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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
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 Moderate Low Vinita Chauhan (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens 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 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: Moderate

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 relationship between endothelial function and vascular remodeling is well supported through a number of in-depth reviews about the mechanisms behind the connection. In a functional endothelial layer, the endothelial cells both contribute and react to the high levels of bioavailable nitric oxide (NO). The result is a vasomotive balance primed for vasodilation and an elevated ratio of antioxidant to pro-oxidant species (Deanfield et al., 2007). Endothelial cells can become activated through various signals, including vascular endothelial growth factor (VEGF), that subsequently induce angiogenesis (Carmeliet & Jain, 2011). Lastly, the endothelial cells form tight junctions and together with pericytes form a basement membrane in tight control of vessel and cell permeability (Carmeliet & Jain, 2011).  

Initial endothelial tissue injury can lead to premature cellular senescence resulting in endothelial dysfunction (Hughson et al., 2018). Cell death in the vessels can lead to overall cell loss and reduced vascular density. Although recovery in the form of revascularization following the decrease in vascular density occurs, it is complicated in cases of continuous exposure as it negatively impacts the angiogenic process (Hughson et al., 2018). Stressors such as radiation are thought to disturb angiogenesis through decreasing VEGF secretion causing a decrease in tubule formation (Sylvester et al., 2018). Following the initial tissue injury, the body’s ability to heal is also compromised, in part due to the prolonged state of oxidative stress and simultaneous decrease in endothelium-dependent vasorelaxation leading to increase in non-laminar blood flow. To compensate for the damage caused by this turbulent flow, there is intima-media thickening and potential for eventual atherosclerosis (Bonetti et al., 2003; Hughson et al., 2018; Slezak et al., 2017; Sylvester et al., 2018). Continued injury also leaves the vessels vulnerable to maladaptive repair and ensuing fibrosis (Hsu et al., 2019). 

When activated within healthy limits, endothelial cells loosen at their junction and the presence of VEGF induces increased vessel permeability allowing for the vessels to expand and undergo angiogenesis (Carmeliet & Jain, 2011). However, prolonged increase in permeability is also a marker of dysfunction, where increases in adhesion proteins, and elevated levels of cell senescence accompany this change (Demontis et al., 2017; Hughson et al., 2018). Disruption of endothelial integrity can also lead to cell detachment from the basement membrane; with cardiovascular deconditioning following bedrest leading to significantly elevated levels of circulating endothelial cells in microcirculation (Zhang, 2013). In addition to vessel permeability, there are changes to permeability of endothelial cells themselves, which is shown to increase and not recover following removal of the stressor (Baran et al., 2021).  

The elevated bioavailability of NO associated with proper endothelial function correlates with a decrease in prothrombotic factors, while a dysfunction in the endothelium creates a pro-thrombotic environment (Krüger-Genge et al., 2019). This is also true in the case of certain kinds of vascular damage, where a dysfunctional endothelial layer following stressor exposure has been shown to lead to lymphocyte adhesion and thrombus formation. This pro-thrombotic environment causes vessel occlusion and a decrease in capillary and vascular density, which in turn results in increased vascular resistance requiring further vascular remodeling as compensation (Slezak et al., 2017). Cell senescence following damage also induces monocyte adhesion and can further contribute to creating a pro-atherosclerotic environment (Hughson et al., 2018). 

There is also evidence that the relationship between endothelial function and vascular remodeling is regionally affected following the exposure to localized varied mechanical stressors such as microgravity. Under microgravity conditions (and in simulated microgravity models such as hindlimb unloading (HU)), there is a cephalic shift in blood and fluid resulting in a change of transmural pressure, increasing pressure in vessels above the heart and decreasing in those below (Hargens & Watenpaugh, 1996; Zhang, 2001). The heart continues to pump as usual; however, above the heart the arterial flow is no longer pushing against gravity resulting in increased arterial vascular pressure, while venous return is simultaneously slowed without gravitational assistance. This results in changes such distended veins and arteries in the upper body, increased carotid intima-media thickness and vascular stiffness (Garrett-Bakelman et al., 2019). In the lower limb, the opposite is true as arterial perfusion is decreased and venous return is increased resulting in muscle atrophy. Blood pressure and related fluid shear stress act as important mechanical input for the mechanosensing endothelial cells, which translate these forces into biochemical signals that guide vascular remodeling through affecting the balance between vascular smooth muscle cell proliferation and apoptosis (Baeyens et al., 2016). Above the heart, remodeling presents as hypertrophy and increase in vasoreactivity, while below the heart there is hypotrophy and decrease in myogenic tone and vasoreactivity (Zhang, 2013). This trend has been observed by various reviews and studies; a review examining studies using HU rats summarized that the models studied showed both a decrease in response to drugs inducing vasodilation and constriction and a subsequent increased stiffness in the aorta and carotid arteries (Platts et al., 2014). In humans, bedrest study participants showed both a decrease in endothelium-dependent vasodilation and an increase in circulating endothelial cells – both markers of endothelial dysfunction. Additional bedrest studies also show a decrease in vessel diameter and intimal-medial thickness in arteries below the heart while those above the heart remain unaffected (Zhang, 2013). Ultrasound measurements of cosmonauts having travelled aboard Mir and Salyut-7 showed that after spaceflight, blood supply to the brain remained stable while below the heart vascular tone and arterial resistance was severely compromised (Zhang, 2013).  

Research comparing the changes in vascular structure and vasodilation response between the various muscle resistance arteries following HU also showed changes to regionally vary between the vessels studied (Delp et al., 2000; Zhang, 2013). Additionally, HU models showed differences in the arterial response to vasoconstrictors and changes to artery diameter in cutaneous versus skeletal muscle arteries (Tarasova et al., 2020). The ASM and Cer pathway has been investigated for its role in remodeling. The work of Cheng et al. (2017) and Su et al. (2020) both found that a decrease in ASM activity and subsequent Cer production was linked to a decrease in apoptosis levels and a resulting thickening of vessel structure (Cheng et al., 2017; Su et al., 2020). It is important to note that some of the vascular changes following microgravity are protective adaptations that serve to safeguard the cardiovascular system in altered gravity conditions. Under continued microgravity conditions, these changes maintain their protective purpose and are thought not to contribute to adverse outcome progression. The problem arises upon return to earth when the vessels that have adapted to microgravity blood distribution are faced with earth conditions and issues like a decreased orthostatic tolerance surface. 

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 

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. 

References

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

Baeyens, N. et al. (2016), “Endothelial fluid shear stress sensing in vascular health and disease”, The Journal of Clinical Investigation, Vol. 126/3, American Society for Clinical Investigation, Ann Arbor, https://doi.org/10.1172/JCI83083.

Baran, R. et al. (2022), “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.

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.

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

Cheng, Y. P. et al. (2017), “Acid sphingomyelinase/ceramide regulates carotid intima-media thickness in simulated weightless rats”, Pflugers Archiv European Journal of Physiology, Vol. 469, Springer, New York, https://doi.org/10.1007/s00424-017-1969-z.

Deanfield, J.E., J. P. Halcox and T. J. Rabelink (2007), “Endothelial function and dysfunction: Testing and clinical relevance”, Circulation, Vol. 115/10, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/CIRCULATIONAHA.106.652859.

Delp, M.D. et al. (2000), “Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity”, American Journal of Physiology - Heart and Circulatory Physiology, Vol. 278, American Physiological Society, Rockville, https://doi.org/10.1152/ajpheart.2000.278.6.h1866.

Demontis, G.C. et al. (2017), “Human Pathophysiological Adaptations to the Space Environment”, Frontiers in Physiology, Vol. 8, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphys.2017.00547.

Garrett-Bakelman, F. E. et al. (2019) “The NASA Twins Study: A multidimensional analysis of year-long human spaceflight”, Science, Vol. 364/6436, American Association for the Advancement of Science, Washington, D.C., https://doi.org/10.1126/science.aau8650

Hargens, A.R. and D. E. Watenpaugh (1996), “Cardiovascular adaptation to spaceflight”, Medicine & Science in Sports & Exercise, Vol. 28/8, Lippincott Williams & Wilkins, Piladelphia, https://doi.org/10.1097/00005768-199608000-00007.

Hsu, T., H. H. Nguyen-Tran and M. Trojanowska (2019), “Active roles of dysfunctional vascular endothelium in fibrosis and cancer”, Journal of Biomedical Science, Vol. 26/1, BioMed Central, London, https://doi.org/10.1186/S12929-019-0580-3.

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, Nature Portfolio, London, https://doi.org/10.1038/nrcardio.2017.157

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, Vol. 98/12. https://doi.org/10.1080/09553002.2022.2110306

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.

Lee, S. M. C. et al. (2020), “Arterial structure and function during and after long-duration spaceflight”, Journal of Applied Physiology, Vol. 129, American Physiological Society, Rockville, https://doi.org/10.1152/japplphysiol.00550.2019.

Platts, S.H. et al. (2014), “Effects of sex and gender on adaptation to space: Cardiovascular alterations”, Journal of Women’s Health, Vol. 23/11, Mary Ann Liebert, Larchmont, https://doi.org/10.1089/jwh.2014.4912.

Rajashekhar, G. et al. (2006), “Continuous Endothelial Cell Activation Increases Angiogenesis: Evidence for the Direct Role of Endothelium Linking Angiogenesis and Inflammation”, Journal of Vascular Research, Vol. 43/2, Karger Publishers, Berlin, https://doi.org/10.1159/000090949.

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.

Sofronova, S. I. et al. (2015), “Spaceflight on the Bion-M1 biosatellite alters cerebral artery vasomotor and mechanical properties in mice”, Journal of Applied Physiology, Vol. 118/7, American Physiological Society, Rockville, https://doi.org/10.1152/japplphysiol.00976.2014.

Soucy, K. G. et al. (2011), “HZE 56Fe-ion irradiation induces endothelial dysfunction in rat aorta: Role of xanthine oxidase”, Radiation Research, Vol. 176/4, Radiation Research Society, Bozeman, https://doi.org/10.1667/RR2598.1.

Soucy, K. G. et al. (2010), “Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta”, Journal of Applied Physiology, Vol. 108/5, American Physiological Society, Rockville, https://doi.org/10.1152/japplphysiol.00946.2009.

Soucy, K. G. et al. (2007), “Single exposure gamma-irradiation amplifies xanthine oxidase activity and induces endothelial dysfunction in rat aorta”, Radiation and Environmental Biophysics, Vol. 46, Springer, New York, https://doi.org/10.1007/s00411-006-0090-z.

Su, Y. T. et al. (2020), “Acid sphingomyelinase/ceramide mediates structural remodeling of cerebral artery and small mesenteric artery in simulated weightless rats”, Life Sciences, Vol. 243, Elsevier, Amsterdam, https://doi.org/10.1016/j.lfs.2019.117253.

Sylvester, C. B. et al. (2018), “Radiation-Induced Cardiovascular Disease: Mechanisms and Importance of Linear Energy Transfer”, Frontiers in Cardiovascular Medicine, Vol. 5/5, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fcvm.2018.00005.

Tarasova, O. S. et al. (2020), “Simulated Microgravity Induces Regionally Distinct Neurovascular and Structural Remodeling of Skeletal Muscle and Cutaneous Arteries in the Rat”, Frontiers in Physiology, Vol. 11, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphys.2020.00675.

Zhang, L. F. (2013), “Region-specific vascular remodeling and its prevention by artificial gravity in weightless environment”, European Journal of Applied Physiology, Vol. 113, American Physiological Society, Rockville, https://doi.org/10.1007/s00421-013-2597-8.

Zhang, L. F. (2001), “Vascular adaptation to microgravity: What have we learned?”, Journal of Applied Physiology, Vol. 91/6, American Physiological Society, Rockville, https://doi.org/10.1152/jappl.2001.91.6.2415.