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AOP: 470

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Deposition of energy leads to vascular remodeling

Short name
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Deposition of energy leads to vascular remodeling
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.5

Graphical Representation

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Authors

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Tatiana Kozbenko1,2, Nadine Adam, Veronica Grybas1, Benjamin Smith1, Dalya Alomar1, Robyn Hocking1, Janna Abdelaziz3, Amanda Pace3, Carole Yauk2, Ruth Wilkins1, Vinita Chauhan1

(1) Health Canada, Ottawa, Ontario, K1A 0K9, Canada  

(2) University of Ottawa, Ottawa, Ontario K1N 6N5, Canada 

(3) Carelton University, Ottawa, Ontario K1S 5B6, Canada 

Consultants

Marjan Boerma1, Omid Azimzadeh2, Steve Blattnig3, Nobuyuki Hamada4

(1) University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA

(2) Federal Office for Radiation Protection (BfS), Section Radiation Biology, 85764 Neuherberg, Germany

(3) NASA Langley Research Center Hampton, VA  23681, USA

(4) Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Tokyo, Japan

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Vinita Chauhan   (email point of contact)

Contributors

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  • Vinita Chauhan

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on May 03, 2023 09:41

Revision dates for related pages

Page Revision Date/Time
Deposition of Energy March 08, 2024 11:49
Oxidative Stress March 08, 2024 12:28
Increased Pro-inflammatory mediators March 21, 2023 15:50
Altered Signaling Pathways February 13, 2024 07:31
Altered, Nitric Oxide Levels April 13, 2023 09:00
Increase, Endothelial Dysfunction March 21, 2023 12:17
Occurrence, Vascular Remodeling March 21, 2023 12:24
Increase, DNA strand breaks March 08, 2024 12:05
Energy Deposition leads to Oxidative Stress March 08, 2024 13:28
Energy Deposition leads to Increase, DNA strand breaks March 08, 2024 12:44
Oxidative Stress leads to Increase, DNA strand breaks March 08, 2024 14:44
Increase, DNA strand breaks leads to Altered Signaling March 21, 2023 13:09
Oxidative Stress leads to Altered Signaling February 13, 2024 16:53
Energy Deposition leads to Altered, Nitric Oxide Levels March 21, 2023 11:06
Oxidative Stress leads to Increased pro-inflammatory mediators March 21, 2023 14:44
Energy Deposition leads to Increase, Endothelial Dysfunction March 21, 2023 10:37
Altered Signaling leads to Altered, Nitric Oxide Levels March 21, 2023 11:44
Energy Deposition leads to Occurrence, Vascular Remodeling March 21, 2023 10:32
Oxidative Stress leads to Altered, Nitric Oxide Levels March 21, 2023 11:35
Oxidative Stress leads to Increase, Endothelial Dysfunction March 21, 2023 09:23
Altered Signaling leads to Increase, Endothelial Dysfunction March 21, 2023 09:20
Increased pro-inflammatory mediators leads to Increase, Endothelial Dysfunction March 21, 2023 10:39
Increase, Endothelial Dysfunction leads to Occurrence, Vascular Remodeling March 21, 2023 09:43
Altered, Nitric Oxide Levels leads to Increase, Endothelial Dysfunction March 21, 2023 11:58
Ionizing Radiation May 07, 2019 12:12

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

The present qualitative AOP (AOP#470) summarizes the evidence for a progression beginning with the deposition of energy  to vascular remodeling. The pathway is initiated by ionization/excitation events from the deposition of energy (MIE: Event #1686) leading to an enviorment  of reactive oxygen species (ROS), if this occurs at a rate that outpaces the antioxidant defense system, oxidative stress ensues (KE: Event #1392). Deposition of energy can concurrently induce DNA strand breaks (KE: Event #1635) either directly or through damage from ROS. Excessive ROS damages cellular compartments, thereby altering signaling pathways (KE: Event #2066), and increasing levels of pro-inflammatory mediators (KE: Event #1493). Within the vascular wall, activation of certain signaling molecules can alter nitric oxide (NO) levels (KE: Event #2067). All the upstream KEs of the pathway then converge to cause endothelial dysfunction (KE: Event #2068). Modified levels of NO can alter the blood flow within the endothelium resulting in subsequent compensatory vascular remodeling (AO: Event #2069). Vascular remodeling is an important precursor for many diverse cardiovascular pathologies and serves as an important marker for cardiovascular disease. Vascular remodeling includes many structural changes such as increased vessel stiffness, vessel wall thickening, and decreased capillary density. Studies informing this AOP include clinical follow-up studies of radiotherapy patients, epidemiological cohort studies of atomic bomb survivors and nuclear plant workers as well as biological studies using mouse and rat models. Knowledge gaps in the weight of evidence include inconsistencies in NO evaluation, and relatively few studies exploring chronic and low dose exposures including the lack of studies focusing on female biology. 

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Cardiovascular disease (CVD) includes any health condition affecting the heart and blood vessels. CVD is one of the leading causes of death worldwide, accounting for millions of deaths yearly and is surpassed in some countries, by only cancer (Bray et al., 2021; Tsao et al., 2022). This class of diseases includes congenital defects, as well as CVDs that can develop throughout life such as peripheral artery disease, atherosclerosis, coronary artery disease and myocardial infarction. While the progression to a CVD outcome is slow, many CVDs are often preceded by much earlier changes to vascular structure. Vascular remodeling entails various structural changes of existing vasculature arising from cell death, cell migration and changes to the endothelial cell membrane. It is important to note that changes to vascular structure are not inherently detrimental, and the cardiovascular system undergoes continuous adaptation to protect vascular health (Pries et al., 2001; Santamaría et al., 2020; Zakrzewicz et al., 2002). However, certain remodeling can also serve as an important marker and risk factor for future adverse cardiovascular events (Cohn et al., 2004; Van Varik et al., 2012). Changes to vascular structure can be triggered through perturbations such oxidative stress, inflammation, and alterations to cellular signaling pathways. Adverse remodeling of the vasculature encompasses structural and functional changes to vessel wall intima-media, elevated stiffness, and decreased lumen diameter which are all predictive of the development of and mortality and morbidity from CVD (Heald et al., 2006; Hodis et al., 1998; Polak et al., 2011; Zieman et al., 2005).  

The risk of CVD increases with several factors such as age and available evidence suggests that environmental factors such as radiation can also contribute to increased risk (Belzile-Dugas & Eisenberg, 2021; Boerma et al., 2016; Francula-Zaninovic & Nola, 2018; Wang et al., 2019). The deposition of energy from radiation is a stochastic event, with adverse effects emerging years or decades after the exposure (Boerma et al., 2016; Dörr, 2015; EPRI, 2020; Menezes et al., 2018). The effects of high-dose radiation on the cardiovascular system have been well-characterized while the effects of low-dose exposure are more contended. However, growing evidence suggests that lower doses than previously thought are linked to cardiovascular outcomes (Boerma et al., 2016; EPRI, 2020; Little et al., 2021; UNSCEAR, 2008). Much of the high-dose data is from follow up studies in radiotherapy patient cohorts who have elevated risk for adverse cardiovascular events (Zou et al., 2019). In addition to clinical exposure scenarios, epidemiological studies of occupational exposures and Japanese atomic bomb survivors provide supporting evidence. Cohort studies of atomic bomb survivors show CVD risk can be modulated by factors such as age at exposure and estimated dose received (Ozasa et al., 2012; Preston et al., 2003; Shimizu et al., 2010; Takahashi et al., 2017). Long-term follow up of individuals exposed in the Chernobyl disaster also identified statistically significant elevation in CVD risk (Ivanov et al., 2006; Kashcheev et al., 2017). Occupational exposure studies have also been conducted in various countries in an effort to understand the relationship between low-dose chronic exposure and cardiovascular health of nuclear workers (Azizova et al., 2018; Gillies et al., 2017; Zielinski et al., 2009). Occupational exposure studies suggest positive associations between received dose and excessive relative risk of circulatory diseases (Zielinski et al., 2009), CVD mortality (Gillies et al., 2017) and occurrence of ischemic and cerebrovascular disease (Azizova et al., 2018).  

Beyond earth, space travel presents an additional radiation exposure scenario. With future missions planned beyond low Earth orbit and the protective shield of the magnetosphere, understanding the unique challenges of space radiation is crucial for protection of travelers. In space, radiation is present in the form of high linear energy transfer (LET) particles and high mass, high energy ions (HZE) which indiscriminately impacts the whole body at a low fluence rate (Baker et al., 2011; Durante & Cucinotta, 2008; Norbury et al., 2016). While the present AOP includes an MIE focused on deposition of energy following radiation exposure, it is important to note that the space exposome contains multiple stressors to which space travelers will be exposed simultaneously. Particularly important, in the case of the cardiovascular system, is microgravity. The cardiovascular system is gravity sensitive, with the endothelial layer being responsive to changes in shear stress and blood pressure (Hughson et al., 2018; Maier et al., 2015; Versari et al., 2013). Variation to the pressure gradient throughout the body can also trigger regional adaptations to vascular structure (L. F. Zhang, 2013). While determining a mechanism for an MIE of microgravity has proven challenging, microgravity exposure has been shown to contribute to KEs in the pathway and therefore, evidence from microgravity studies has been included in the weight of evidence (WOE).

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

The present AOP (#470) is a part of a broader network that links the deposition of energy with four AOs: vascular remodeling, bone loss, learning and memory impairment, and cataract formation. The AOP development process began with the creation of a preliminary version of the network through narrative review of key literature as well as extensive subject matter expert consultation (Chauhan et al., 2021).  

Many KEs were proposed for the preliminary network; however, attention was focused on those deemed most essential for disease progression and for which  biological plausibility  was strong for connectivity to the rest of the pathway. The preliminary network served as the basis for the next stage in which a scoping review methodology was used to collect a WOE and refine KEs and KERs. A risk-of-bias evaluation was not undertaken,  details of the methodology are described by Kozbenko et al. and are summarized below (Kozbenko et al. 2022).   

In short, literature collection consisted of structured database searches, followed by prioritization and screening stages. Focused searches were completed for each of the KERs in the pathway using combinations of key words related to involved KEs, as well as an overarching search, collecting all references broadly related to the MIE and AO. Following the literature searches, the results were processed in two stages to determine their inclusion in the pathways WOE. Both stages determined reference relevance according to inclusion and exclusion criteria that had been outlined prior to screening in a PEOE (Population, Exposure, Outcome, and Endpoint) statement.  

In the first stage, search results were prioritized using the SWIFT Review software. This software was used to identify the references most closely related to the PEOE statement as determined by the software created tags. The most relevant references identified by SWIFT were then screened by human screeners using screening forms created in Distiller SR. Screening in Distiller was split into title and abstract, full text and data extraction levels and human screeners were instructed to include references that met the  PEOE criteria. Human screeners additionally evaluated references for their demonstration of Bradford Hill criteria. At the end of the process, collected studies were used for the WOE.  

The final pathway includes several KEs previously existing in the AOP-Wiki, these include the deposition of energy (KE #1686), oxidative stress (KE #1392), increased DNA strand breaks (KE #1635) and increased pro-inflammatory mediators (KE #1493). Newly created KEs for this pathway include altered signaling pathways (KE #2066), altered NO levels (KE #2067), increased endothelial dysfunction (KE #2068) and occurrence of vascular remodeling (AO: KE #2069).

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1686 Deposition of Energy Energy Deposition
KE 1392 Oxidative Stress Oxidative Stress
KE 1635 Increase, DNA strand breaks Increase, DNA strand breaks
KE 1493 Increased Pro-inflammatory mediators Increased pro-inflammatory mediators
KE 2066 Altered Signaling Pathways Altered Signaling
KE 2067 Altered, Nitric Oxide Levels Altered, Nitric Oxide Levels
KE 2068 Increase, Endothelial Dysfunction Increase, Endothelial Dysfunction
AO 2069 Occurrence, Vascular Remodeling Occurrence, Vascular Remodeling

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI
rabbit Oryctolagus cuniculus Low NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Summary of evidence (KE & KER Relationships and evidence)  

The AOP is supported by high biological plausibility and moderate empirical evidence. Research, primarily from laboratory studies, has supported  dose- and temporal-concordance for each KER.  

Biological Plausibility  

Described below is the well-established understanding of the mechanisms underlying this AOP with supporting literature. More detailed examples of the empirical data can be found in the individual entries for each KER. 

It is well accepted that when energy is deposited in the cell from ionizing radiation (IR), direct damage to cellular structures can occur (Desouky et al., 2015). When traveling through a cell, IR can induce the radiolysis of water forming reactive oxygen species (ROS). Deposition of energy can also induce feedback loops of ROS production where structures and molecules damaged by ROS including the mitochondria and NADPH oxidase (NOX) further produce ROS (Mittal et al., 2014; Soloviev & Kizub, 2019). Additionally, deposited energy can directly upregulate enzymes involved in ROS and reactive nitrogen species (RNS) (collectively RONS) production (de Jager, Cockrell and Du Plessis, 2017). If reactive nitrogen species RONS production outpaces the antioxidant defense, a state of oxidative stress occurs (Fletcher et al., 2010; Slezak et al., 2017; Tahimic & Globus, 2017; Wang et al., 2019). Damage to macromolecules can occur due to oxidative stress, including strand breaks to DNA, oxidation of amino acid residues in proteins and peroxidation of lipids (Ping et al., 2020). Lipid peroxidation can induce further damage to cellular structures as a chain reaction is created by the lipid peroxidation radicals, attacking other lipids, proteins and nucleic acids (Ping et al., 2020). Consequently, oxidative stress can directly lead to multiple downstream KEs including altered signaling pathways, increased DNA strand breaks, increased pro-inflammatory mediators and altered nitric oxide (NO) levels. 

DNA strand breaks in endothelial cells can be induced either directly through energy deposition or indirectly through oxidative stress. DNA strand breaks can recruit and activate the protein kinases ataxia telangiectasia mutated (ATM) and ATM/RAD3-related (ATR) (Nagane et al., 2021). Downstream signaling pathways involved in cell death and senescence like the p53/p21 pathway can be activated by ATM/ATR. Furthermore, DNA strand breaks induced by radiation directly or through oxidative stress can cause mutations or changes in transcription of proteins in signaling pathways (Ping et al., 2020; Schmidt-Ullrich et al., 2000). Therefore, DNA strand breaks will induce death and senescence of endothelial cells through altered signaling, resulting in endothelial dysfunction. 

Oxidative stress can also induce altered signaling pathways. The effects of oxidative stress on signaling pathways occur through protein oxidation of signaling components (Ping et al., 2020; Schmidt-Ullrich et al., 2000; Valerie et al., 2007). Oxidation of cysteine and methionine residues, which are particularly sensitive to oxidation, can result in structural and functional detriments to the protein (Ping et al., 2020). RONS can influence various pathways including the Akt/PI3K/mTOR pathway, where impaired cell survival signaling can induce cellular senescence (Hassan et al., 2013; Ping et al., 2020). Additionally, inhibition of tyrosine phosphatases by ROS can increase the phosphorylation of mitogen-activated protein kinase (MAPK) pathways, resulting in various downstream effects (Schmidt-Ullrich et al., 2000; Valerie et al., 2007). A phosphorylated p53 induced by oxidative DNA damage can also activate MAPK signaling and initiates a cascade ending in apoptosis (Ashcroft et al., 1999; Gen, 2004). Through affecting cell signaling pathways, damage caused by elevated RONS affects cells beyond those that have been directly irradiated (Ramadan et al., 2021). 

Excessive RONS produced by IR disrupt cellular balance and can increase pro-inflammatory mediators (Lumniczky et al., 2021; Schaue et al., 2015). Similar to activation of the immune system by damage from a pathogen, activation by oxidative stress promotes many repair mechanisms, some of which involve rapid release of pro-inflammatory cytokines (Stanojković et al., 2020). The cytokines released vary based on tissue type and radiation parameters (Di Maggio et al., 2015), but tumor necrosis factor (TNF)-α and interleukin (IL)-1 can trigger a cytokine cascade that initiates an inflammatory response (Slezak et al., 2017; Srinivasan et al., 2017). A prolonged state of inflammation in endothelial cells can lead to endothelial dysfunction (Baran et al., 2021). 

Both oxidative stress and altered signaling can directly result in altered NO levels. NO is synthesized from L-arginine by the three nitric oxide synthase (NOS) enzymes, endothelial NOS (eNOS), inducible NOS (iNOS) and neuronal NOS (nNOS). ROS can directly reduce NO levels by reacting with NO to produce the RNS peroxynitrite (Deanfield et al., 2007). Furthermore, the cofactor of NOS enzymes, tetrahydrobiopterin (BH4), can be oxidized by RONS leading to inhibition of NOS dimerization, also called NOS uncoupling (Deanfield et al., 2007). Uncoupled NOS will produce superoxide instead of NO, leading to a positive feedback loop of ROS production and reduced NO (Förstermann, 2010; Förstermann & Münzel, 2006; Mitchell et al., 2019; Nagane et al., 2021; Soloviev & Kizub, 2019). 

Modulation of NO through altered signaling pathways occurs through changing the activity of NOS enzymes. Phosphorylation of eNOS at Ser1177 will activate the enzyme while phosphorylation at Thr495 inhibits it (Förstermann, 2010; Nagane et al., 2021). Protein kinase B (Akt), part of the phosphoinositide 3-kinase (PI3K)/Akt pathway, can activate eNOS through phosphorylation at Ser1177 to increase NO production (Karar & Maity, 2011). In contrast, activation of the RhoA/Rho kinase (ROCK) pathway will inhibit NO production by destabilizing eNOS mRNA and preventing Ser1177 phosphorylation by Akt (Yao et al., 2010). Angiotensin II (AngII), the end product of the renin-angiotensin-aldosterone system (RAAS), is involved in both downregulating Ser1177 phosphorylation to prevent NO creation (Ding et al., 2020) and activating eNOS as a corrective measure (Millatt et al., 1999). Alterations to these pathways due to IR will result in changes in NO levels. 

Each of the components of the pathway described above converge at endothelial dysfunction. Endothelial cells lining the blood vessels throughout the body are an important component for maintaining vascular homeostasis (Bonetti et al., 2003; Deanfield et al., 2007). Endothelial cells are quiescent with high levels of NO most of the time (Carmeliet & Jain, 2011). Endothelial dysfunction can occur due to prolonged activation of the endothelium, characterized by the prolonged lack of bioavailable NO, lack of endothelium-dependent vasodilation and chronic pro-thrombotic and inflammatory state (Baran et al., 2021; Bonetti et al., 2003; Deanfield et al., 2007; Krüger-Genge et al., 2019). A prolonged reduction in NO will decrease vasodilation, increase leukocyte adhesion and increase fibrous plaque formation contributing to the pro-thrombotic dysfunctional environment (Schiffrin, 2008; Senoner & Dichtl, 2019; Venkatesulu et al., 2018). Furthermore, signaling in pathways like p53/p21 or PI3K/Akt/mammalian target of rapamycin (mTOR) can induce apoptosis or premature senescence of endothelial cells as part of endothelial dysfunction due to DNA damage or oxidative stress (Borghini et al., 2013; Hughson et al., 2018; Schiffrin, 2008; Senoner & Dichtl, 2019; Soloviev & Kizub, 2019). Senescent cells have decreased levels of NO production and a pro-inflammatory secretory phenotype, which feed back to further promote endothelial dysfunction (Ungvari et al., 2013; Wang et al., 2016). 

Endothelial dysfunction subsequently leads to vascular remodeling, which encompasses multiple structural changes to the vasculature. Chronic inflammation combined with impaired healing and lack of endothelium-dependent vasodilation during endothelial dysfunction increases vulnerability to damage from non-laminar flow and maladaptive repair (Sylvester et al., 2018). As compensation, vessel walls can thicken and atherosclerotic risk can increase (Hughson et al., 2018; Slezak et al., 2017; Sylvester et al., 2018). In cases of maladaptive repair of vessels, vascular remodeling can be exhibited through an increase in fibrosis (Hsu et al., 2019). The pro-thrombotic environment with increased lymphocyte adhesion induced by endothelial cell senescence can increase the likelihood of vessel occlusion, decreasing vascular density such that the corresponding increase in vascular resistance will induce remodeling as a compensatory measure (Slezak et al., 2017). Thus, increased leukocyte adhesion during endothelial dysfunction occurs early in the development of atherosclerosis (Senoner & Dichtl, 2019). Increased arterial stiffness can also occur in response to endothelial dysfunction (Boerma et al., 2015, 2016; Patel et al., 2020), with increased collagen and smooth muscle content paired with decreased elastin and degradation of the extracellular matrix (Zieman et al., 2005). The changes to the vascular structure in response to the deposition of energy are similar to a form of accelerated age-related atherosclerosis (Boerma et al., 2016; Sylvester et al., 2018; Vernice et al., 2020). 

Temporal, Dose, and Incidence Concordance  

Evidence for time, dose, and incidence concordance in this AOP is moderate. It has been repeatedly shown using many study designs and systems that deposition of energy occurs immediately following irradiation, and downstream events occur at a later timepoint. Endpoints indicating oxidative stress have been observed within minutes following irradiation (Wortel et al., 2019). Studies show that oxidative stress, increased DNA strand breaks, increased pro-inflammatory mediators, and altered signaling may occur over a similar time period; however, alteration in signaling pathways, increased DNA strand breaks, and increased pro-inflammatory mediators can be observed following oxidative stress (Ramadan et al., 2020; Baselet et al., 2017; Sakata et al., 2015; Yang et al., 1998). Increases in NO levels occur in hours to weeks after irradiation (Azimzadeh et al., 2017; Sonveaux et al., 2003; Sakata et al., 2015). Then, from weeks to months following irradiation both endothelial dysfunction and vascular remodeling occur, though concordance between these events is difficult to determine, possibly due to inter-study differences in experimental design and markers (Yentrepalli et al., 2017; Soucy et al., 2007; Yu et al., 2011; Shen et al., 2018). 

Overall, the majority of studies demonstrate that upstream KEs occur at the same or lower doses and earlier or the same time as downstream KEs. For example, endothelial cells show a dose-dependent increase in oxidative stress to X-ray irradiation at 0.1 and 5 Gy, while 0.1 Gy induced few changes in pro-inflammatory mediators with significant increases only observed at 5 Gy (Ramadan et al., 2020). Some studies also show that the upstream and downstream KEs can be observed at the same doses of radiation. For example, X-ray irradiation of mice resulted in oxidative stress, altered signaling and reduced NO levels at both 8 and 16 Gy (Azimzadeh et al., 2015). Dose concordance is not consistent across studies, but this may be due to differences in models, timepoints, and radiation types used.  

A limited number of studies support incidence concordance. In these, the upstream KE demonstrates a greater change than the downstream KE following exposure to a stressor. For example, mice exposed to 18 Gy of X-rays showed a roughly 2-fold increases in both oxidative stress and pro-inflammatory markers. A 1.3-fold increase in markers for endothelial dysfunction was observed (Shen et al., 2018).

Uncertainties and inconsistencies  

The collection of WOE identifies several important uncertainties in the literature. These include lack of quantitative understanding, low-dose or chronic-exposure studies, data from female models and consistency in measurement of NO levels.  

The WOE contained data from a wide variety of interdisciplinary fields; consequently, experimental design was equally varied. Overall, studies did not use consistent doses, radiation types, time-points, or evaluation of endpoints. Since dose and type of radiation can affect biological responses, quantitative understanding of relationships could not be determined and was low overall. Additionally, most studies used single or select doses, with limited studies exploring relatively low doses (<0.5 Gy (EPRI, 2020)). Harmonized experiments evaluating changes to adjacent endpoints across a wide range of doses or time-points with consistency of radiation type would greatly benefit quantitative understanding for this AOP.  

Similarly, the WOE is lacking in evidence using female models. Sex is an important modulating factor in cardiovascular changes and studies suggest vascular remodeling responses of astronauts can vary by sex (Hughson et al., 2016). The consequence of the general bias in clinical research (Rios et al., 2020; Yakerson, 2019) from which the current WOE draws, is the very large knowledge gaps in mechanistic data for the female body. Filling these knowledge gaps at all levels of biological organization will be an important step in solidifying the AOP.   

Evaluation of NO levels was inconsistent between studies. According to the biological plausibility, deposition of energy and subsequent oxidative stress would lead to a decrease in NO that then contributes to impaired vascular relaxation as part of endothelial dysfunction. However, primary research concludes that NO can either increase (Abdel-Magied & Shedid, 2020; Hirakawa et al., 2002; Sakata et al., 2015; Sonveaux et al., 2003) or decrease (Baker et al., 2009; Fuji et al., 2016) following irradiation. Proxy measures used to detect NO, like NOS enzyme activities or nitrite/nitrate levels, may not directly correspond to changes in NO levels. Further standardization in NO measurement and interpretation could refine this KE to become the depletion of NO. 

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

The empirical evidence supports that this AOP is relevant to human (Hong et al., 2013; Siamwala et al., 2010; Jiang et al., 2020; Lee, et al., 2020; Ramadan et al., 2020), rat (Hatoum et al., 2006; Soucy et al., 2010; Hong et al., 2013; Abdel-Magied & Shedid, 2019: Hasan et al., 2020), mouse (Yu et al., 2011; Coleman et al., 2015; Sofronova et al., 2015; Shen et al., 2018; Hamada et al., 2020), and rabbit (Soloviev et al., 2003, Hong et al., 2013) models. Biological plausibility suggests that events in this AOP are not sex specific; however, more studies used male models. Similarly, while biological plausibility suggests the pathway is not age-specific, most studies used adult models. 

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

The essentiality of the MIE to a downstream KE is supported by a non-irradiated control. The comparison of irradiated and non-irradiated groups has shown that the effects of downstream events are enhanced or accelerated by the deposition of energy.  

The essentiality of other KEs can be determined by the impact of the manipulation of the upstream KE on the resulting downstream effects. For example, the essentiality of oxidative stress is frequently assessed through antioxidant treatments, which can decrease oxidative stress markers through decreased ROS production or strengthened antioxidant defense activity. SOD administration decreased free radicals, superoxide and peroxide, and improved endothelium-dependent vasodilation, a downstream KE, which had been previously decreased due to radiation exposure (Hatoum et al., 2006). Additionally, oxypurinol treatment inhibited xanthine oxidase (XO) enzyme, which limited the enzyme’s contribution to cardiac ROS and improved endothelium-dependent vasodilation and the recovery of vascular stiffness to control levels (Soucy et al., 2007, 2010, 2011). 

The essentiality of DNA strand breaks was not assessed often. One study used mesenchymal stem cell conditioned media (MSC-CM) to reduce the level of ROS-mediated DNA double-stranded breaks and found decreases in signaling molecules including p53, Bax and cleaved caspase 3 (Huang et al., 2021). 

The essentiality for altered signaling pathways KE was evaluated by studies using pathway inhibitors or conditioned media. Signaling pathways were shown to be suppressed by inhibitors such as ROCK inhibitor Y27632 and acid sphingomyelinase (ASM) inhibitor desipramine (dpm), which have demonstrated decreased apoptosis and recovered endothelium-dependent vasodilation (Soloviev & Kizub, 2019; Venkatesulu et al., 2018; Wang et al., 2016). Incubation of endothelial cells in MSC-CM was shown to increase cell signaling components, Akt and p-Akt, and decrease apoptosis (Chang et al., 2017). PI3K inhibitors, such as LY294002 and wortmannin, and angiotensin-converting enzyme inhibitor bradykinin-potentiating factor (BPF) were studied for their impact on NO levels. The increase in p-Akt and subsequently eNOS, p-eNOS and NO levels were reversed following PI3K inhibition (Shi et al., 2012; Siamwala et al., 2010). AngII and iNOS levels were returned to control following BPF treatment of irradiated groups (Hasan et al., 2020). Further studies are required for a better understanding of the changes in NO levels and endothelial dysfunction due to altered signaling pathways. Overall, the flexibility of signaling pathways makes it difficult to assess essentiality. 

The essentiality for pro-inflammatory mediators was assessed by studies that suppress their expression. The decrease in pro-inflammatory mediators was observed following the use of TAT-Gap19 to block connexin43 hemichannels. This decrease was associated with a decrease in radiation-induced endothelial cell senescence (Ramadan et al., 2020). Additionally, MSC-CM incubation resulted in decreased pro-inflammatory cytokines, IL-1α, IL-6 and TNF-α and decreased endothelial apoptosis (Chang et al., 2017). 

Changes in vascular remodeling were evaluated through vascular structure, among other endpoints. Following hindlimb unloading, ASM inhibition in the small mesenteric artery was found to reverse the changes in apoptosis and intima-media thickness (IMT) (Su et al., 2020). Comparisons between irradiated and sham or non-irradiated control groups of various studies using animal and human models have demonstrated differences in vascular structures (Hamada et al., 2020, 2021; Sárközy et al., 2019; Shen et al., 2018; Sridharan et al., 2020; Yu et al., 2011).

Essentiality of the key events 

Defining Question 

High 

Moderate 

Low 

Support for Essentiality of KEs 

Are downstream KEs and/or the AO prevented if an upstream KE is blocked? 

Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs 

Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE 

No or contradictory experimental evidence of the essentiality of any of the KEs 

MIE: KE #1689 Deposition of energy 

Evidence for Essentiality of KE: High 

This event is difficult to test for essentiality as deposition of energy is a physical stressor and cannot be blocked/decreased using chemicals. However, studies show that control or sham-irradiated groups do not show the occurrence of downstream KEs. 

KE #1392 Oxidative stress 

Evidence for Essentiality of KE: High 

Essentiality was well supported within the literature. Antioxidant treatments led to recovery of antioxidant enzyme activity, decreases in DNA strand breaks, and decreases in pro-inflammatory mediators, while ZNO-NP also restored NO levels. Oxypurinol (Oxp) treatment was found to aid in the acetylcholine (ACh) vasodilation response and restore NO levels as it decreased xanthine oxidase (XO) activity and reactive oxygen species (ROS).  

KE #1635 

Increase, DNA strand breaks 

Evidence for Essentiality of KE: Low 

Few studies use countermeasures to reduce the number of DNA strand breaks in cells. A few studies show that reducing DNA strand breaks induced by radiation restores signaling pathways and reduces endothelial dysfunction. 

KE #1493 Increase, pro-inflammatory mediators 

Evidence for Essentiality of KE: Low 

Essentiality of this event can be determined with countermeasures that limit the increase of pro-inflammatory mediators. Limited research does show essentiality, evidenced by a decrease in apoptosis of endothelial cells following treatment with MSC-CM, which contains angiogenic cytokines that have therapeutic potential for microvascular injury, and a decrease in endothelial cell senescence following treatment with TAT-Gap19, a connexin hemichannel blocker. 

KE #2066 

Altered signaling pathways 

Evidence for Essentiality of KE: Moderate 

Essentiality of this relationship can be determined with the use of signaling molecule inhibitors. Signaling molecule inhibitors reduced downstream changes in eNOS, NO, p-Akt, angiotensin II (AngII) and aldosterone following stressors such as irradiation and altered gravity.  Inhibitors also prevented impaired contractile response and decreased apoptosis in the arterial endothelium. 

KE #2067 Altered, NO levels 

Evidence for Essentiality of KE: Moderate 

The evidence for essentiality of this KE can be determined by using countermeasures that limit changes in NO levels, such as Oxp, L-NA (NOS inhibitor), AG (iNOS inhibitor), DAHP (Gch1 inhibitor) and losartan (AT1 receptor antagonist). Use of these countermeasures reduced NOS levels and decreased the ratio of couple-to-uncoupled eNOS. Endothelial relaxation increased after Oxp and losartan treatment after microgravity exposure, while relaxation decreased in the presence of DAHP, L-NA and AG. When treated with these countermeasures following radiation or microgravity, changes to NO were limited or restored and as a result, endothelial dysfunction was limited. 

KE #2068 

Increase, endothelial dysfunction 

Evidence for Essentiality of KE: Moderate 

The essentiality of endothelial dysfunction leading to vascular remodeling is moderately supported within literature. Oxp treatment, an XO inhibitor, restored vasodilator response and reduced vascular stiffness following irradiation. Both dpm and DOX decreased apoptosis and reduced Caspase-3 protein expression. Ceramide treatment following microgravity was found to return proliferation to control levels and increase apoptosis.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Defining Question 

High 

Moderate 

Low 

Review of Biological Plausibility for the KER 

Is there a mechanistic (structural or functional) relationship between the upstream KE and downstream KE consistent with established biological knowledge 

The relationship is well understood based on extensive previous documentation and has an established mechanistic basis and broad acceptance 

The KER is plausible based on an analogy to accepted biological relationships but scientific understanding is not completely established 

There is empirical support for a statistical association between KEs but structural or functional relationship between them is not understood 

Deposition of energy (MIE: KE #1686) leads to oxidative stress (KE #1392) 

Evidence for Biological Plausibility of KER: High  

Deposition of energy onto the water and biological components of a cell creates ROS, and as ROS production outpaces the cell’s antioxidant defense system, oxidative stress is induced. Both ROS production and subsequent oxidative stress have been extensively studied and the mechanisms are well described in numerous review articles across many biological systems.  

Deposition of energy (MIE: KE #1686) leads to increase, DNA strand breaks (KE #1635) 

Evidence for Biological Plausibility of KER: High 

The deposition of energy onto the DNA molecule will directly cause single- or double-strand breaks in the DNA. Deposited energy can induce chemical modifications to the phosphodiester backbone of both strands of the DNA, possibly resulting in breaks in one or both strands. 

Oxidative stress (KE #1392) leads to increase, DNA strand breaks (KE #1635) 

Evidence for Biological Plausibility of KER: High 

Increased ROS during oxidative stress can result in the oxidation of bases on the DNA strand, triggering base excision repair, which removes the oxidized bases. When multiple bases in close proximity are removed, the repair efforts cause strain which can lead to strand breaks. 

Increase, DNA strand breaks (KE #1635) leads to altered signaling pathways (KE #2066) 

Evidence for Biological Plausibility of KER: High 

Strand breaks induce the recruitment of the kinases ataxia-telangiectasia mutated (ATM) and ATM/RAD3-related (ATR). ATM and ATR can subsequently phosphorylate multiple downstream signaling molecules. High levels of DNA strand breaks can increase the recruitment of ATM and ATR, leading to greater activation of pathways like the p53/p21 pathway and subsequently greater downstream effects. 

Oxidative stress (KE #1392) leads to increase, pro-inflammatory mediators (KE #1493) 

Evidence for Biological Plausibility of KER: High 

Excess ROS during oxidative stress damages cellular structures and thus activates the immune system and repair mechanisms, many of which involve release of pro-inflammatory mediators. Cells involved with host-defense can themselves also produce ROS, further exacerbating the state of oxidative stress. The biological plausibility of the linkage between oxidative stress and increases in pro-inflammatory mediators is highly supported in literature.   

Oxidative stress (KE #1392) leads to altered signaling pathways (KE #2066) 

Evidence for Biological Plausibility of KER: High 

Oxidative stress can alter signaling pathways both directly and indirectly. Directly, oxidative stress conditions can lead to oxidation of amino acid residues. This can cause conformational changes, protein expansion, and protein degradation, leading to changes in the activity and level of signaling proteins. Oxidation of key functional amino acids can also alter the activity of signaling proteins, resulting in downstream alterations in signaling pathways. Indirectly, oxidative stress can damage DNA causing changes in the expression of signaling proteins as well as the activation of DNA damage response signaling. The mechanisms of this relationship are widely accepted.  

Oxidative stress (KE #1392) leads to increase, endothelial dysfunction (KE #2068)  

Evidence for Biological Plausibility of KER: High 

ROS can interact with NO, taking a vasodilator crucial for endothelial function and turning it into peroxynitrite, a RNS that further contributes to oxidative stress. Furthermore, cellular senescence, inhibition of vasodilation, induced inflammatory environments and cellular apoptosis are all part of endothelial dysfunction that can be indirectly caused by oxidative stress.  

Increase, pro-inflammatory mediators (KE #1493) leads to increase, 

endothelial dysfunction (KE #2068) 

Evidence for Biological Plausibility of KER: High 

Inflammation provides a protective effect to the endothelium but prolonged or repeated exposure to a stressor can exhaust this, leading to senescence or apoptosis in endothelial cells and subsequent leading to endothelial dysfunction. This endothelial dysfunction can also manifest as a dysregulation of vasodilation. Prolonged inflammation is a widely accepted component in the development of endothelial dysfunction.  

Altered signaling pathways (KE #2066) leads to increase, endothelial dysfunction (KE #2068) 

Evidence for Biological Plausibility of KER: High 

Signaling pathways including the PI3K/Akt/mTOR, RhoA-Rho-kinase, ASM/cer pathway, and the p53-p21 pathway have downstream effects on endothelial apoptosis, premature endothelial cell senescence and cytoskeletal proteins to impair contraction, indicators of endothelial dysfunction. 

Increase, endothelial dysfunction (KE #2068) leads to occurrence, vascular remodeling (AO: KE #2069) 

Evidence for Biological Plausibility of KER: High 

Key components of endothelial dysfunction include deficiency in bioavailable NO, impaired vasodilation, inflamed endothelium and prothrombotic environment. These events can ultimately lead to vascular remodeling to compensate for decreased capillary and vascular density and increased vascular resistance. Regional pressure changes in vessels due to microgravity can also result in regional changes to vascular structure. 

Deposition of energy (MIE: KE #1686) leads to increase, endothelial dysfunction (KE #2068) 

Evidence for Biological Plausibility of KER: High 

Irradiation can cause cellular and tissue level markers of endothelial dysfunction. Following prolonged exposure to radiation, the protective effect of the endothelium can become exhausted and lead to endothelial dysfunction. Consequently, endothelial cells may lose their integrity and become senescent or apoptotic via alterations to signaling pathways, leading to endothelial dysfunction evidenced by dysregulation of vasodilation. Endothelial dysfunction is commonly considered a hallmark for the development of various cardiovascular pathologies.  

Deposition of energy (MIE: KE #1686) leads to occurrence, vascular remodeling (AO: KE #2069) 

Evidence for Biological Plausibility of KER: High 

Radiation can accelerate the natural processes of vascular remodeling related to aging. An increase in ROS, produced by IR, can reduce NO bioavailability, leading to endothelial dysfunction and vascular stiffness. In addition, the low level of inflammation during early stages of radiation leads to inhibition of tissue and vessel recovery, and later results in intimal thickening and vascular remodeling. Changes in vessel composition, such as collagen content, may also occur from energy deposition and affect vascular remodeling. 

Deposition of energy (MIE: KE#1686) leads to altered, NO levels (KE #2067) 

Evidence for Biological Plausibility of KER: High 

NO is produced by NOS enzymes or by the reduction of nitrite to NO. Deposition of energy can interfere with this process in several ways. Radiolysis of water forms ROS that interacts with NO to produce peroxynitrite which reduces NO bioavailability. ROS can also cause NOS uncoupling, which can reduce NO levels. In contrast, NO can also increase as a result of IR through activation of iNOS during oxidative stress. IR can also influence various signaling pathways that control NO levels, causing radiation to indirectly affect NO levels.  

Oxidative stress (KE #1392) leads to altered, NO levels (KE #2067) 

Evidence for Biological Plausibility of KER: High 

It is thought that excessive ROS production can lead to altered NO bioavailability both through direct interaction and indirectly through decreasing its production. Elevated O2- can interact with NO converting it to peroxynitrite leading to decreased bioavailability. ROS can also oxidize the eNOS cofactor BH4, causing eNOS uncoupling inhibiting NO production. Electron leakage in uncoupled eNOS produces additional ROS, exacerbating the state of oxidative stress.  

Altered signaling pathways (KE #2066) leads to altered, NO levels (KE #2067) 

Evidence for Biological Plausibility of KER: High 

Various pathways are well known to influence NO levels. Some well-studied examples include the PI3K/Akt pathway, the RhoA/ROCK pathway, the RAAS pathway and the acidic sphingomyelinase/ceramide pathway. The PI3K/Akt, RhoA/ROCK and RAAS pathways and their components are involved in the phosphorylation of various eNOS residues affecting the enzymes activation. The activation or deactivation of eNOS affects the levels of NO production. In contrast, the acidic sphingomyelinase/ceramide pathway can activate NADPH oxidase (NOX), leading to the production of ROS that goes on to scavenge NO decreasing its bioavailability.  

Altered, NO levels (KE #2067) leads to increase, endothelial dysfunction (KE #2068) 

Evidence for Biological Plausibility of KER: High 

Lack of bioavailable NO is considered one of the key drivers of endothelial dysfunction. Under normal conditions NO binds with soluble guanylyl cyclase (sGC) creating cGMP and cAMP to activate cellular kinase cascades and Ca2+-dependent vasodilation through smooth-muscle relaxation. Lack of bioavailable NO interrupts this process, reducing the relaxation of smooth muscle cells and dilation of the blood vessels. In contrast, an increase in NO combined with simultaneous excessive ROS can drive cellular senescence through increased peroxynitrite formation. Prolonged impaired vasodilation and elevated premature endothelial cell senescence are important characteristics of endothelial dysfunction. 

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

In addition to drugs and treatments that modulate individual relationships, there are a variety of factors that modulate the overall progression of CVD and related vascular remodeling.  

Genetics and heritable traits are the basis for individual predisposition and CVD risk; indeed, traits associated with heart disease are associated with genetics and are heritable. For example, baseline vascular stiffness, carotid intima-medial thickness (CIMT) and coronary calcification are in part hereditary and vary between ethnicities (Berk & Korshunov, 2006; Winham et al., 2014). Furthermore, how CVD manifests also differs between biological sexes. For example, men have higher age-adjusted mortality rates for coronary heart disease while the women living with CVD and dying of stroke outnumber men (Mosca et al., 2011). The genetic component of sex also plays a role, with polymorphisms of genes related to adverse cardiac remodeling found on the Y chromosome and X chromosome inactivation being linked to remodeling (Berk & Korshunov, 2006). Overall, sex plays a role in both predisposition for CVD risk and the form in which adverse cardiovascular effects progress.  

Age is an additional well-established risk factor. Natural aging of the cardiovascular system leads to structural changes like increased arterial stiffness, wall thickening and decreased endothelial function (North & Sinclair, 2012; Zieman et al., 2005). With aging also comes changes to sex-hormone levels further modulating CVD risk and progression (Kessler et al., 2019; Mosca et al., 2011; Rodgers et al., 2019; Winham et al., 2014). Some radiation induced vascular changes have been compared to accelerated versions of the natural aging process (Boerma et al., 2016; EPRI, 2020). The age at which radiation exposure occurs also plays a role in the eventual outcomes, with younger age of exposure leading to elevated risk of radiation induced CVD (Belzile-Dugas & Eisenberg, 2021; Yang et al., 2021).  

Finally, lifestyle factors contribute to the risk for CVD. In fact, positive modifications to lifestyle are sometimes considered the most impactful prevention strategy for CVD (Chiuve et al., 2006). Poor diet, inadequate physical activity, smoking and adiposity are linked with downstream risk factors like high blood pressure, elevated cholesterol and perturbations of glucose-insulin homeostasis (Mozaffarian et al., 2008). Several measures such as income level, educational attainment, employment status and neighborhood socioeconomic factors can be predictive of CVD risk (Schultz et al., 2018). Importantly, health and fitness requirements for astronauts leads to a cohort subject to the healthy worker effect (Chowdhury et al., 2017) and can serve to reduce the occurrence of CVD potentially masking adverse effects of workplace hazards.

Modulating Factor

Influence or Outcome

KER(s) involved

Genetic

Baseline vascular stiffness and intima thickness can vary by individual. This can affect how radiation influences these parameters. 

Deposition of energy leading to vascular remodeling

Endothelial dysfunction leading to vascular remodeling

Age 

Older age can increase baseline vascular stiffness and intima thickness and decrease endothelial function. 

Younger age at radiation exposure leads to an elevated risk of CVD. 

Deposition of energy leading to oxidative stress

Deposition of energy leading to endothelial dysfunction

Deposition of energy leading to vascular remodeling

Endothelial dysfunction leading to vascular remodeling

Sex 

Sex can have various influences on CVD. For example, men have higher age-adjusted mortality rates for coronary heart disease while the women dying from a stroke outnumber men. 

Deposition of energy leading to vascular remodeling

Endothelial dysfunction leading to vascular remodeling

Diet and smoking

Linked with high blood pressure, elevated cholesterol and perturbations of glucose-insulin homeostasis. 

Deposition of energy to vascular remodeling

Physical activity

Can be associated with various risk factors for CVD. Certain groups (e.g., astronauts) may have greater levels of physical activity which could influence changes to CVD outcomes. 

Deposition of energy to vascular remodeling

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Despite biological plausibility and empirical evidence demonstrating the qualitative linkages within the AOP, quantitative understanding is low. As described above, the lack of quantitative understanding of the KERs is due to the diversity in experimental design, including doses tested and radiation types used. The evidence is primarily from laboratory studies that show dose and time response relationships for KEs; however, the strength of the response can vary with factors such as dose-rate, type of radiation, and cell type. Particularly relevant are the relative lack of low-dose studies and exposure scenarios relevant to space radiation. Future work could use the present qualitative AOP to guide experimental design and strengthen quantitative understanding. Standardized studies simultaneously measuring endpoints across several KEs, and across a range of doses and timepoints would be beneficial in filling important gaps in the quantitative understanding.

Deposition of energy (MIE: KE #1686) leads oxidative stress (KE #1392) 

Evidence for Quantitative Understanding of KER: High 

There is a large amount of evidence supporting how much of a change in the deposition of energy is needed to produce a change in the level of oxidative stress. Several different endpoints representing oxidative stress have been used, including changes in the levels or activity of catalase, GSH, superoxide dismutase, GSH-Px, MDA, and ROS. Measurements have also been made over a large range of doses and dose rates, and changes to oxidative stress levels have been shown to depend on the nature, dose and dose rate of energy deposition.  

Deposition of energy (MIE: KE #1686) leads to increase, DNA strand breaks (KE #1635) 

Evidence for Quantitative Understanding of KER: High 

Studies examining energy deposition leading to strand breaks suggest a positive, linear relationship between these two events. The exact number of strand breaks is difficult to predict from the deposition of energy. The relationship depends on the biological model, the type of radiation, and the dose. 

Oxidative stress (KE #1392) leads to increase, DNA strand breaks (KE #1635) 

Evidence for Quantitative Understanding of KER: Moderate 

There is a considerable amount of evidence showing increased DNA strand breaks following exposure to oxidative stress. However, no model has emerged that predicts the number of DNA strand breaks following oxidative stress. Measurements of oxidative stress vary across studies. 

Increase, DNA strand breaks (KE #1635) leads to altered signaling pathways (KE #2066) 

Evidence for Quantitative Understanding of KER: Moderate 

There is much evidence showing changes in the expression or activity of signaling pathways following increased DNA strand breaks. However, no model has been developed to accurately predict the changes to signaling pathways due to increased DNA strand breaks. Furthermore, the changes to signaling pathways are very context- and cell type-dependent. 

Oxidative Stress (KE #1392) leads to altered signaling pathways (KE #2066)

Evidence for Quantitative Understanding of KER: Low 

The quantitative understanding of oxidative stress leading to altered signaling pathways is low as a precise quantitative relationship between the key events is difficult to determine due to differences in experimental design. The exact changes to signaling pathways due to oxidative stress will depend on the cell type and species.

Oxidative stress (KE #1392) leads to increase, endothelial dysfunction (KE #2068) 

Evidence for Quantitative Understanding of KER: Low 

Although studies quantitatively measure both oxidative stress and endothelial dysfunction following a stressor, it is difficult to compare results and identify a quantitative relationship as studies use different models, stressors, doses and time scales. In addition, many factors and pathways can contribute to endothelial dysfunction. Thus, no model has been established to predict the extent of changes in endothelial dysfunction after oxidative stress.  

Oxidative stress (KE #1392) leads to increase, pro-inflammatory mediators (KE #1493) 

Evidence for Quantitative Understanding of KER: Moderate 

Current primary research shows that an increase in oxidative stress will be followed by a more significant increase in pro-inflammatory mediators. A quantitative association between the two KEs is difficult to determine, as multiple positive feedback mechanisms exist between oxidative stress and inflammation

Increase, pro-inflammatory mediators (KE #1493) leads to increase, endothelial dysfunction (KE #2068) 

Evidence for Quantitative Understanding of KER: Low 

Although studies reveal increases in markers for endothelial dysfunction in response to increased pro-inflammatory mediators, no quantitative understanding has been established to predict the changes in endothelial dysfunction markers. There are various pro-inflammatory mediators that may contribute to various markers of endothelial dysfunction such as apoptosis and cellular senescence. Studies investigate changes in the levels of different pro-inflammatory mediators and different measures of endothelial dysfunction; therefore, it is difficult to compare the results and identify trends.  

Altered signaling pathways (KE #2066) leads to increase, endothelial dysfunction (KE #2068) 

Evidence for Quantitative Understanding of KER: Low 

Although studies show increases in markers for endothelial dysfunction in response to altered signaling pathways, no quantitative understanding has been established to predict the changes in endothelial dysfunction markers. There are various signaling pathways that may contribute to endothelial dysfunction, including the Akt/PI3K/mTOR pathway, the RhoA-Rho-kinase pathway, and the ASM/cer pathway. Studies investigate changes to the levels of different signaling pathway molecules; therefore, it is difficult to compare the results and identify trends.  

Increase, endothelial dysfunction (KE #2068) leads to occurrence, vascular remodeling (AO: KE #2069) 

Evidence for Quantitative Understanding of KER: Low 

Vascular remodeling is consistently shown with endothelial dysfunction. However, it is difficult to compare results and identify a quantitative relationship as various models, stressors, doses and endpoint measures were used. Thus, no model has been established to accurately predict the changes in vascular remodeling.  

Deposition of energy (MIE: KE #1686) leads to increase, endothelial dysfunction (KE #2068) 

Evidence for Quantitative Understanding of KER: Low 

Studies revealed consistent increases in levels of indicators of endothelial dysfunction such as apoptosis, premature endothelial cell senescence and diminished relaxation response. There is consistent evidence that shows that as the dose increases, the maximum relaxation response decreases. However, more studies are required to quantify this association to show how this relates to levels of cellular markers of apoptosis and senescence.  

Deposition of energy (MIE: KE #1686) leads to occurrence, vascular remodeling (AO: KE #2069) 

Evidence for Quantitative Understanding of KER: Low 

Deposition of energy from IR is consistently demonstrated to drive vascular remodeling. However, it is difficult to compare results and quantify relationships as each study uses different models, stressors, doses and time scales. In addition, many factors and pathways contribute to the components of vascular remodeling. Thus, no model has been established to predict the changes in vascular remodeling after deposition of energy.  

Deposition of energy (MIE: KE #1686) leads to altered, NO levels (KE #2067) 

Evidence for Quantitative Understanding of KER: Low 

Altered nitric oxide levels occur consistently with deposition of energy. However, it is difficult to compare results and determine a quantitative relationship as each study uses different models, stressors, doses and endpoint measures of NO. As well, cancerous cells and normal cells can show different production of NO. Thus, no model has been established to predict the changes in nitric oxide levels at a given dose of IR. 

Oxidative stress (KE #1392) leads to altered, NO levels (KE #2067) 

Evidence for Quantitative Understanding of KER: Low 

Alterations in NO levels cannot be predicted from relevant measures of oxidative stress changes, such as increased ROS production and antioxidant enzyme activity. Nevertheless, a general decrease in NO is observed following ROS production. 

Altered signaling pathways (KE #2066) leads to altered, NO levels (KE #2067) 

Evidence for Quantitative Understanding of KER: Low 

Altered NO, iNOS and eNOS levels occur in response to altered signaling pathways; however, a model has not been established to predict the changes in NO levels. Different models, stressors, time scales, doses and dose rates make trends difficult to identify. The studies investigated the levels of different altered signaling pathway molecules and their effects on NO levels, making it difficult to compare and identify quantitative relationships across the results.  

Altered, NO levels (KE #2067) leads to increase, endothelial dysfunction (KE #2068) 

Evidence for Quantitative Understanding of KER: Low 

Increased vascular tension occurs consistently with decreased NO levels. Although many studies quantitatively measure a change in endothelial function after changes in NO levels, no model has been established. Each study cited used different models, stressors, time scales, doses and dose rates, which makes it difficult to determine if response levels are consistent between studies.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

The present AOP serves as a platform to promote broader collaborative efforts to understand non-cancer health risks from radiation exposures. It will be a foundational AOP of regulatory interest to researchers seeking areas of knowledge gaps to prioritize research in understanding mechanisms of CVD. The AOP is also relevant to space agencies and clinicians working to improve the guidance on health risks from long-term spaceflight and radiotherapy treatments, respectively. The WOE for this AOP may also inform parameters in biologically based risk models and can serve to develop countermeasures to protect the cardiovascular systems of future space travelers on deep space missions. The present qualitative AOP can be used to guide the design of experiments that will provide quantitative understanding for the KERs to support risk-model development and inform additional guidelines for radiation protection; additionally, the identified research gaps could help prioritize research needs for funding strategies.

References

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

Abdel-Magied, N., & Shedid, S. M. (2020). Impact of zinc oxide nanoparticles on thioredoxin-interacting protein and asymmetric dimethylarginine as biochemical indicators of cardiovascular disorders in gamma-irradiated rats. Environmental Toxicology, 35(4), 430–442. https://doi.org/10.1002/tox.22879 

Ashcroft, M., Kubbutat, M. H. G., & Vousden, K. H. (1999). Regulation of p53 Function and Stability by Phosphorylation. Molecular and Cellular Biology, 19(3), 1751. https://doi.org/10.1128/MCB.19.3.1751 

Azimzadeh, O., Subramanian, V., Sievert, W., Merl-Pham, J., Oleksenko, K., Rosemann, M., Multhoff, G., Atkinson, M. J., & Tapio, S. (2021). Activation of pparα by fenofibrate attenuates the effect of local heart high dose irradiation on the mouse cardiac proteome. Biomedicines, 9(12). https://doi.org/10.3390/biomedicines9121845 

Azimzadeh, O. et al. (2017), “Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways”, International Journal of Radiation Biology, Vol. 93/9, Informa, London, https://doi.org/10.1080/09553002.2017.1339332. 

Azimzadeh, O. et al. (2015), “Integrative Proteomics and Targeted Transcriptomics Analyses in Cardiac Endothelial Cells Unravel Mechanisms of Long-Term Radiation-Induced Vascular Dysfunction”, Journal of Proteome Research, Vol. 14/2, American Chemical Society, Washington, https://doi.org/10.1021/pr501141b. 

Azizova, T. V., Batistatou, E., Grigorieva, E. S., McNamee, R., Wakeford, R., Liu, H., De Vocht, F., & Agius, R. M. (2018). An Assessment of Radiation-Associated Risks of Mortality from Circulatory Disease in the Cohorts of Mayak and Sellafield Nuclear Workers. Radiation Research, 189(4), 371–388. https://doi.org/10.1667/RR14468.1 

Baeyens, N., Bandyopadhyay, C., Coon, B. G., Yun, S., & Schwartz, M. A. (2016). Endothelial fluid shear stress sensing in vascular health and disease. The Journal of Clinical Investigation, 126(3), 821–828. https://doi.org/10.1172/JCI83083 

Baker, J. E., Fish, B. L., Su, J., Haworth, S. T., Strande, J. L., Komorowski, R. A., Migrino, R. Q., Doppalapudi, A., Harmann, L., Allen Li, X., Hopewell, J. W., & Moulder, J. E. (2009). 10 Gy total body irradiation increases risk of coronary sclerosis, degeneration of heart structure and function in a rat model. International Journal of Radiation Biology, 85(12), 1089–1100. https://doi.org/10.3109/09553000903264473 

Baker, J. E., Moulder, J. E., & Hopewell, J. W. (2011). Radiation as a Risk Factor for Cardiovascular Disease. Antioxidant and Redox Signaling, 15(7). https://doi.org/10.1089/ars.2010.3742 

Balasubramanian, D. (2000). Ultraviolet radiation and cataract. Journal of Ocular Pharmacology and Therapeutics, 16(3), 285–297. https://doi.org/10.1089/jop.2000.16.285 

Baran, R., Marchal, S., Campos, S. G., Rehnberg, E., Tabury, K., Baselet, B., Wehland, M., Grimm, D., & Baatout, S. (2021). The Cardiovascular System in Space: Focus on In Vivo and In Vitro Studies. Biomedicines 2022, Vol. 10, Page 59, 10(1), 59. https://doi.org/10.3390/BIOMEDICINES10010059 

Baselet, B., Belmans, N., Coninx, E., Lowe, D., Janssen, A., Michaux, A., Tabury, K., Raj, K., Quintens, R., Benotmane, M. A., Baatout, S., Sonveaux, P., & Aerts, A. (2017). Functional gene analysis reveals cell cycle changes and inflammation in endothelial cells irradiated with a single X-ray dose. Frontiers in Pharmacology, 8. https://doi.org/10.3389/fphar.2017.00213 

Belzile-Dugas, E., & Eisenberg, M. J. (2021). Radiation‐Induced Cardiovascular Disease: Review of an Underrecognized Pathology. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 10(18), 21686. https://doi.org/10.1161/JAHA.121.021686 

Berk, B. C., & Korshunov, V. A. (2006). Genetic determinants of vascular remodelling. Canadian Journal of Cardiology, 22(SUPPL. B). https://doi.org/10.1016/s0828-282x(06)70980-1 

Boerma, M., Nelson, G. A., Sridharan, V., Mao, X.-W., Koturbash, I., & Hauer-Jensen, M. (2015). Space radiation and cardiovascular disease risk. World Journal of Cardiology, 7(12), 882. https://doi.org/10.4330/wjc.v7.i12.882 

Boerma, M., Sridharan, V., Mao, X.-W., Nelson, G. A., Cheema, A. K., Koturbash, I., Singh, S. P., Tackett, A. J., & Hauer-Jensen, M. (2016). Effects of Ionizing Radiation on the Heart. Mutation Research - Reviews in Mutation Research, 770, 319–327. https://doi.org/10.1016/j.mrrev.2016.07.003 

Bonetti, P. O., Lerman, L. O., & Lerman, A. (2003). Endothelial dysfunction: A marker of atherosclerotic risk. Arteriosclerosis, Thrombosis, and Vascular Biology, 23(2), 168–175. https://doi.org/10.1161/01.ATV.0000051384.43104.FC 

Borghini, A., Luca Gianicolo, E. A., Picano, E., & Andreassi, M. G. (2013). Ionizing radiation and atherosclerosis: Current knowledge and future challenges. Atherosclerosis, 230(1), 40–47. https://doi.org/10.1016/j.atherosclerosis.2013.06.010 

Bray, F., Laversanne, M., Weiderpass, E., & Soerjomataram, I. (2021). The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer, 127(16), 3029–3030. https://doi.org/10.1002/cncr.33587 

Carmeliet, P., & Jain, R. K. (2011). Molecular mechanisms and clinical applications of angiogenesis. https://doi.org/10.1038/nature10144 

Cervelli, T., Panetta, D., Navarra, T., Gadhiri, S., Salvadori, P., Galli, A., Caramella, D., Basta, G., Picano, E., & Del Turco, S. (2017). A New Natural Antioxidant Mixture Protects against Oxidative and DNA Damage in Endothelial Cell Exposed to Low-Dose Irradiation. Oxidative Medicine and Cellular Longevity, 2017. https://doi.org/10.1155/2017/9085947 

Chang, P. Y., Zhang, B. Y., Cui, S., Qu, C., Shao, L. H., Xu, T. K., Qu, Y. Q., Dong, L. H., & Wang, J. (2017). MSC-derived cytokines repair radiation-induced intra-villi microvascular injury. Oncotarget, 8(50). https://doi.org/10.18632/oncotarget.21236 

Chauhan, V., Hamada, N., Monceau, V., Ebrahimian, T., Adam, N., Wilkins, R. C., Sebastian, S., Patel, Z. S., Huff, J. L., Simonetto, C., Iwasaki, T., Kaiser, J. C., Salomaa, S., Moertl, S., & Azimzadeh, O. (2021). Expert consultation is vital for adverse outcome pathway development: a case example of cardiovascular effects of ionizing radiation. International Journal of Radiation Biology, 97(11). https://doi.org/10.1080/09553002.2021.1969466 

Cheng, Y. P., Zhang, H. J., Su, Y. T., Meng, X. X., Xie, X. P., Chang, Y. M., & Bao, J. X. (2017). Acid sphingomyelinase/ceramide regulates carotid intima-media thickness in simulated weightless rats. Pflugers Archiv European Journal of Physiology, 469(5–6). https://doi.org/10.1007/s00424-017-1969-z 

Chiuve, S. E., McCullough, M. L., Sacks, F. M., & Rimm, E. B. (2006). Healthy lifestyle factors in the primary prevention of coronary heart disease among men: Benefits among users and nonusers of lipid-lowering and antihypertensive medications. Circulation, 114(2), 160–167. https://doi.org/10.1161/CIRCULATIONAHA.106.621417 

Chowdhury, R., Shah, D., & Payal, A. (2017). Healthy worker effect phenomenon: Revisited with emphasis on statistical methods-A review. Indian Journal of Occupational and Environmental Medicine, 21(1), 2–8. https://doi.org/10.4103/ijoem.IJOEM_53_16 

Cohn, J. N., Quyyumi, A. A., Hollenberg, N. K., & Jamerson, K. A. (2004). Surrogate markers for cardiovascular disease: Functional markers. Circulation, 109(25). 

de Jager, T. L., A. E. Cockrell, S. S. Du Plessis (2017), “Ultraviolet Light Induced Generation of Reactive Oxygen Species”, in: Ultraviolet Light in Human Health, Diseases and Environment, vol 996. Springer Cham, https://doi.org/10.1007/978-3-319-56017-5_2.

Deanfield, J. E., Halcox, J. P., & Rabelink, T. J. (2007). Endothelial function and dysfunction: Testing and clinical relevance. Circulation, 115(10), 1285–1295. https://doi.org/10.1161/CIRCULATIONAHA.106.652859 

Desouky, O., Ding, N., & Zhou, G. (2015). Targeted and non-targeted effects of ionizing radiation. Journal of Radiation Research and Applied Sciences, 8(2), 247–254. https://doi.org/10.1016/J.JRRAS.2015.03.003 

Di Maggio, F. M., Minafra, L., Forte, G. I., Cammarata, F. P., Lio, D., Messa, C., Gilardi, M. C., & Bravatà, V. (2015). Portrait of inflammatory response to ionizing radiation treatment. In Journal of Inflammation (Vol. 12, Issue 1, pp. 1–11). BioMed Central Ltd. https://doi.org/10.1186/s12950-015-0058-3 

Ding, J., Yu, M., Jiang, J., Luo, Y., Zhang, Q., Wang, S., Yang, F., Wang, A., Wang, L., Zhuang, M., Wu, S., Zhang, Q., Xia, Y., & Lu, D. (2020). Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT1R Nox/ROS/PP2A Pathway. Frontiers in Physiology, 11, 1245. https://doi.org/10.3389/fphys.2020.566410 

Dörr, W. (2015). Radiobiology of tissue reactions. Annals of the ICRP, 44, 58–68. https://doi.org/10.1177/0146645314560686 

Durante, M., & Cucinotta, F. A. (2008). Heavy ion carcinogenesis and human space exploration. Nature Reviews Cancer, 8(6), 465–472. https://doi.org/10.1038/nrc2391 

Eaton, J. W. (1994). UV-mediated cataractogenesis: A radical perspective. Documenta Ophthalmologica, 88(3–4), 233–242. https://doi.org/10.1007/BF01203677 

EPRI. (2020). Cardiovascular Risks from Low Dose Radiation Exposure: Review and Scientific Appraisal of the Literature. 

Fletcher, A. E. (2010). Free radicals, antioxidants and eye diseases: Evidence from epidemiological studies on cataract and age-related macular degeneration. Ophthalmic Research, 44(3), 191–198. https://doi.org/10.1159/000316476 

Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q., & Griendling, K. K. (2018). Reactive oxygen species in metabolic and inflammatory signaling. Circulation Research, 122(6), 877–902. https://doi.org/10.1161/CIRCRESAHA.117.311401 

Förstermann, U. (2010). Nitric oxide and oxidative stress in vascular disease. Pflugers Archiv European Journal of Physiology, 459(6), 923–939. https://doi.org/10.1007/s00424-010-0808-2 

Förstermann, U., & Münzel, T. (2006). Endothelial Nitric Oxide Synthase in Vascular Disease. Circulation, 113(13), 1708–1714. https://doi.org/10.1161/CIRCULATIONAHA.105.602532 

Francula-Zaninovic, S., & Nola, I. A. (2018). Management of Measurable Variable Cardiovascular Disease’ Risk Factors. Current Cardiology Reviews, 14(3), 153–163. https://doi.org/10.2174/1573403x14666180222102312 

Fuji, S., Matsushita, S., Hyodo, K., Osaka, M., Sakamoto, H., Tanioka, K., Miyakawa, K., Kubota, M., Hiramatsu, Y., & Tokunaga, C. (2016). Association between endothelial function and micro-vascular remodeling measured by synchrotron radiation pulmonary micro-angiography in pulmonary arterial hypertension. General Thoracic and Cardiovascular Surgery, 64(10), 597–603. https://doi.org/10.1007/s11748-016-0684-6 

Ganea, E., & Harding, J. J. (2006). Glutathione-related enzymes and the eye. In Current Eye Research (Vol. 31, Issue 1, pp. 1–11). Taylor & Francis. https://doi.org/10.1080/02713680500477347 

Gen, S. W. (2004). The functional interactions between the p53 and MAPK signaling pathways. Cancer Biology and Therapy, 3(2), 156–161. https://doi.org/10.4161/cbt.3.2.614 

Gillies, M., Richardson, D. B., Cardis, E., Daniels, R. D., O’Hagan, J. A., Haylock, R., Laurier, D., Leuraud, K., Moissonnier, M., Schubauer-Berigan, M. K., Thierry-Chef, I., & Kesminiene, A. (2017). Mortality from circulatory diseases and other non-cancer outcomes among nuclear workers in France, the United Kingdom and the United States (inworks). Radiation Research, 188(3), 276–290. https://doi.org/10.1667/RR14608.1 

Grabham, P., & Sharma, P. (2013). The effects of radiation on angiogenesis. Vascular Cell, 5(1), 19. https://doi.org/10.1186/2045-824X-5-19 

Hamada, N., Kawano, K. I., Nomura, T., Furukawa, K., Yusoff, F. M., Maruhashi, T., Maeda, M., Nakashima, A., & Higashi, Y. (2021). Vascular damage in the aorta of wild-type mice exposed to ionizing radiation: Sparing and enhancing effects of dose protraction. Cancers, 13(21). https://doi.org/10.3390/cancers13215344 

Hamada, N., Kawano, K. I., Yusoff, F. M., Furukawa, K., Nakashima, A., Maeda, M., Yasuda, H., Maruhashi, T., & Higashi, Y. (2020). Ionizing irradiation induces vascular damage in the aorta of wild-type mice. Cancers, 12(10), 1–11. https://doi.org/10.3390/cancers12103030 

Hasan, H. F., Radwan, R. R., & Galal, S. M. (2020). Bradykinin-potentiating factor isolated from Leiurus quinquestriatus scorpion venom alleviates cardiomyopathy in irradiated rats via remodelling of the RAAS pathway. Clinical and Experimental Pharmacology and Physiology, 47(2), 263–273. https://doi.org/10.1111/1440-1681.13202 

Hassan, B., Akcakanat, A., Holder, A. M., & Meric-Bernstam, F. (2013). Targeting the PI3-Kinase/Akt/mTOR Signaling Pathway. Surgical Oncology Clinics of North America, 22(4), 641–664. https://doi.org/10.1016/j.soc.2013.06.008 

Hatoum, O. A., Otterson, M. F., Kopelman, D., Miura, H., Sukhotnik, I., Larsen, B. T., Selle, R. M., Moulder, J. E., & Gutterman, D. D. (2006). Radiation induces endothelial dysfunction in murine intestinal arterioles via enhanced production of reactive oxygen species. Arteriosclerosis, Thrombosis, and Vascular Biology, 26(2), 287–294. https://doi.org/10.1161/01.ATV.0000198399.40584.8c 

Heald, C. L., Fowkes, F. G. R., Murray, G. D., & Price, J. F. (2006). Risk of mortality and cardiovascular disease associated with the ankle-brachial index: Systematic review. Atherosclerosis, 189(1), 61–69. https://doi.org/10.1016/J.ATHEROSCLEROSIS.2006.03.011 

Hemmings, B. A., & Restuccia, D. F. (2012). PI3K-PKB/Akt pathway. Cold Spring Harbor Perspectives in Biology, 4(9). https://doi.org/10.1101/cshperspect.a011189 

Hirakawa, M., Oike, M., Masuda, K., & Ito, Y. (2002). Tumor cell apoptosis by irradiation-induced nitric oxide production in vascular endothelium. Cancer Research, 62(5), 1450–1457. 

Hladik, D., & Tapio, S. (2016). Effects of ionizing radiation on the mammalian brain. Mutation Research - Reviews in Mutation Research, 770, 219–230. https://doi.org/10.1016/j.mrrev.2016.08.003 

Hodis, H. N., Mack, W. J., LaBree, L., Selzer, R. H., Liu, C. R., Liu, C. H., & Azen, S. P. (1998). The role of carotid arterial intima - Media thickness in predicting clinical coronary events. Annals of Internal Medicine, 128(4), 262–269. https://doi.org/10.7326/0003-4819-128-4-199802150-00002 

Hong, C. W., Kim, Y. M., Pyo, H., Lee, J. H., Kim, S., Lee, S., & Noh, J. M. (2013). Involvement of inducible nitric oxide synthase in radiation-Induced vascular endothelial damage. Journal of Radiation Research, 54(6), 1036–1042. https://doi.org/10.1093/jrr/rrt066 

Hsu, T., Nguyen-Tran, H. H., & Trojanowska, M. (2019). Active roles of dysfunctional vascular endothelium in fibrosis and cancer. Journal of Biomedical Science, 26(1), 1–12. https://doi.org/10.1186/s12929-019-0580-3 

Huang, Y. et al. (2021), “Mesenchymal Stem Cell-Conditioned Medium Protects Hippocampal Neurons From Radiation Damage by Suppressing Oxidative Stress and Apoptosis”, Dose-response, Vol. 19/1, Sage Publishing, https://doi.org/10.1177/1559325820984944 

Hughson, R. L., Helm, A., & Durante, M. (2018). Heart in space: Effect of the extraterrestrial environment on the cardiovascular system. In Nature Reviews Cardiology (Vol. 15, Issue 3). https://doi.org/10.1038/nrcardio.2017.157 

Hughson, R. L., Robertson, A. D., Arbeille, P., Shoemaker, J. K., Rush, J. W. E., Fraser, K. S., & Greaves, D. K. (2016). Increased postflight carotid artery stiffness and inflight insulin resistance resulting from 6-mo spaceflight in male and female astronauts. American Journal of Physiology - Heart and Circulatory Physiology, 310(5), H628–H638. https://doi.org/10.1152/ajpheart.00802.2015 

Ismail, A. F. M., & El-Sonbaty, S. M. (2016). Fermentation enhances Ginkgo biloba protective role on gamma-irradiation induced neuroinflammatory gene expression and stress hormones in rat brain. Journal of Photochemistry and Photobiology B: Biology, 158, 154–163. https://doi.org/10.1016/j.jphotobiol.2016.02.039 

Ivanov, V. K., Maksioutov, M. A., Chekin, S. Y., Petrov, A. V., Biryukov, A. P., Kruglova, Z. G., Matyash, V. A., Tsyb, A. F., Manton, K. G., & Kravchenko, J. S. (2006). The risk of radiation-induced cerebrovascular disease in chernobyl emergency workers. Health Physics, 90(3), 199–207. https://doi.org/10.1097/01.HP.0000175835.31663.EA 

Karam, H. M., & Radwan, R. R. (2019). Metformin modulates cardiac endothelial dysfunction, oxidative stress and inflammation in irradiated rats: A new perspective of an antidiabetic drug. Clinical and Experimental Pharmacology and Physiology, 46(12), 1124–1132. https://doi.org/10.1111/1440-1681.13148 

Karar, J., & Maity, A. (2011). PI3K/AKT/mTOR Pathway in Angiogenesis. Frontiers in Molecular Neuroscience, 4, 51. https://doi.org/10.3389/fnmol.2011.00051 

Karimi, N., Monfared, A., Haddadi, G., Soleymani, A., Mohammadi, E., Hajian-Tilaki, K., & Borzoueisileh, S. (2017). Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats. International Journal of Pharmaceutical Investigation, 7(3), 149. https://doi.org/10.4103/jphi.jphi_60_17 

Kashcheev, V. V., Chekin, S. Y., Karpenko, S. V., Maksioutov, M. A., Menyaylo, A. N., Tumanov, K. A., Kochergina, E. V., Kashcheeva, P. V., Gorsky, A. I., Shchukina, N. V., Lovachev, S. S., Vlasov, O. K., & Ivanov, V. K. (2017). Radiation Risk of Cardiovascular Diseases in the Cohort of Russian Emergency Workers of the Chernobyl Accident. Health Physics, 113(1), 23–29. https://doi.org/10.1097/HP.0000000000000670 

Kessler, E. L., Rivaud, M. R., Vos, M. A., & Van Veen, T. A. B. (2019). Sex-specific influence on cardiac structural remodeling and therapy in cardiovascular disease. Biology of Sex Differences, 10(1). https://doi.org/10.1186/s13293-019-0223-0 

Konukoglu, D., & Uzun, H. (2016). Endothelial dysfunction and hypertension. In Advances in Experimental Medicine and Biology (Vol. 956, pp. 511–540). Adv Exp Med Biol. https://doi.org/10.1007/5584_2016_90 

Korpela, E., & Liu, S. K. (2014). Endothelial perturbations and therapeutic strategies in normal tissue radiation damage. Radiation Oncology, 9(1). https://doi.org/10.1186/s13014-014-0266-7 

Kozbenko, T., Adam, N., Lai, V., Sandhu, S., Kuan, J., Flores, D., Appleby, M., Parker, H., Hocking, R., Tsaioun, K., Yauk, C., Wilkins, R., & Chauhan, V. (2022). Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example. International Journal of Radiation Biology, 1–12. https://doi.org/10.1080/09553002.2022.2110306 

Krüger-Genge, A., Blocki, A., Franke, R.-P., & Jung, F. (2019). Vascular Endothelial Cell Biology: An Update. International Journal of Molecular Sciences, 20(18), 4411. https://doi.org/10.3390/ijms20184411 

Lee, M. S., Finch, W., & Mahmud, E. (2013). Cardiovascular complications of radiotherapy. American Journal of Cardiology, 112(10), 1688–1696. https://doi.org/10.1016/j.amjcard.2013.07.031 

Li, J., De Leon, H., Ebato, B., Cui, J., Todd, J., Chronos, N. A. F., & Robinson, K. A. (2002). Endovascular irradiation impairs vascular functional responses in noninjured pig coronary arteries. Cardiovascular Radiation Medicine, 152–162. https://doi.org/10.1016/S1522-1865(03)00096-9 

Little, M. P., Azizova, T. V., & Hamada, N. (2021). Low- and moderate-dose non-cancer effects of ionizing radiation in directly exposed individuals, especially circulatory and ocular diseases: a review of the epidemiology. International Journal of Radiation Biology, 97(6), 782–803. https://doi.org/10.1080/09553002.2021.1876955 

Luiking, Y. C., Engelen, M. P. K. J., & Deutz, N. E. P. (2010). Regulation of nitric oxide production in health and disease. Current Opinion in Clinical Nutrition and Metabolic Care, 13(1), 97–104. https://doi.org/10.1097/MCO.0B013E328332F99D 

Lumniczky, K., Impens, N., Armengol, G., Candéias, S., Georgakilas, A. G., Hornhardt, S., Martin, O. A., Rödel, F., & Schaue, D. (2021). Low dose ionizing radiation effects on the immune system. Environment International, 149, 106212. https://doi.org/10.1016/j.envint.2020.106212 

Maier, J. A. M., Cialdai, F., Monici, M., & Morbidelli, L. (2015). The impact of microgravity and hypergravity on endothelial cells. BioMed Research International, 2015. https://doi.org/10.1155/2015/434803 

Matsubara, K., Higaki, T., Matsubara, Y., & Nawa, A. (2015). Nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. International Journal of Molecular Sciences, 16(3), 4600–4614. https://doi.org/10.3390/ijms16034600 

Menezes, K. M., Wang, H., Hada, M., & Saganti, P. B. (2018). Radiation Matters of the Heart: A Mini Review. Frontiers in Cardiovascular Medicine, 5, 83. https://doi.org/10.3389/FCVM.2018.00083 

Millatt, L. J., Abdel-Rahman, E. M., & Siragy, H. M. (1999). Angiotensin II and nitric oxide: A question of balance. Regulatory Peptides, 81(1–3), 1–10. https://doi.org/10.1016/S0167-0115(99)00027-0 

Mitchell, A., Pimenta, D., Gill, J., Ahmad, H., & Bogle, R. (2019). Cardiovascular effects of space radiation: implications for future human deep space exploration. European Journal of Preventive Cardiology, 26(16), 1707–1714. https://doi.org/10.1177/2047487319831497 

Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P., & Malik, A. B. (2014). Reactive oxygen species in inflammation and tissue injury. Antioxidants and Redox Signaling, 20(7), 1126–1167. https://doi.org/10.1089/ars.2012.5149 

Mosca, L., Barrett-Connor, E., & Kass Wenger, N. (2011). Sex/gender differences in cardiovascular disease prevention: What a difference a decade makes. Circulation, 124(19), 2145–2154. https://doi.org/10.1161/CIRCULATIONAHA.110.968792 

Mozaffarian, D., Wilson, P. W. F., & Kannel, W. B. (2008). Beyond Established and Novel Risk Factors. Circulation, 117(23), 3031–3038. https://doi.org/10.1161/CIRCULATIONAHA.107.738732 

Nagane, M., Yasui, H., Kuppusamy, P., Yamashita, T., & Inanami, O. (2021). DNA damage response in vascular endothelial senescence: Implication for radiation-induced cardiovascular diseases. Journal of Radiation Research, 62(4), 564–573. https://doi.org/10.1093/jrr/rrab032 

Nathan, C., & Xie, Q. wen. (1994). Nitric oxide synthases: Roles, tolls, and controls. Cell, 78(6), 915–918. https://doi.org/10.1016/0092-8674(94)90266-6 

Norbury, J. W., Schimmerling, W., Slaba, T. C., Azzam, E. I., Badavi, F. F., Baiocco, G., Benton, E., Bindi, V., Blakely, E. A., Blattnig, S. R., Boothman, D. A., Borak, T. B., Britten, R. A., Curtis, S., Dingfelder, M., Durante, M., Dynan, W. S., Eisch, A. J., Robin Elgart, S., … Zeitlin, C. J. (2016). Galactic cosmic ray simulation at the NASA Space Radiation Laboratory. Life Sciences in Space Research, 8, 38–51. https://doi.org/10.1016/j.lssr.2016.02.001 

North, B. J., & Sinclair, D. A. (2012). The intersection between aging and cardiovascular disease. Circulation Research, 110(8), 1097–1108. https://doi.org/10.1161/CIRCRESAHA.111.246876 

Ozasa, K., Shimizu, Y., Suyama, A., Kasagi, F., Soda, M., Grant, E. J., Sakata, R., Sugiyama, H., & Kodama, K. (2012). Studies of the mortality of atomic bomb survivors, report 14, 1950-2003: An overview of cancer and noncancer diseases. In Radiation Research (Vol. 177, Issue 3). https://doi.org/10.1667/RR2629.1 

Padgaonkar, V. A., Leverenz, V. R., Bhat, A. V., Pelliccia, S. E., & Giblin, F. J. (2015). Thioredoxin reductase activity may be more important than GSH level in protecting human lens epithelial cells against UVA light. Photochemistry and Photobiology, 91(2), 387–396. https://doi.org/10.1111/php.12404 

Patel, Z. S., Brunstetter, T. J., Tarver, W. J., Whitmire, A. M., Zwart, S. R., Smith, S. M., & Huff, J. L. (2020). Red risks for a journey to the red planet: The highest priority human health risks for a mission to Mars. Npj Microgravity, 6(1), 1–13. https://doi.org/10.1038/s41526-020-00124-6 

Ping, Z., Peng, Y., Lang, H., Xinyong, C., Zhiyi, Z., Xiaocheng, W., Hong, Z., & Liang, S. (2020). Oxidative Stress in Radiation-Induced Cardiotoxicity. Oxidative Medicine and Cellular Longevity, 2020. https://doi.org/10.1155/2020/3579143 

Polak, J. F., Pencina, M. J., Pencina, K. M., O’Donnell, C. J., Wolf, P. A., & Ralph B. D’Agostino, S. (2011). Carotid-Wall Intima–Media Thickness and Cardiovascular Events. The New England Journal of Medicine, 365(3), 213. https://doi.org/10.1056/NEJMOA1012592 

Preston, D. L., Shimizu, Y., Pierce, D. A., Suyama, A., & Mabuchi, K. (2003). Studies of Mortality of Atomic Bomb Survivors. Report 13: Solid Cancer and Noncancer Disease Mortality: 1950–1997. Https://Doi.Org/10.1667/RR3049, 160(4), 381–407. https://doi.org/10.1667/RR3049 

Pries, A. R., Reglin, B., & Secomb, T. W. (2001). Structural adaptation of microvascular networks: Functional roles of adaptive responses. American Journal of Physiology - Heart and Circulatory Physiology, 281(3). https://doi.org/10.1152/ajpheart.2001.281.3.h1015 

Ramadan, R., Baatout, S., Aerts, A., & Leybaert, L. (2021). The role of connexin proteins and their channels in radiation-induced atherosclerosis. Cellular and Molecular Life Sciences, 78(7), 3087–3103. https://doi.org/10.1007/s00018-020-03716-3 

Ramadan, R., Vromans, E., Anang, D. C., Goetschalckx, I., Hoorelbeke, D., Decrock, E., Baatout, S., Leybaert, L., & Aerts, A. (2020). Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage. Frontiers in Pharmacology, 11. https://doi.org/10.3389/fphar.2020.00212 

Rehman, M. U., Jawaid, P., Uchiyama, H., & Kondo, T. (2016). Comparison of free radicals formation induced by cold atmospheric plasma, ultrasound, and ionizing radiation. Archives of Biochemistry and Biophysics, 605, 19–25. https://doi.org/10.1016/j.abb.2016.04.005 

Rios, A., Joshi, R., & Shin, H. (2020). Quantifying 60 Years of Gender Bias in Biomedical Research with Word Embeddings. 1–13. https://doi.org/10.18653/v1/2020.bionlp-1.1 

Rodgers, J. L., Jones, J., Bolleddu, S. I., Vanthenapalli, S., Rodgers, L. E., Shah, K., Karia, K., & Panguluri, S. K. (2019). Cardiovascular risks associated with gender and aging. Journal of Cardiovascular Development and Disease, 6(2). https://doi.org/10.3390/jcdd6020019 

Sadhukhan, R., Leung, J. W. C., Garg, S., Krager, K. J., Savenka, A. V., Basnakian, A. G., & Pathak, R. (2020). Fractionated radiation suppresses Kruppel-like factor 2 pathway to a greater extent than by single exposure to the same total dose. Scientific Reports, 10(1), 1–13. https://doi.org/10.1038/s41598-020-64672-3 

Sakata, K., Kondo, T., Mizuno, N., Shoji, M., Yasui, H., Yamamori, T., Inanami, O., Yokoo, H., Yoshimura, N., & Hattori, Y. (2015). Roles of ROS and PKC-βII in ionizing radiation-induced eNOS activation in human vascular endothelial cells. Vascular Pharmacology, 70, 55–65. https://doi.org/10.1016/j.vph.2015.03.016 

Santamaría, R., González-Álvarez, M., Delgado, R., Esteban, S., & Arroyo, A. G. (2020). Remodeling of the Microvasculature: May the Blood Flow Be With You. Frontiers in Physiology, 11, 1256. https://doi.org/10.3389/FPHYS.2020.586852/XML/NLM 

Sárközy, M., Gáspár, R., Zvara, A., Kiscsatári, L., Varga, Z., Kővári, B., Kovács, M. G., Szűcs, G., Fabian, G., Diószegi, P., Cserni, G., Puskás, L. G., Thum, T., Kahán, Z., Csont, T., & Batkai, S. (2019). Selective heart irradiation induces cardiac overexpression of the pro-hypertrophic miR-212. Frontiers in Oncology, 9(JUN), 598. https://doi.org/10.3389/fonc.2019.00598 

Schaue, D., Micewicz, E. D., Ratikan, J. A., Xie, M. W., Cheng, G., & McBride, W. H. (2015). Radiation and Inflammation. In Seminars in Radiation Oncology (Vol. 25, Issue 1, pp. 4–10). W.B. Saunders. https://doi.org/10.1016/j.semradonc.2014.07.007 

Schiffrin, E. L. (2008). Oxidative stress, nitric oxide synthase, and superoxide dismutase: A matter of imbalance underlies endothelial dysfunction in the human coronary circulation. Hypertension, 51(1), 31–32. https://doi.org/10.1161/HYPERTENSIONAHA.107.103226 

Schmidt-Ullrich, R. K., Dent, P., Grant, S., Mikkelsen, R. B., & Valerie, K. (2000). Signal transduction and cellular radiation responses. Radiation Research, 153(3), 245–257. https://doi.org/10.1667/0033-7587(2000)153[0245:STACRR]2.0.CO;2 

Schultz, W. M., Kelli, H. M., Lisko, J. C., Varghese, T., Shen, J., Sandesara, P., Quyyumi, A. A., Taylor, H. A., Gulati, M., Harold, J. G., Mieres, J. H., Ferdinand, K. C., Mensah, G. A., & Sperling, L. S. (2018). Socioeconomic Status and Cardiovascular Outcomes: Challenges and Interventions. Circulation, 137(20). https://doi.org/10.1161/circulationaha.117.029652 

Senoner, T., & Dichtl, W. (2019). Oxidative stress in cardiovascular diseases: Still a therapeutic target? Nutrients, 11(9). https://doi.org/10.3390/nu11092090 

Shen, Y., Jiang, X., Meng, L., Xia, C., Zhang, L., & Xin, Y. (2018). Transplantation of bone marrow mesenchymal stem cells prevents radiation-induced artery injury by suppressing oxidative stress and inflammation. Oxidative Medicine and Cellular Longevity, 2018. https://doi.org/10.1155/2018/5942916 

Shi, F., Wang, Y. C., Zhao, T. Z., Zhang, S., Du, T. Y., Yang, C. Bin, Li, Y. H., & Sun, X. Q. (2012). Effects of simulated microgravity on human umbilical vein endothelial cell angiogenesis and role of the PI3K-Akt-eNOS signal pathway. PLoS ONE, 7(7). https://doi.org/10.1371/journal.pone.0040365 

Shimizu, Y., Kodama, K., Nishi, N., Kasagi, F., Suyama, A., Soda, M., Grant, E. J., Sugiyama, H., Sakata, R., Moriwaki, H., Hayashi, M., Konda, M., & Shore, R. E. (2010). Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003. The BMJ, 340(7739), 193. https://doi.org/10.1136/BMJ.B5349 

Siamwala, J. H., Reddy, S. H., Majumder, S., Kolluru, G. K., Muley, A., Sinha, S., & Chatterjee, S. (2010). Simulated microgravity perturbs actin polymerization to promote nitric oxide-associated migration in human immortalized Eahy926 cells. Protoplasma, 242(1), 3–12. https://doi.org/10.1007/s00709-010-0114-z 

Slezak, J., Kura, B., Babal, P., Barancik, M., Ferko, M., Frimmel, K., Kalocayova, B., Kukreja, R. C., Lazou, A., Mezesova, L., Okruhlicova, L., Ravingerova, T., Singal, P. K., Bacova, B. S., Viczenczova, C., Vrbjar, N., & Tribulova, N. (2017). Potential markers and metabolic processes involved in the mechanism of Radiation-Induced heart injury. Canadian Journal of Physiology and Pharmacology, 95(10), 1190–1203. https://doi.org/10.1139/cjpp-2017-0121 

Soloviev, A. I., & Kizub, I. V. (2019). Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction. Biochemical Pharmacology, 159, 121–139. https://doi.org/10.1016/j.bcp.2018.11.019 

Sonveaux, P., Brouet, A., Havaux, X., Grégoire, V., Dessy, C., Balligand, J. L., & Feron, O. (2003). Irradiation-induced angiogenesis through the up-regulation of the nitric oxide pathway: Implications for tumor radiotherapy. Cancer Research, 63(5), 1012–1019. https://doi.org/10.1016/s0167-8140(03)80572-8 

Soucy, K. G., Lim, H. K., Attarzadeh, D. O., Santhanam, L., Kim, J. H., Bhunia, A. K., Sevinc, B., Ryoo, S., Vazquez, M. E., Nyhan, D., Shoukas, A. A., & Berkowitz, D. E. (2010). Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta. Journal of Applied Physiology, 108(5), 1250–1258. https://doi.org/10.1152/japplphysiol.00946.2009 

Soucy, K. G., Lim, H. K., Benjo, A., Santhanam, L., Ryoo, S., Shoukas, A. A., Vazquez, M. E., & Berkowitz, D. E. (2007). Single exposure gamma-irradiation amplifies xanthine oxidase activity and induces endothelial dysfunction in rat aorta. Radiation and Environmental Biophysics, 46(2), 179–186. https://doi.org/10.1007/s00411-006-0090-z 

Soucy, K. G., Lim, H. K., Kim, J. H., Oh, Y., Attarzadeh, D. O., Sevinc, B., Kuo, M. M., Shoukas, A. A., Vazquez, M. E., & Berkowitz, D. E. (2011). HZE 56Fe-ion irradiation induces endothelial dysfunction in rat aorta: Role of xanthine oxidase. Radiation Research, 176(4), 474–485. https://doi.org/10.1667/RR2598.1 

Sridharan, V., Seawright, J. W., Landes, R. D., Cao, M., Singh, P., Davis, C. M., Mao, X. W., Singh, S. P., Zhang, X., Nelson, G. A., & Boerma, M. (2020). Effects of single-dose protons or oxygen ions on function and structure of the cardiovascular system in male Long Evans rats. Life Sciences in Space Research, 26, 62–68. https://doi.org/10.1016/j.lssr.2020.04.002 

Srinivasan, L., Harris, M. C., & Kilpatrick, L. E. (2017). Cytokines and Inflammatory Response in the Fetus and Neonate. In Fetal and Neonatal Physiology, 2-Volume Set (pp. 1241–1254). https://doi.org/10.1016/B978-0-323-35214-7.00128-1 

Stanojković, T. P., Matić, I. Z., Petrović, N., Stanković, V., Kopčalić, K., Besu, I., Đorđić Crnogorac, M., Mališić, E., Mirjačić-Martinović, K., Vuletić, A., Bukumirić, Z., Žižak, Ž., Veldwijk, M., Herskind, C., & Nikitović, M. (2020). Evaluation of cytokine expression and circulating immune cell subsets as potential parameters of acute radiation toxicity in prostate cancer patients. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-75812-0 

Su, Y. T., Cheng, Y. P., Zhang, X., Xie, X. P., Chang, Y. M., & Bao, J. X. (2020). Acid sphingomyelinase/ceramide mediates structural remodeling of cerebral artery and small mesenteric artery in simulated weightless rats. Life Sciences, 243. https://doi.org/10.1016/j.lfs.2019.117253 

Summers, S. M., Nguyen, S. V., & Purdy, R. E. (2008). Hindlimb unweighting induces changes in the RhoA-Rho-kinase pathway of the rat abdominal aorta. Vascular Pharmacology, 48(4–6), 208–214. https://doi.org/10.1016/j.vph.2008.03.006 

Sylvester, C. B., Abe, J. I., Patel, Z. S., & Grande-Allen, K. J. (2018). Radiation-Induced Cardiovascular Disease: Mechanisms and Importance of Linear Energy Transfer. Frontiers in Cardiovascular Medicine, 5, 1. https://doi.org/10.3389/FCVM.2018.00005 

Tahimic, C. G. T., & Globus, R. K. (2017). Redox signaling and its impact on skeletal and vascular responses to spaceflight. International Journal of Molecular Sciences, 18(10). https://doi.org/10.3390/ijms18102153 

Takahashi, I., Shimizu, Y., Grant, E. J., Cologne, J., Ozasa, K., & Kodama, K. (2017). Heart disease mortality in the life span study, 1950-2008. In Radiation Research (Vol. 187, Issue 3). https://doi.org/10.1667/RR14347.1 

Tapio, S. (2016). Pathology and biology of radiation-induced cardiac disease. Journal of Radiation Research, 57(5), 439–448. https://doi.org/10.1093/jrr/rrw064 

Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Alonso, A., Beaton, A. Z., Bittencourt, M. S., Boehme, A. K., Buxton, A. E., Carson, A. P., Commodore-Mensah, Y., Elkind, M. S. V., Evenson, K. R., Eze-Nliam, C., Ferguson, J. F., Generoso, G., Ho, J. E., Kalani, R., Khan, S. S., Kissela, B. M., … Martin, S. S. (2022). Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation, 145(8), e153–e639. https://doi.org/10.1161/CIR.0000000000001052/FORMAT/EPUB 

Ungvari, Z., Podlutsky, A., Sosnowska, D., Tucsek, Z., Toth, P., Deak, F., Gautam, T., Csiszar, A., & Sonntag, W. E. (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 radiosens. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 68(12 A), 1443–1457. https://doi.org/10.1093/gerona/glt057 

UNSCEAR. (2008). UNSCEAR 2006 report. Annex B. Epidemiological evaluation of cardiovascular disease and other non_cancer diseases following radiation exposure. 

Valerie, K., Yacoub, A., Hagan, M. P., Curiel, D. T., Fisher, P. B., Grant, S., & Dent, P. (2007). Radiation-induced cell signaling: Inside-out and outside-in. Molecular Cancer Therapeutics, 6(3), 789–801. https://doi.org/10.1158/1535-7163.MCT-06-0596 

Van Varik, B. J., Rennenberg, R. J. M. W., Reutelingsperger, C. P., Kroon, A. A., De Leeuw, P. W., & Schurgers, L. J. (2012). Mechanisms of arterial remodeling: Lessons from genetic diseases. Frontiers in Genetics, 3(DEC), 290. https://doi.org/10.3389/FGENE.2012.00290/BIBTEX 

Varma, S. D., Kovtun, S., & Hegde, K. R. (2011). Role of ultraviolet irradiation and oxidative stress in cataract formation-medical prevention by nutritional antioxidants and metabolic agonists. Eye and Contact Lens, 37(4), 233–245. https://doi.org/10.1097/ICL.0b013e31821ec4f2 

Venkatesulu, B. P., Mahadevan, L. S., Aliru, M. L., Yang, X., Bodd, M. H., Singh, P. K., Yusuf, S. W., Abe, J. ichi, & Krishnan, S. (2018). Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms. JACC: Basic to Translational Science, 3(4), 563–572. https://doi.org/10.1016/j.jacbts.2018.01.014 

Verma, S., Buchanan, M. R., & Anderson, T. J. (2003). Endothelial Function Testing as a Biomarker of Vascular Disease. Circulation, 108(17), 2054–2059. https://doi.org/10.1161/01.CIR.0000089191.72957.ED 

Vernice, N. A., Meydan, C., Afshinnekoo, E., & Mason, C. E. (2020). Long-term spaceflight and the cardiovascular system. Precision Clinical Medicine, 3(4), 284–291. https://doi.org/10.1093/PCMEDI/PBAA022 

Versari, S., Longinotti, G., Barenghi, L., Maier, J. A. M., & Bradamante, S. (2013). The challenging environment on board the International Space Station affects endothelial cell function by triggering oxidative stress through thioredoxin interacting protein overexpression: the ESA-SPHINX experiment. FASEB Journal, 27(11), 4466–4475. https://doi.org/10.1096/fj.13-229195 

Wang, H., Wei, J., Zheng, Q., Meng, L., Xin, Y., Yin, X., & Jiang, X. (2019). Radiation-induced heart disease: a review of classification, mechanism and prevention. International Journal of Biological Sciences, 15(10), 2128. https://doi.org/10.7150/IJBS.35460 

Wang, Y., Boerma, M., & Zhou, D. (2016). Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases. Radiation Research, 186(2), 153–161. https://doi.org/10.1667/RR14445.1 

Winham, S. J., de Andrade, M., & Miller, V. M. (2014). Genetics of cardiovascular disease: Importance of sex and ethnicity. Atherosclerosis, 241(1), 219–228. https://doi.org/10.1016/j.atherosclerosis.2015.03.021 

Yakerson, A. (2019). Women in clinical trials: A review of policy development and health equity in the Canadian context. International Journal for Equity in Health, 18(1), 56. https://doi.org/10.1186/s12939-019-0954-x 

Yan, T., Zhang, T., Mu, W., Qi, Y., Guo, S., Hu, N., Zhao, W., Zhang, S., Wang, Q., Shi, L., & Liu, L. (2020). Ionizing radiation induces BH4 deficiency by downregulating GTP-cyclohydrolase 1, a novel target for preventing and treating radiation enteritis. Biochemical Pharmacology, 180, 114102. https://doi.org/10.1016/j.bcp.2020.114102 

Yang, Y. et al. (1998), “The Effect of Catalase Amplification on Immortal Lens Epithelial Cell Lines”, Experimental Eye Research, Vol. 67/6, Elsevier, Amsterdam https://doi.org/10.1006/exer.1998.0560 

Yang, E. H., Marmagkiolis, K., Balanescu, D. V., Hakeem, A., Donisan, T., Finch, W., Virmani, R., Herrman, J., Cilingiroglu, M., Grines, C. L., Toutouzas, K., & Iliescu, C. (2021). Radiation-Induced Vascular Disease—A State-of-the-Art Review. Frontiers in Cardiovascular Medicine, 8, 223. https://doi.org/10.3389/FCVM.2021.652761/XML/NLM 

Yao, L., Romero, M. J., Toque, H. A., Yang, G., Caldwell, R. B., & Caldwell, R. W. (2010). The role of RhoA/Rho kinase pathway in endothelial dysfunction. Journal of Cardiovascular Disease Research, 1(4), 165–170. https://doi.org/10.4103/0975-3583.74258 

Yentrapalli, R., Azimzadeh, O., Barjaktarovic, Z., Sarioglu, H., Wojcik, A., Harms-Ringdahl, M., Atkinson, M. J., Haghdoost, S., & Tapio, S. (2013). Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation. Proteomics, 13(7), 1096–1107. https://doi.org/10.1002/pmic.201200463 

Yentrapalli, R., Azimzadeh, O., Sriharshan, A., Malinowsky, K., Merl, J., Wojcik, A., Harms-Ringdahl, M., Atkinson, M. J., Becker, K. F., Haghdoost, S., & Tapio, S. (2013). The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation. PLoS ONE, 8(8). https://doi.org/10.1371/journal.pone.0070024 

Yu, T., Parks, B. W., Yu, S., Srivastava, R., Gupta, K., Wu, X., Khaled, S., Chang, P. Y., Kabarowski, J. H., & Kucik, D. F. (2011). Iron-ion radiation accelerates atherosclerosis in apolipoprotein E-Deficient mice. Radiation Research, 175(6), 766–773. https://doi.org/10.1667/RR2482.1 

Zakrzewicz, A., Secomb, T. W., & Pries, A. R. (2002). Angioadaptation: Keeping the vascular system in shape. News in Physiological Sciences, 17(5). https://doi.org/10.1152/nips.01395.2001 

Zhang, L. F. (2013). Region-specific vascular remodeling and its prevention by artificial gravity in weightless environment. European Journal of Applied Physiology, 113(12), 2873–2895. https://doi.org/10.1007/S00421-013-2597-8 

Zhang, R., Bai, Y. G., Lin, L. J., Bao, J. X., Zhang, Y. Y., Tang, H., Cheng, J. H., Jia, G. L., Ren, X. L., & Jin, M. (2009). Blockade of at 1 receptor partially restores vasoreactivity, NOS expression, and superoxide levels in cerebral and carotid arteries of hindlimb unweighting rats. Journal of Applied Physiology, 106(1), 251–258. https://doi.org/10.1152/japplphysiol.01278.2007 

Zielinski, J. M., Ashmore, P. J., Band, P. R., Jiang, H., Shilnikova, N. S., Tait, V. K., & Krewski, D. (2009). Low dose ionizing radiation exposure and cardiovascular disease mortality: Cohort study based on Canadian national dose registry of radiation workers. International Journal of Occupational Medicine and Environmental Health, 22(1), 27–33. https://doi.org/10.2478/v10001-009-0001-z 

Zieman, S. J., Melenovsky, V., & Kass, D. A. (2005). Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(5), 932–943. https://doi.org/10.1161/01.ATV.0000160548.78317.29 

Zigman, S., McDaniel, T., Schultz, J., & Reddan, J. (2000). Effects of intermittent UVA exposure on cultured lens epithelial cells. Current Eye Research, 20(2), 95–100. https://doi.org/10.1076/0271-3683(200002)2021-DFT095 

Zou, B., Schuster, J. P., Niu, K., Huang, Q., Rühle, A., & Huber, P. E. (2019). Radiotherapy-induced heart disease: a review of the literature. Precision Clinical Medicine, 2(4), 270–282. https://doi.org/10.1093/pcmedi/pbz025