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Relationship: 2784

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

Increase, Endothelial Dysfunction leads to Occurrence, Vascular Remodeling

Upstream event

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

Increase, Endothelial Dysfunction

Downstream event

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

Occurrence, 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 vascular remodeling	adjacent	Moderate	Low	Cataia Ives (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	Moderate	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	Moderate

Life Stage Applicability

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

Term	Evidence
Adult	Moderate
Juvenile	Low
Not Otherwise Specified	Moderate

Key Event Relationship Description

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

Proper endothelial activation is a key step in the growth of new vessels through the process of angiogenesis, a process also affected by a dysfunctional endothelium (Rajashekhar et al., 2006). Regional responses to stressors are also possible, with mechanical stressors differentially affecting pressure in vessels above (superior to) and below (inferior to) the heart (Hargens & Watenpaugh, 1996; Zhang, 2001). The endothelial layer is responsive to these variations in mechanical stresses and can adapt through altering the balance between hypertrophic and hypotrophic remodeling in smooth vessel cells lining vasculature (Baeyens et al., 2016) in part through altering the progression of the acid sphingomyelinase (ASM)/ceramide (Cer) pathway (Cheng et al., 2017).

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

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

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

Lower doses (0.5 Gy and 1.6 Gy) did not show changes in vasomotion compared to control, but vascular stiffness increased at these doses (Soucy et al., 2007).
Tarasova et al. (2020) showed differences in the vascular remodeling and vasoconstriction responses between skeletal and cutaneous arteries. While the two groups demonstrated differences, all vessels followed different trends showing no clear relationship between KEs.
Studies exploring vasoreactivity, vascular structure and vessel stiffness endpoints in humans (Lee et al., 2020) and mice (Sofronova et al., 2015) flown in space, found changes in these endpoints to be inconsistent and/or changes were not statistically significant.
C6-Cer incubation in cerebral arteries showed increased apoptosis with HU in the study by Cheng et al. (2017); however, in Su et al. (2020), there was a slight decrease in apoptosis, measured by TUNEL.

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	Oxp (xanthine oxidase inhibitor)	Treatment with Oxp after irradiation led to increased vasodilation and decreased PWV	Soucy et al., 2007; Soucy et al., 2010; Soucy et al., 2011
Drug	hBMSCs (protect against vascular damage)	Treatment with hBMSCs after irradiation led to decreased apoptosis and aortic thickness	Shen et al., 2018
Drug	C6-Cer (activates the ASM/Cer pathway)	Treatment with C6-Cer after microgravity caused increased apoptosis along with a return of proliferation to control levels	Cheng et al., 2017; Su et al., 2020
Drug	dpm (ASM inhibitor)	dpm treatment showed apoptosis and proliferation levels returned to control after microgravity	Su et al., 2020
Drug	DOX (ASM inhibitor)	Treatment with DOX after microgravity showed decreased apoptosis and increased IMT in rat carotid arteries	Su et al., 2020

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 are a few 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/Incidence Concordance

Reference	Experiment Description	Result
Soucy et al., 2007	In vivo. Sprague-Dawley rats were whole-body irradiated with ¹³⁷Cs gamma radiation at 0.5 Gy, 1.6 Gy and 5 Gy. Vasodilation response to ACh was used to evaluate endothelial function. Vascular stiffness was measured by PWV.	No changes in endothelial relaxation were observed after 0.5 or 1.6 Gy, but relaxation decreased about 20 percentage points at 5 Gy. 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.
Soucy et al., 2010	In vivo. Sprague-Dawley rats were whole-body irradiated with ¹³⁷Cs gamma radiation at 5 Gy. Aortic relaxation response to ACh and PWV were measured.	Relaxation decreased about 30 percentage points after 5 Gy. PWV increased to 4.93 m/s from 4.06 m/s (control) after 5 Gy.
Soucy et al., 2011	In vivo. Wistar rats were exposed to 0.5 and 1 Gy doses of ⁵⁶Fe-ion radiation. ACh-induced vasodilation response was measured. PWV was measured with Doppler probe and electrocardiogram (ECG) while aortic wall thickness:lumen diameter ratio was measured by histological analysis.	0.5 Gy dose – 9% (non-significant) decrease in endothelium-dependent vasodilation and no significant change in PWV. 1 Gy dose - 13% decrease in endothelium-dependent vasodilation and PWV increased by 0.42 m/s. Neither dose showed changes to aortic wall thickness:lumen diameter.
Shen et al., 2018	In vivo. Male mice were irradiated with 18 Gy X-rays. Endothelial dysfunction was determined through a TUNEL apoptosis assay. To measure vascular remodeling, aortic thickness was determined at various times using hematoxylin and eosin (HE) staining, and the accumulation of collagen was measured using Sirius red staining.	Irradiation with 18 Gy caused a ~4.5-fold maximum increase in TUNEL positive cells and a maximum increase of 1.4-fold in aortic thickness and collagen content compared to controls.
Su et al., 2020	In vivo. The effects of simulated microgravity by 0 day, 3 day, 1 week, 2 week or 4 week HU on cerebral and small mesenteric rat arteries were studied. Apoptosis was used as a measure of endothelial dysfunction by TUNEL assay and IMT and media CSA were used as measures of vascular remodeling.	Significant changes occurred in small mesenteric artery following 1 week of HU with a ~2-fold increase in apoptosis, ~0.8-fold decrease in IMT and ~0.6-fold decrease in CSA. Rat cerebral artery exhibited significant changes following 4 weeks of HU at which point there was a 0.3-fold decrease in apoptosis, a ~2-fold increase in IMT, and a ~2.1-fold increase in CSA.
Delp et al., 2000	In vivo. Male Sprague-Dawley rats had 2 arteries and 2 arterioles analyzed after 2-week HU. Endothelial dysfunction was measured through the relaxation response to ACh and remodeling was determined through media cross-sectional area, wall thickness and perimeter.	2-week HU led to the following changes: Soleus muscle feed artery – Cross sectional area decreased 0.5-fold, media thickness did not change, outer-media perimeter decreased 0.7-fold. Response to ACh (i.e. endothelium-dependent vasodilation) in arterioles decreased 50% after 2-week HU, but no change was observed after 4-week HU. Gastrocnemius muscle feed artery – Cross sectional area decreased 0.5-fold, media thickness decreased 0.6-fold and outer-media perimeter did not significantly change. Response to ACh (i.e. endothelium-dependent vasodilation) in arterioles did not significantly change.
Tarasova et al., 2020	In vivo. Male Wistar rats’ skin and skeletal muscle arteries were analyzed after 2-week HU. Endothelial dysfunction was determined through contractile response to noradrenaline and serotonin vasoconstrictors, and remodeling was determined through vessel inner diameter.	Following 2-week HU, the following changes occurred: Forelimb arteries - Brachial artery: Inner artery diameter increased 22.5%, active tension response to noradrenaline increased ~2-fold while response to serotonin increased ~1.5-fold. Median artery: Inner artery diameter increased 10%, no significant changes in noradrenaline or serotonin responses. Hindlimb arteries - Sural artery: Inner artery diameter decreased 16.8%, ~0.7-fold decrease in active tension response for both noradrenaline and serotonin. Saphenous artery: Inner artery diameter showed no significant change, and active tension response following noradrenaline and serotonin was elevated above the control but this increase was not significant across all doses studied.
Cheng et al., 2017	In vivo. Male rat carotid arteries were studied with HU. Apoptosis, measured by a TUNEL assay, was used as a measure of endothelial dysfunction. IMT and CSA were markers of vascular remodeling using HE staining.	Following HU, IMT in the carotid artery increased 1.8-fold and intima-media area increased 2.1-fold. Apoptosis decreased by 0.5-fold after HU.
Lee et al., 2020	In vivo. Ten male and three female astronauts who participated in various durations of spaceflight (189 ± 61 days). Irradiation measurements showed the crew experienced an average of 0.048 ± 0.018 Gy from 0.031 to 0.077 Gy. Endothelial dysfunction was measured through flow-mediated vasodilation of the brachial artery. Vascular remodeling was measured through intima-media area and vascular stiffness.	No changes in endothelium-dependent or -independent vasodilation were observed from preflight to postflight. From preflight to postflight, intima-media area increased by 1.04 mm2 and stiffness increased by 4.4 arbitrary units. However, none of the changes were significant.
Sofronova et al., 2015	In vivo. Male mice were placed under microgravity environment to study the properties of cerebral arteries, including endothelial dysfunction measured by vascular tension, vessels response to ACh (vasodilator) and vascular remodeling determined by elastin-collagen content using staining tissue with Verhoeff-van Gieson.	Spaceflight mice (SF) showed a 30% decrease in relaxation response of basilar arteries to ACh compared to habitat control (HC) group. No significant changes in elastin or elastin-collagen ratio were observed between HC, vivarium control (VC) and SF mice. There was a 5% collagen content increase in VC mice compared to HC and SF groups.

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
Soucy et al., 2007	In vivo. Sprague-Dawley rats were whole-body irradiated with ¹³⁷Cs gamma radiation at 50, 160 and 500 cGy. Relaxation response to ACh was used to evaluate endothelial function. Vascular stiffness was measured by PWV at various times.	Relaxation decreased a maximum of about 20 percentage points and PWV increased from 3.9 m/s to a maximum of 4.6 m/s 2 weeks after irradiation.
Soucy et al., 2010	In vivo. Sprague-Dawley rats were whole-body irradiated with ¹³⁷Cs gamma radiation at 5 Gy. Aortic relaxation response to ACh and PWV were measured after 2 weeks.	Relaxation decreased about 30 percentage points and PWV increased to 4.93 m/s from 4.06 m/s (control) after 2 weeks.
Soucy et al., 2011	In vivo. Wistar rats were exposed to 0.5 and 1 Gy doses of ⁵⁶Fe-ion radiation. ACh-induced vasodilation response was measured. PWV was measured with Doppler probe and ECG while aortic wall thickness:lumen diameter ratio was measured by histological analysis. Relaxation and PWV were measured at 4 and 8 months post-irradiation.	At 4 months, endothelial relaxation decreased 13 percentage points and PWV increased from 4.03 to 4.45 m/s. At 8 months, endothelial relaxation decreased about 16 percentage points and PWV increased from 4.53 to 5.06 m/s. No changes in wall thickness:lumen diameter were observed.
Shen et al., 2018	In vivo. Male mice were irradiated with 18 Gy X-rays. Endothelial dysfunction was determined through a TUNEL apoptosis assay. To measure vascular remodeling, aortic thickness was determined at various times using hematoxylin and eosin (HE) staining, and the accumulation of collagen was measured using Sirius red staining. Measurements were taken at various times between 3 and 84 days.	Irradiation showed a significant increase in TUNEL positive cells at 3, 7, 14, 28, and 84 days, with a ~4.5-fold maximum increase at day 7. Irradiation also showed a 1.4-fold increase in collagen after 14, 28 and 84 days. Aortic thickness was significantly increased after 7, 14 and 28 days, with a maximum 1.4-fold increase after 7 days.

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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

There is a substantial amount of evidence for this KER from in vivo rodent models and from human studies. The sex applicability is high for males and moderate for females as many studies were done only using male animals. Most studies indicated that the animals used were adult.