such as arterial stiffness occurs naturally with aging, but deposition of energy can accelerate this process (Zieman, Melenovsky & Kass, 2005). Since deposited energy initiates events immediately, the removal of deposited energy also supports the essentiality of the key event. Studies that do not deposit energy are observed to have no downstream effects.

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

Not all results show the expected dose-response. For example, total collagen and collagen type III peptide levels studied in Sridharan et al. (2020) did not consistently increase with increasing dose. Similarly, oxLDL levels were higher at the 8 Gy dose compared to the 16 Gy dose (Azimzadeh et al., 2015).

Low doses of radiation administered at a low dose rate have been shown to be anti-inflammatory leading to improved vascular function (reviewed in Guéguen et al., 2019).

Ebrahimian et al. (2015) highlights the importance of dose-rate effects, demonstrating that lower dose rates of radiation exposure in vitro can lead to a more subdued inflammatory response and reduced changes in vascular networks compared to high dose rates.

Yu et al. (2011) showed that intimal thickness increased at 13 weeks after iron ion irradiation of apoE-deficient mice. At 40 weeks post-irradiation, intimal thickness remained at similar levels, but the level was no longer statistically significant because the sham-irradiated group showed higher intimal thickness.

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	Oxypurinol (Oxp, a xanthine oxidase (XO) inhibitor to prevent ROS production)	Oxp treatment reduced PWV after irradiation through reduced oxidative stress	(Soucy et al., 2010; Soucy et al., 2011)
Drug	hBMSCs (human bone marrow mesenchymal stem cells, assist in repairing vascular injuries)	Treatment with hBMSCs reduced aortic thickness after irradiation	(Shen et al., 2018)
Sex	Epidemiology and pathophysiology of vascular remodeling related to CVD progression differs between the sexes.	Sex hormones are thought to play a role in several remodeling mechanisms such as hypertrophy, inflammation, fibrosis and apoptosis. Sex-specific genetic components are also involved in the variation of remodelling between sexes.	(Winham, de Andrade & Miller, 2015; Kessler et al., 2019)
Age	Increased age increases the occurrence and severity of vascular remodelling	Advanced age is linked to vascular changes such as luminal enlargement with wall thickening and decrease of endothelial function with related increase in vessel stiffness. The effect of radiation exposure is sometimes referred to as an acceleration of age-related cardio-pathology. Additionally, age-related changes in sex hormones are modulators of vascular structure.	(North & Sinclair, 2012; Harvey, Montezano, & Touyz, 2015; Ungvari et al., 2018; Kessler et al., 2019)
Genetics	CVD progression (of which vascular remodelling is part) are complex traits with genetic	Traits such as baseline carotid intima-medial thickness (CIMT), vascular stiffness and prevalence of coronary calcification have been found to have a hereditary component and some are shown to vary by ethnicity. Sex-specific genetics also play a role in genetic modulation with some genes relaxed to hypertension and adverse cardiac remodeling processes found on the Y chromosome. Additionally, X chromosome inactivation is implicated in remodelling.	(Berk & Korshunov, 2006; Winham, de Andrade & Miller, 2015)

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The following table provides examples of quantitative understanding of the relationship. All data that is represented is statistically significant unless otherwise indicated.

Response-response Relationship

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

Dose Concordance

Reference	Experimental Description	Result
Sridharan et al., 2020	In vivo. In study B, male rats were exposed to oxygen ions (0.01-0.25 Gy). Heart tissue analysis was performed 6-7 and 12 months after radiation using histology and western blots.	Study B: At 12 months after 16O exposure, the tissue content of the 75 kDa collagen type III peptide increased 2.3-fold and 2-fold at 0.05 Gy and 0.25 Gy respectively.
Soucy et al., 2007	In vivo. Sprague-Dawley rats were irradiated with 137Cs gamma rays (0.5, 1.6, 5 Gy). Vascular stiffness was calculated using PWV with an ECG and doppler probe.	At 0.5 and 1.6 Gy, PWV increased from 3.9 m/s (before irradiation) to 4.2 m/s. At 5 Gy PWV increased to 4.6 m/s.
Grabham et al., 2011	In vitro. 3D models of human vessels were created using human endothelial cells in gel matrix. Mature and developing vessel models were exposed to iron-ion (1 GeV/nucleon; LET 151 keV/um) and proton (1 GeV/nucleon; LET 0.22 keV/um) radiation at a 0.1-1 Gy/min dose rate or 137Cs gamma radiation at 85 cGy/min dose rate. Vessel length as determined by length of capillary with lumen per cell was evaluated by DTAF staining for proteins and propidium iodide for nuclei.	In mature vessels, iron-ion exposure reduced vessel length significant starting after 0.8 Gy with a 44% decrease in length after 1.6 Gy. Proton exposure produced no significant change, while gamma exposure required a dose of 6.4 Gy for significant vessel length breakdown. In developing vessels iron-ion exposure of 0.8 Gy decreased length by 50%, proton exposure of 0.4 Gy inhibited development and 0.8 Gy decreased length by 60%, while gamma exposure of 0.8 Gy inhibited vessel growth, and 6.4 Gy was required to reduce vessel length.
Soucy et al., 2011	In vivo. 56Fe ions were used to irradiate rats at 0.5 or 1 Gy (0.5 Gy/min). PWV measured with Doppler probe and ECG and aortic wall thickness:lumen diameter ratio measured with histological analysis were used to determine vascular remodeling.	After 0.5 Gy, there was no significant change in PWV, but at 1 Gy there was a significant 1.1-fold increase in PWV. No change in aortic wall thickness:lumen diameter was observed after either dose.
Yu et al., 2011	In vivo. 56Fe ions were irradiated onto apoE-/- mice, and intima thickness of the carotid artery was measured using hematoxylin and eosin staining at 0, 2 and 5 Gy doses and a 13- and 40-weeks post-irradiation.	13-weeks post irradiation, both 2 and 5 Gy doses showed a maximum 1.5-fold elevation in thickness compared to controls. 40-weeks post irradiation there was no significant difference between the control, 2 Gy, and 5 Gy groups.
Soucy et al., 2010	In vivo. Rats were irradiated with 5 Gy 137Cs gamma radiation and PWV, measured with Doppler probe and ECG was used as a measure of aortic stiffness and vascular remodeling.	After 5 Gy, maximum PWV increased 1.2-fold compared to PWV pre-irradiation.
Hamada et al., 2020	In vivo. Male mice were irradiated by 5 Gy 137Cs gamma rays (0.5 Gy/min) and compared to 0 Gy control. Vascular remodeling was measured through a Miles assay to show vascular permeability, vascular endothelial cadherin (VE-cadherin, a marker for adherens junctions) levels and number of endothelial detachments.	Vascular permeability increased to a maximum of 16-fold as shown by staining intensity; VE-cadherin decreased to a maximum of 0.2-fold and percent of mice with total endothelial detachments increased from 0 to 90% at the maximum response.
Hamada et al., 2021	In vivo. Either acute or chronic doses of X-rays and 137Cs gamma rays were given to B6J mice, all resulting in 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. Vascular remodeling was measured by IMT, collagen content (aniline blue staining), VE-cadherin levels and number of mice with detachments 6 months post-irradiation.	IMT in the aorta increased about 2-fold after all X-ray treatments, but chronic gamma rays did not cause a change and acute gamma rays were not measured. Stained intensity to show collagen content increased about 1.5-fold for both the acute and 25 fractions X-ray regimens, but not in others. VE-cadherin decreased after acute gamma rays (0.2-fold) and all X-ray doses (0.2- to 0.3-fold). After acute gamma and X-rays and 25 fraction X-rays the percent of mice with a detachment went from 0 to a maximum of 100%.
Hamada et al., 2022	In vivo. Either acute or chronic doses of X-rays and 137Cs gamma rays were given to B6J mice, all resulting in 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 chronically at <1.4 mGy/h for 153 days. Vascular remodeling was measured by IMT, collagen content (aniline blue staining), VE-cadherin levels and number of mice with detachments 12 months post-irradiation.	IMT in the aorta increased about 1.3-fold after X-rays in acute or 25 fraction regimens, but not after other regimens. Collagen content increased about 1.1-fold for all regimens except X-rays at 100 fractions. VE-cadherin decreased after all X-ray doses (maximum 0.5-fold). No mice were observed to have a detachment.
Azimzadeh et al., 2015	In vivo. 10-week-old male C57Bl/6 mice received cardiac irradiation at 8 or 16 Gy with X-rays. Serum oxLDL was measured using ELISA.	oxLDL increased 1.2-fold after 8 Gy and 1.1-fold after 16 Gy compared to 0 Gy control.
Shen et al., 2018	In vivo. Male mice irradiated with 18 Gy X-rays had measurements of aortic thickness determined at various times using hematoxylin and eosin staining. The accumulation of collagen was measured using Sirius red staining. Endpoints were evaluated at 3-, 7-, 14-, 28- and 84-days post exposure and compared to a sham-irradiated control group.	Sham-irradiated control: Thickness and collagen accumulation remained unchanged throughout the timepoints tested. 18 Gy irradiated: Thickness and collagen accumulation were elevated above control at all time points tested. Thickness peaked 7-days post exposure with a 1.4-fold increase compared to controls. Collagen accumulation peaked at 14-days post exposure with a 1.4-fold increase above controls.
Sarkozy et al., 2019	In vivo. Rats were irradiated with 50 Gy electrons (5 Gy/min). Various markers of vascular remodeling, anterior and inferior wall thicknesses in systole (AWTs and IWTs) and diastole (AWTd and IWTd) were measured with an echocardiograph. Endpoints were evaluated at 1, 3 and 19-weeks post-irradiation.	All three timepoints tested showed significant differences in cardiac structure measures between 50 Gy irradiated and 0 Gy control groups. By week 19, AWTs increased 1.3-fold, IWTs increased 1.1-fold, AWTd increased 1.5-fold and IWTd increased 1.2-fold.
Russel et al., 2009	Ex vivo. Recipient arteries from 147 patients receiving reconstructive surgery following treatment for head and neck cancer (H&N) or breast cancer (BC) were studied. H&N treatment group received 66 Gy (standard deviation 7 Gy) dose of radiation, while BC group received 49 Gy (standard deviation 3 Gy). Intimal-medial thickness in the form of intima-media ratio (IMR) was assessed through histology and proteoglycan and collagen content were scored. Analysis compared irradiated vessels, unirradiated vessels from the same patient as well as donor controls.	In the H&N group the IMR was 1.5-fold greater without correction for the control artery. In the BC group the IMR increased 1.4-fold after correction for the control artery at a mean of 4 years following irradiation. There was an increase in the proteoglycan content of the intima of the irradiated IMA vessels, from 65% to 73%.

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
Sridharan et al., 2020	In vivo. Male rats were exposed to oxygen ions and whole-body protons (0.5 Gy) to measure cardiac function and blood flow in study A. Measurements were taken at 3, 5, 9 and 12 months after radiation. Ultrasound, histology and Western blots were used as measurement methods. In study B, male rats were exposed to oxygen ions (0.01-0.25 Gy). Heart tissue analysis was performed 6-7 and 12 months after radiation using histology and western blots.	Study A: At 3 and 5 months after proton and oxygen ion radiation, there was a significant decrease in left ventricular posterior wall thickness. 12 months after oxygen ion exposures, velocity measures of pulsed wave Doppler of abdominal aorta increased. Cardiac volume increased at all time points in proton exposed rats, with a significance at 3 and 9 months. Collagen type III increased 2.4-fold after 12 months of 0.5 Gy protons radiation. Protein T lymphocyte markers CD2, CD4 and CD8 content in the rat hearts increased 6 months after a dose of 16O at 0.1 Gy. CD2, CD4 and CD8 increased 1.4-fold 12 months after 16O at 0.5 Gy.
Soucy et al., 2007	In vivo. Sprague-Dawley rat aorta was irradiated with 0.5, 1.6 and 5 Gy 137Cs gamma rays. A measure of vascular stiffness and vascular remodeling was calculated using PWV and measurements taken with an ECG and doppler probe.	At 1 day post irradiation in each group PWV significantly increased. At 1- and 2-weeks levels remained similar to the 1-day results, but slightly increased in the 500 cGy group and slightly decreased in the 50 and 160 cGy groups.
Soucy et al., 2011	In vivo. 56Fe ions were used to irradiate rats (0.5 Gy/min). PWV measured with Doppler probe and ECG was used to determine vascular remodeling.	At 4 months after irradiation with 1 Gy, PWV increased by ~0.5 m/s. At 8 months, PWV remained at a 0.5 m/s increase over control.
Yu et al., 2011	In vivo. 2 and 5 Gy 56Fe ions were irradiated onto apoE-/- mice, and intima thickness of the carotid artery was measured using hematoxylin and eosin staining after 13 and 40 weeks.	At both doses, after 13 weeks, intima thickness increased 1.4-fold. Intima thickness was the same as control after 40 weeks.
Soucy et al., 2010	In vivo. Rats were irradiated with 5 Gy 137Cs gamma radiation and PWV, measured with Doppler probe and electrocardiogram (ECG) over 2 weeks, was used as a measure of aortic stiffness and vascular remodeling.	PWV increased 1.1-fold (not significant) after 1 day, 1.2-fold after 1 week and 1.2-fold after 2 weeks.
Hamada et al., 2020	In vivo. Male mice were irradiated by 5 Gy 137Cs gamma rays (0.5 Gy/min). Vascular remodeling was measured after 1, 3 and 6 months through a Miles assay to show vascular permeability, vascular endothelial cadherin (VE-cadherin, a marker for adherens junctions) levels and number of endothelial detachments.	Vascular permeability increased 8-fold at 1 month, 16-fold at 3 months and 5-fold at 6 months shown by staining intensity. VE-cadherin decreased about 0.2-fold after 1, 3, and 6 months. Percent of mice with total endothelial detachments increased from 0 to 20% at 1 month, 34% at 3 months and 90% at 6 months post-irradiation.
Shen et al., 2018	In vivo. Male mice irradiated with 18 Gy X-rays had measurements of aortic thickness determined from 3 to 84 days post-irradiation using hematoxylin and eosin staining. The accumulation of collagen was measured using Sirius red staining from 3 to 84 days.	Aortic thickness increased 1.1-fold after 3 days (ns), 1.4-fold after 7 days, 1.3-fold after 14 and 28 days and 1.2-fold (ns) after 84 days. Collagen increased 1.4-fold 14-, 28- and 84- days post-irradiation.
Azimzadeh et al., 2015	In vivo. 10-week-old male C57Bl/6 mice received cardiac irradiation at 8 or 16 Gy with X-rays. Serum oxLDL was measured using ELISA 16 weeks post-irradiation.	After 16 weeks, oxLDL increased 1.2-fold after 8 Gy and 1.1-fold after 16 Gy compared to 0 Gy control.

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

None exist

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 relationship has been shown in vivo in mice and rats and ex vivo in human models. Majority of studies used males. Evidence came from either adult or adolescent animals. However, the relationship is plausible at any life stage.

References

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

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