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Relationship: 2773
Title
Altered Signaling leads to Altered, Nitric Oxide Levels
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Deposition of energy leads to vascular remodeling | adjacent | Moderate | Low | Vinita Chauhan (send email) | Open for citation & comment |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Male | Low |
Female | Low |
Unspecific | Moderate |
Life Stage Applicability
Term | Evidence |
---|---|
Adult | Low |
Not Otherwise Specified | Moderate |
Key Event Relationship Description
Multiple signaling pathways can regulate nitric oxide (NO) levels. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway can activate nitric oxide synthase (NOS), an enzyme that produces NO, through phosphorylation (Hemmings & Restuccia 2012; Nagane et al., 2021). The RhoA/Rho kinase (ROCK) pathway inhibits both the expression and phosphorylation of NOS (Yao et al., 2010). Furthermore, the renin-angiotensin-aldosterone system (RAAS) can both inhibit NOS to reduce vasodilation and activate NOS as a countermeasure for vasoconstriction (Millatt, Abdel-Rahman & Siragy, 1999). The extracellular signal-regulated protein kinase 5 (ERK5)/kruppel-like factor 2 (KLF2) pathway can increase transcription of endothelial NOS (eNOS), which results in increased NO levels (Paudel, Fusi & Schmidt, 2021). Lastly, the acidic sphingomyelinase/ceramide pathway can activate NADPH oxidase (NOX) production of reactive oxygen species (ROS) that react with NO, resulting in lower NO levels (Soloviev & Kizub, 2019). Alterations in these pathways will result in altered NO levels.
Evidence Collection Strategy
The strategy for collating the evidence on radiation stressors to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.
Evidence Supporting this KER
Overall weight of evidence: Moderate
Biological Plausibility
The biological plausibility surrounding the connection between altered signaling pathways and altered NO levels is well-supported by the literature. Studies have shown that altered signaling pathways lead to altered NO levels (Azimzadeh et al., 2015; Azimzadeh et al., 2017; Hasan, Radwan & Galal, 2019; Shi et al., 2012; Siamwala et al., 2010).
Multiple signaling pathways can influence NO levels. Under normal physiological conditions, the PI3K/Akt pathway is regulated by various growth factors and other signaling molecules to modulate eNOS phosphorylation and therefore NO production (Hemmings & Restuccia, 2012). Phosphorylation of eNOS can affect its function. Phosphorylation at Ser1177 activates the enzyme, while phosphorylation at Thr495 acts in reverse and decreases enzymatic activity instead (Forstermann, 2010; Nagane et al., 2021). In endothelial cells, Thr495 is constitutively phosphorylated by kinases like protein kinase C (PKC) (Forstermann, 2010). Following Akt activation, eNOS is phosphorylated on Ser1177 to activate the enzyme and thus NO production is upregulated (Karar & Maity, 2011). Although peroxisome proliferator-activated receptor α (PPARα) can increase eNOS directly through transcription, it can also increase vascular endothelial growth factor (VEGF) (Du, Wagner & Wagner, 2020), which can activate the PI3K pathway to activate eNOS (Hicklin & Ellis, 2005). Alternatively, activation of the RhoA/ROCK pathway leads to a decrease in NO bioavailability (Yao et al., 2010). The RhoA/ROCK pathway causes eNOS mRNA destabilization and prevents Ser1177 eNOS phosphorylation by Akt (Yao et al., 2010). However, phosphorylation of RhoGDI, a regulator in the RhoA/ROCK pathway, causes increased affinity to GTP-RhoA, sequestering the active form of RhoA and preventing eNOS inhibition (Dovas & Couchman, 2005). The RAAS pathway results in the production of angiotensin II (AngII) which can cause various downstream effects on vascular homeostasis, including inducing vasoconstriction (Millatt, Abdel-Rahman & Siragy, 1999). AngII can downregulate eNOS Ser1177 phosphorylation to prevent vasodilation (Ding et al., 2020; Millatt, Abdel-Rahman & Siragy, 1999), or activate eNOS as a corrective measure (Millatt, Abdel-Rahman & Siragy, 1999). As a result, depending on the mechanism, NO levels can either increase or decrease after AngII stimulation. The ERK5/KLF2 pathway results in activation of the KLF2 transcription factor, which increases transcription of eNOS (Paudel, Fusi & Schmidt, 2021).
Empirical Evidence
The empirical evidence to support this KER is provided by in vivo mouse and rat models and in vitro models of human coronary artery endothelial cell (HCAECs), human umbilical vein endothelial cells (HUVECs), and EA.hy96 cells (a hybrid of HUVECs and A549 cells). The effects of altered signaling pathways on the levels of NO as well as inducible NOS (iNOS) and eNOS have been investigated. These studies examined levels of signaling molecules in insulin-dependent PI3K/Akt pathway such as IGFR1, PPARα, PI3K, Akt, and the phosphorylated versions of each (Azimzadeh et al., 2015; Azimzadeh et al., 2021; Shi et al., 2012), RAAS pathway indicator, AngII (Hasan, Radwan & Galal, 2019), phosphorylated Rho GDP-dissociation inhibitor (p-RhoGDI) in the RhoA/ROCK pathway (Azimzadeh et al., 2017), ERK5 and KLF2 (Sadhukhan et al., 2020), and the effect they have on NO. The studies used stressors such as X-rays (Azimzadeh et al., 2015; Azimzadeh et al., 2017; Azimzadeh et al., 2021), gamma rays (Hasan, Radwan & Galal, 2019; Sadhukhan et al., 2020) and altered gravity (Shi et al., 2012; Siamwala et al., 2010).
Dose Concordance
There is moderate evidence to demonstrate dose concordance between altered signaling pathways leading to altered NO levels. Activated RhoA reduces the activity and abundance of eNOS (Yao et al., 2010). HCAECs irradiated with 0.5 Gy demonstrated a 0.7-fold decrease in p-RhoGDI, a 0.6-fold decrease in p-eNOS and a 0.8-fold decrease in cellular NO, 7 days after exposure (Azimzadeh et al., 2017). The decrease in p-RhoGDI, involved in the RhoA/ROCK pathway, was correlated with a decrease in p-eNOS and NO (Azimzadeh et al., 2017). HSP90, a protein that binds to and activates eNOS (Karar & Maity, 2011), decreased 0.8-fold following 0.5 Gy X-ray irradiation (Azimzadeh et al., 2017).
High doses (>2 Gy) also show dose concordance between altered signaling pathways and altered NO levels. X-ray irradiation of BAECs and HUVECs caused a 5.6-fold increase in p-Akt/Akt after 6 Gy (Sonveaux et al., 2003). eNOS increased 3-fold after 6 Gy, while p-eNOS increased 1.2-fold after 2 Gy and 1.7-fold after 6 Gy (Sonveaux et al., 2003). Although the p-Akt/Akt ratio was not significantly increased after 2 Gy, p-Akt alone had increased, indicating changes in the PI3K/Akt pathway had occurred at 2 Gy. Therefore, a decrease in PI3K/Akt pathway proteins, such as p-IGFR1, p-Akt and p-PI3K are correlated with decreases in p-eNOS and NO (Azimzadeh et al., 2015), while an increase in p-Akt correlates with increases in eNOS and p-eNOS (Shi et al., 2012; Sonveaux et al., 2003). In rat blood serum, 6 Gy gamma ray irradiation led to a 1.4-fold increase in AngII and aldosterone levels and a 3.3-fold increase in iNOS expression indicating that a change in the RAAS pathway can lead to altered NO levels (Hasan, Radwan & Galal, 2019).
Mice that received high dose (8 or 16 Gy) X-ray irradiation on the heart showed alterations in the levels of signalling proteins involved in the PI3K/Akt pathway, including a 0.4 and 0.3-fold decrease of p-IGFR1, a 0.5-fold decrease of PI3K, a 0.2 and 0.1-fold decrease of p-Akt and a 0.6 and 0.2-fold decrease of p-eNOS at 8 Gy and 16 Gy, respectively (Azimzadeh et al., 2015). Concurrently to changes to PI3K/Akt pathway signaling molecules, the level of serum NO decreased 0.3-fold and 0.3-fold following 8 Gy and 16 Gy X-ray irradiation, respectively (Azimzadeh et al., 2015). As well, following X-ray irradiation, the ERK/MAPK pathway decreased 0.5-fold at 16 Gy and the p38/MAPK pathway increased 1.3-fold at 16 Gy (Azimzadeh et al., 2015). X-ray irradiation in mice at 16 Gy also inhibited PPARα resulting in decreased activity and phosphorylation of eNOS through the PI3K/Akt pathway and decreased NO levels (Azimzadeh et al., 2021). This study also showed an increase in p-ERK, and p-p38 at 16 Gy (Azimzadeh et al., 2021). After irradiation of HUVECs with 10 or 12 Gy, p-ERK5, KLF2 and eNOS were all found to decrease after fractionated doses, while KLF2 and eNOS both decreased after acute doses (Sadhukhan et al., 2020).
Microgravity in HUVEC-C was simulated by a clinostat using rotation at a slow speed to negate centrifugal force. Following clinorotation, levels of eNOS and p-eNOS expression were significantly increased by 5.2-fold and 5.5-fold, respectively. As well, p-Akt increased by 2.9-fold after exposure to simulated microgravity in HUVEC-C (Shi et al., 2012).
Time Concordance
There is some evidence to demonstrate time concordance between altered signaling pathways leading to altered NO levels. After 0.5 Gy X-ray of HCAECs, p-Rho-GDI significantly decreased after 1 day, while NO was not significantly lower after 1 day (Azimzadeh et al., 2017). After 24 h, p-Akt was increased, while eNOS was increased 24 and 48 h after X-ray irradiation of BAECs and HUVECs (Sonveaux et al., 2003). After 7 days, p-Rho-GDI decreased further and NO showed a significant decrease. HUVECs irradiated with 10 or 12 Gy acute or fractionated X-rays showed decreased levels of p-ERK5, KLF2 and eNOS at 4 h, and decreased KLF2 and eNOS at 24 h after irradiation (Sadhukhan et al., 2020).
Incidence Concordance
The evidence of incidence concordance for this relationship is moderate, as a few studies demonstrated incidence concordance. In mice hearts irradiated with X-rays, p-Akt, the direct upstream activator of eNOS, decreased 0.2-fold after 8 Gy and 0.1-fold after 16 Gy, while NO decreased 0.3-fold after 8 Gy and 0.2-fold after 16 Gy (Azimzadeh et al., 2015). Similarly, after 0.5 Gy X-ray irradiation of HCAECs, p-RhoGDI decreased 0.7-fold while NO decreased 0.8-fold (Azimzadeh et al., 2017). X-ray irradiation of BAECs and HUVECs at 6 Gy resulted in a 5.6-fold increase in the ratio of p-Akt/Akt and a 3-fold increase to p-eNOS (Sonveaux et al., 2003).
Essentiality
Several studies have investigated the essentiality of various signalling pathways in altering NO levels. Under normal conditions, the phosphorylation of eNOS by the PI3K/Akt pathway activates NOS, resulting in NO production. LY294002 treatment, a PI3K inhibitor, led to significant decreases in eNOS and p-eNOS levels in HUVEC-C samples (Shi et al., 2012). After exposure to simulated microgravity by clinorotation, LY294002 treatment led to decreased p-Akt levels to below control levels (Shi et al., 2012). The inhibition of the PI3K/Akt pathway with wortmanin, another PI3K inhibitor, also led to a 0.3-fold decrease in NO production (Siamwala et al., 2010). Irradiation inhibited PPARα and eNOS, while treatment with fenofibrate, a PPARα activator, kept both p-PPARα and NO at control levels (Azimzadeh et al., 2021).
Bradykinin-potentiating factor (BPF) is implicated in muscle contraction, inflammatory responses and angiotensin-converting enzyme (ACE) inhibition. ACE in endothelial cells converts AngI to AngII. Irradiation at 6 Gy led to increased iNOS, AngII, and aldosterone, while the subsequent treatment with BPF decreased all endpoints measured following irradiation, including the levels of iNOS, AngII, and aldosterone. The recovery of iNOS serum levels in 6 Gy gamma irradiated rats following BPF treatment indicates that the signaling pathways play a role in NO levels (Hasan, Radwan & Galal, 2019). In addition, bradykinin signaling through bradykinin receptor 2 (B2R) activates eNOS (Ancion et al., 2019). Nitrite concentration was found to increase after both microgravity and treatment with bradykinin (Siamwala et al., 2010).
Various inhibitors of the mevalonate pathway were used to recover KLF2 levels after irradiation, which resulted in increased KLF2 and eNOS levels (Sadhukhan et al., 2020).
Uncertainties and Inconsistencies
- Due to the high reactivity of NO, it can be difficult to obtain its direct measures (Luiking, Engelen & Deutz, 2010). The inconsistencies in NO levels may be attributed to the challenges in measuring NO. Directionality of NO changes cannot be compared between studies due to a variety of experimental conditions like stressor type, dose, dose rate, model and time course of the experiment.
Known modulating factors
Modulating factor |
Details |
Effects on the KER |
References |
Drug |
BPF (ACE inhibitor) |
BPF treatment led to decreased iNOS, angiotensin II and aldosterone following irradiation. |
Hasan, Radwan & Galal, 2019 |
Drug |
LY294002 (PI3K inhibitor) |
LY294002 treatment led to reduced phosphorylation of both Akt and eNOS. |
Shi et al., 2012; |
Drug |
Wortmanin (PI3K inhibitor) |
Wortmanin decreased NO production. |
Siamwala et al., 2010 |
Drug |
Fenofibrate (PPARα activator) |
Treatment with PPARα prevented the decrease in eNOS levels after irradiation. |
Azimzadeh et al., 2021 |
Drug |
Atorvastatin (HMG-CoA reductase inhibitor) |
Treatment with atorvastatin increased KLF2 and eNOS levels slightly. |
Sadhukhan et al., 2020 |
Drug |
Gamma tocotrienol (HMG-CoA reductase inhibitor) |
Treatment with gamma tocotrienol prevented the radiation-induced decrease in KLF2 and eNOS levels. |
Sadhukhan et al., 2020 |
Drug |
Geranylgeranyltransferase I inhibitor 298 |
Treatment with Geranylgeranyltransferase I inhibitor 298 prevented the radiation-induced decrease in KLF2 and eNOS levels. |
Sadhukhan et al., 2020 |
Quantitative Understanding of the Linkage
The following are a few examples of quantitative understanding of the relationship. All data that is represented is statistically significant unless otherwise indicated.
Response-response Relationship
Dose/Incidence Concordance
Reference |
Experiment Description |
Result |
Shi et al., 2012 |
In vitro. Microgravity was stimulated with a clinostat using rotation at a slow speed to negate centrifugal force and simulate weightlessness. eNOS expression and Akt phosphorylation in HUVEC-C were measured by western blot. |
After clinorotation, eNOS and p-eNOS expression increased by 5.2-fold and 5.5-fold respectively. p-Akt increased by 2.9-fold, while there was no significant change in Akt after clinorotation in HUVEC-C. |
Hasan, Radwan & Galal, 2019 |
In vivo. Rat heart serum were exposed to irradiation by 6 Gy Gamma rays. iNOS levels were measured by ELISA. RAAS indices, AngII and aldosterone, were also measured in serum by ELISA. |
Irradiation with 6 Gy led to a 3.3-fold increase in iNOS expression, ~1.4-fold increase in AngII and aldosterone. |
Azimzadeh et al., 2015 |
In vivo. Mice were exposed to heart X-ray irradiation at either 8 or 16 Gy. Levels of proteins in the insulin-dependent PI3K/Akt pathway with and without phosphorylation were determined along with levels of NO and eNOS. Protein levels in various signaling pathways were measured using immunoblotting, and NO was measured using an ELISA assay. |
Many key proteins in each pathway showed significant changes in abundance and phosphorylation after 8 and 16 Gy irradiation. For example, phosphorylation of the insulin receptor IGFR1 decreased 0.4-fold after 8 Gy and 0.2-fold after 16 Gy. Similarly, p-Akt decreased 0.2-fold at 8 Gy and 0.1-fold at 16 Gy. p-eNOS decreased 0.6-fold after 8 Gy and 0.2-fold after 16 Gy. The ERK/MAPK pathway was found decreased 0.5-fold at 16 Gy and the p38/MAPK pathway was found increased 1.3-fold at 16 Gy. NO decreased 0.3-fold after 8 Gy and 0.2-fold after 16 Gy. |
Azimzadeh et al., 2017 |
In vitro. HCAECs were irradiated with 0.5 Gy X-ray irradiation over 1 minute. Phosphorylated RhoGDI and eNOS levels were determined using immunoblotting, and NO levels were determined using ELISA assay. |
p-RhoGDI decreased 0.7-fold, p-eNOS decreased 0.6-fold, HSP90 (positive regulator of eNOS) decreased 0.8-fold and NO decreased 0.8-fold after 0.5 Gy irradiation. |
Sonveaux et al., 2003 |
In vitro. Following X-ray irradiation of BAECs and HUVECs, levels of eNOS, p-eNOS, Akt, and p-Akt were measured with immunoblotting at various doses (0.86 Gy/min). |
Compared to control, 24 h after irradiation, the ratio of p-Akt/Akt increased 1.3-fold after 2 Gy (not significant) and 5.6-fold after 6 Gy. eNOS increased 1.3-fold after 2 Gy (not significant), 2.1-fold after 4 Gy (not significant), 3-fold after 6 and 8 Gy, 4.3-fold after 10 Gy and 3.4-fold after 20 Gy. Compared to control, 24 h after irradiation, p-eNOS increased 1.2-fold after 2 Gy and 1.7-fold after 6 Gy. |
Azimzadeh et al., 2021 |
In vivo. Male C57BL/6J were irradiated with an acute dose of 16 Gy X-rays. Activation of the PI3K-Akt pathway was determined through p-PPARα (deactivated) levels from Ponceau S staining. eNOS activity and NO were measured using fluorometric assay and Griess assay, respectively. The level of proteins in MAPK pathways were determined by ELISA in heart tissue. |
After 16 Gy, p-PPARα increased 1.3-fold. After 16 Gy, p-ERK increased 1.5-fold, and p-p38 increased 1.3-fold, eNOS was unchanged, p-eNOS decreased 0.8-fold and NO decreased to 65% of control levels. |
Sadhukhan et al., 2020 |
In vitro. HUVECs were irradiated with various regimens and doses of gamma radiation. Signaling from the ERK5/KLF2 pathway was determined through KLF2 and p-ERK5 levels from western blot. eNOS levels were determined by western blot. Fractionated doses were separated by 24 h. |
p-ERK5 decreased 0.6-fold after 5 doses of 2 Gy, increased 1.5-fold after acute 10 Gy, decreased 0.5-fold after 5 doses of 2.5 Gy, and increased 1.3-fold after acute 12.5 Gy. KLF2 and eNOS showed similar responses and were often slightly decreased after acute doses. |
Time-scale
Time Concordance
Reference |
Experiment Description |
Result |
Azimzadeh.et al., 2017 |
In vitro. AECs were irradiated with 0.5 Gy X-rays over 1 minute. Phosphorylated RhoGDI and eNOS levels were determined using immunoblotting, and NO levels were determined using ELISA assay. Measurements were taken after 1, 7 or 14 days. |
p-RhoGDI significantly decreased after 1 day, while NO only significantly decreased after 7 days. However, p-eNOS significantly decreased after 1 day. |
Sonveaux et al., 2003 |
In vitro. Levels of eNOS, p-eNOS, Akt, and p-Akt after X-ray irradiation of BAECs and HUVECs were measured with immunoblotting at various doses (0.86 Gy/min). |
p-Akt was significantly increased 24 h after irradiation, while eNOS was significantly increased after 12, 24, and 48 h and p-eNOS was significantly increased after 24 h. |
Sadhukhan et al., 2020 |
In vitro. HUVECs were irradiated with various regimens and doses of gamma radiation. Fractionated doses were separated by 24 h. Signaling from the ERK5/KLF2 pathway was determined through KLF2 and p-ERK5 levels from western blot. eNOS levels were determined by western blot. Measurements were taken 4 or 24 h post-irradiation. |
After 4 h, p-ERK5 decreased 0.6-fold after 5 doses of 2 Gy, increased 1.5-fold after acute 10 Gy, decreased 0.5-fold after 5 doses of 2.5 Gy, and increased 1.3-fold after acute 12.5 Gy. Both KLF2 and eNOS decreased similar to p-ERK5 after 4 h and were slightly decreased after 24 h. |
Known Feedforward/Feedback loops influencing this KER
Not identified
Domain of Applicability
The majority of the evidence for this KER is from rat and mouse models. Most evidence regarding sex and lifestage is unspecified with a small amount of evidence from adult models.
References
Ancion, A. et al. (2019), “A Review of the Role of Bradykinin and Nitric Oxide in the Cardioprotective Action of Angiotensin-Converting Enzyme Inhibitors: Focus on Perindopril”, Cardiology and Therapy, Vol. 8/2, Springer, London, https://doi.org/10.1007/S40119-019-00150-W
Azimzadeh, O. et al. (2021), “Activation of pparα by fenofibrate attenuates the effect of local heart high dose irradiation on the mouse cardiac proteome”, Biomedicines, Vol. 9/12, Multidisciplinary Digital Publishing Institute, Basel, 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
Ding, J. et al. (2020), “Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT1R Nox/ROS/PP2A Pathway”, Frontiers in physiology, Vol.11, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphys.2020.566410
Dovas, A. and J. R. Couchman (2005), “RhoGDI: multiple functions in the regulation of Rho family GTPase activities”, Biochemical Journal, Vol. 390, Portland Press, London, https://doi.org/10.1042/BJ20050104
Du, S., N. Wagner and K. D. Wagner (2020), “The Emerging Role of PPAR Beta/Delta in Tumor Angiogenesis”, PPAR Research, Vol. 2020, Hindawi, London, https://doi.org/10.1155/2020/3608315.
Förstermann, U. (2010), “Nitric oxide and oxidative stress in vascular disease”, Pflugers Archiv : European journal of physiology, Vol. 459/6, Springer, London, https://doi.org/10.1007/s00424-010-0808-2
Hasan, H. F., R. R. Radwan and S. M. Galal (2019), “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, Vol. 47/2, Wiley-Blackwell, Hoboken, https://doi.org/10.1111/1440-1681.13202
Hemmings, B. A. and D. F. Restuccia (2012), “PI3K-PKB/Akt Pathway”, Cold Spring Harbor Perspectives in Biology, Vol. 4/9, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, https://doi.org/10.1101/CSHPERSPECT.A011189
Hicklin, D. J. and L. M. Ellis (2005), “Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis”, Journal of Clinical Oncology, Vol. 23/5, American Society of Clinical Oncology, Virginia, https://doi.org/10.1200/JCO.2005.06.081.
Karar, J. and A. Maity (2011), “PI3K/AKT/mTOR Pathway in Angiogenesis”, Frontiers in Molecular Neuroscience, Vol. 4, Frontiers Media SA, Lausanne, https://doi.org/10.3389/FNMOL.2011.00051
Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, Vol. 98/12. https://doi.org/10.1080/09553002.2022.2110306
Luiking, Y. C., M. P. Engelen and N. E. Deutz (2010), “Regulation of nitric oxide production in health and disease”, Current Opinion in Clinical Nutrition and Metabolic Care, Vol. 13/1, Lippincott Williams and Wilkins Ltd., Philadelphia, https://doi.org/10.1097/MCO.0b013e328332f99d
Millatt, L. J., E. M. Abdel-Rahman and H. M. Siragy (1999), “Angiotensin II and nitric oxide: a question of balance”, Regulatory Peptides, Vol. 81/1-3, Elsevier, Amsterdam, https://doi.org/10.1016/S0167-0115(99)00027-0
Nagane, M. et al. (2021), “DNA damage response in vascular endothelial senescence: Implication for radiation-induced cardiovascular diseases”, Journal of Radiation Research, Vol. 62/4, Oxford University Press, Oxford, https://doi.org/10.1093/JRR/RRAB032
Paudel, R., L. Fusi and M. Schmidt (2021), “The MEK5/ERK5 Pathway in Health and Disease”, International Journal of Molecular Sciences, Vol. 22/14, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms22147594.
Sadhukhan, R. et al. (2020), “Fractionated radiation suppresses Kruppel-like factor 2 pathway to a greater extent than by single exposure to the same total dose”, Scientific Reports, Vol. 10/1, Springer, London, https://doi.org/10.1038/s41598-020-64672-3.
Shi, F. et al. (2012), “Effects of Simulated Microgravity on Human Umbilical Vein Endothelial Cell Angiogenesis and Role of the PI3K-Akt-eNOS Signal Pathway”, PLoS ONE, Vol. 7/7, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0040365
Siamwala, J. H. et al. (2010), “Simulated microgravity perturbs actin polymerization to promote nitric oxide-associated migration in human immortalized Eahy926 cells”, Protoplasma, Vol. 242/1, Springer, London, https://doi.org/10.1007/S00709-010-0114-Z
Soloviev, A. I. and I.V. Kizub (2019), “Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction”, Biochemical pharmacology, Vol. 159, Elsevier, Amsterdam, https://doi.org/10.1016/j.bcp.2018.11.019
Sonveaux, P. et al. (2003), “Irradiation-induced Angiogenesis through the Up-Regulation of the Nitric Oxide Pathway: Implications for Tumor Radiotherapy”, Cancer Research, Vol. 63/5, American Association for Cancer Research, Philadelphia, https://aacrjournals.org/cancerres/article/63/5/1012/511021/Irradiation-induced-Angiogenesis-through-the-Up
Yao, L. et al. (2010), “The role of RhoA/Rho kinase pathway in endothelial dysfunction”, Journal of Cardiovascular Disease Research, Vol. 1/4, Elsevier, Amsterdam, https://doi.org/10.4103/0975-3583.74258