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Relationship: 2780
Title
Energy Deposition leads to Increase, Endothelial Dysfunction
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 abnormal vascular remodeling | non-adjacent | Moderate | Low | Vinita Chauhan (send email) | Open for citation & comment | Under Review |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Male | Moderate |
Female | Moderate |
Unspecific | Low |
Life Stage Applicability
Term | Evidence |
---|---|
Adult | Moderate |
Juvenile | Low |
Not Otherwise Specified | Moderate |
Key Event Relationship Description
Energy deposition can lead to ionization events that can directly interact with molecules within the cell and can subsequently lead to biological changes such as the formation of free radicals and the initiation of DNA damage repair mechanisms. Different radiation types have different physical properties and as a result the biological effects on cells may differ. Dose and dose rate of the deposited energy also play a role as these factors affect the amount and rate of energy deposited (Donaubauer et al., 2020). Repeated or prolonged exposure to radiation can exhaust the protective effect of the endothelium and lead to endothelial dysfunction (Baselet et al., 2019). Consequently, cells within the vascular endothelium may lose their integrity and become senescent or apoptotic via alterations to signaling pathways related to cell survival, leading to dysregulation of vasodilation and eventual endothelial dysfunction (Deanfield et al., 2007; Bonetti et al., 2003). Activation of the endothelium, consisting of inflammation, proliferation, thrombosis and low nitric oxide, occurs as a normal response to pathological conditions and oxidative stress from deposited energy (Krüger-Genge et al., 2019).
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 deposition of energy leading to endothelial dysfunction is well-supported by reviews in the literature and mechanistic understanding. The impact on endothelial dysfunction from deposited energy onto cells may vary with the radiation source and associated parameters of dose, dose rate, and type, which can influence the amount of energy absorbed, among other factors such as tissue type.
Radiation types such as gamma rays, X-rays, and charged particles at doses ranging from 0.05-18 Gy and dose rates as low as 2.4 mGy/h induce endothelial dysfunction through an increase in cellular markers of apoptosis and cellular senescence in human cell and animal models as well as diminished relaxation response of vessels in animal models (Yentrepalli et al., 2013a; Yentrepalli et al., 2013b; Soucy et al., 2011; On et al., 2001; Hatoum et al., 2006; Soucy et al., 2010; Soloviev et al., 2003; Baselet et al., 2017; Shen et al., 2017). Following irradiation, endothelial cells may lose their integrity and become senescent or apoptotic via alterations to signaling pathways related to cell survival, leading to endothelial dysfunction (Deanfield et al., 2007; Bonetti et al., 2003; Guipaud et al. 2018). In vitro studies have shown that radiation increases endothelial permeability through both reducing levels of cell-cell contact proteins and increasing contractility of endothelial cells (Bouten et al. 2021). Senescent endothelial cells show changes in cell morphology, cell-cycle arrest, and increased senescence-associated β-galactosidase (SA-β-gal) staining. They also have a pro-inflammatory secretory phenotype, which further contributes to negative effects. These changes lead to endothelial dysfunction, which results in dysregulation of vasodilation (Wang et al., 2016; Hughson et al., 2018; Ramadan et al., 2021). Prolonged chronic inflammation following irradiation causes an ineffective healing process, further worsened by a decrease in endothelium-dependent relaxation. This leads to endothelial dysfunction, making the vasculature more vulnerable to damage from non-laminar flow (Sylvester et al., 2018). Since the endothelium is largely responsible for controlling fluid flow, dysfunctions in the endothelium can lead to fluid imbalance, blood pressure changes, and blood clot formation (Konukoglu & Uzun, 2017; Korpela & Liu, 2014; Verma et al., 2003).
Empirical Evidence
The empirical evidence supporting this KER is gathered from research utilizing both in vivo and in vitro models. Many in vitro studies have examined this relationship using human endothelial cell cultures, such as telomerase-immortalized coronary artery endothelial cells (TICAE) and human umbilical vein endothelial cells (HUVECs) (Baselet et al., 2017; Yentrapalli et al., 2013b). In vivo studies analyzed changes in murine aorta, white rabbit thoracic aorta, and rat aorta and microvessels (Hatoum et al., 2006; Shen et al., 2018; Soloviev et al., 2003; Soucy et al., 2010; Soucy et al., 2011). The evidence includes use of gamma, X-ray, and heavy ion radiation in the dose range of 0.05-18 Gy. SA-β-gal, a marker for cellular senescence, and therefore endothelial dysfunction, relaxation in response to acetylcholine (ACh) and apoptosis were examined in these studies (Baselet et al., 2017; Hatoum et al., 2006; Shen et al., 2018; Soloviev et al., 2003; Soucy et al., 2010; Soucy et al., 2011; Yentrapalli et al., 2013).
Dose Concordance
Studies using in vitro and in vivo models have shown that deposition of energy as produced by acute and chronic doses of ionizing radiation administered from 0.05-18 Gy, with dose rates ranging from 2.4 mGy/h to 2.43 Gy/min, cause endothelial dysfunction as indicated by cellular markers such as cellular senescence and apoptosis as well as decreased maximum relaxation response of vessels in response to ACh.
For example, chronic gamma irradiation of human endothelial cells at a dose rate as low as 2.4 mGy/h led to an increase of 2-fold in SA-β-gal staining (Yentrapalli et al., 2013a). A similar study showed that 4.1 mGy/h chronic gamma irradiation caused no significant changes after 0.69 Gy, but there was a 2-fold increase in SA-β-gal at 2.07 Gy and a 3-fold increase after 4.13 Gy (Yentrapalli et al., 2013b). Another study also looking at SA-β-gal found a 1.7-fold maximum increase in SA-β-gal after irradiating human endothelial cells with 0.05-2 Gy X-rays (Baselet et al., 2017). A study measuring radiation-induced apoptosis in mouse aorta found a 5-fold increase in the number of apoptotic cells after 18 Gy X-ray irradiation (Shen et al., 2018).
Many studies have measured endothelial dysfunction through the relaxation response of vessels in response to ACh. After rabbit thoracic aortas were irradiated with 6 Gy gamma rays, there was a 0.5-fold decrease in maximum relaxation response to ACh, with a linear decrease in relaxation from 0, 1, 2, and 4 Gy gamma rays (Soloviev et al., 2003). A study that irradiated rat aorta with 0.5 and 1 Gy 56Fe ions found a 0.8-fold decrease in maximum relaxation response to ACh (Soucy et al., 2011). Microvessels from rat intestines irradiated with 2250 cGy of fractionated X-rays showed an ACh-induced maximum dilation of 3%, while controls showed a maximum dilation of 87%. A significant decrease was seen after only three doses of 250 cGy (Hatoum et al., 2006). Gamma ray irradiation of rat aorta at 5 Gy showed a 0.6-fold decrease in relaxation response to ACh (Soucy et al., 2010). Similar results were found in a study using 10 Gy gamma rays on rat aortas, which showed a 9% maximum relaxation response to ACh compared to the 48% maximum relaxation in the control group (On et al., 2001).
Time Concordance
There is moderate evidence to suggest a time concordance between the deposition of energy and endothelial dysfunction. A chronic gamma irradiation study at a dose rate of 2.4 mGy/h examined human endothelial cells in vitro after 1, 6, 10 and 12 weeks and showed an increase in SA-β-gal as early as 10 weeks, with levels remaining significantly increased at 12 weeks (Yentrapalli et al., 2013a). A study by the same group also looked at the effects of 4.1 mGy/h gamma rays on human endothelial cells in vitro, but at 1, 3 and 6 weeks of chronic irradiation, revealing an increase in cellular senescence, indicated by increased SA-β-gal, as soon as 3 weeks, with levels remaining significantly increased at 6 weeks (Yentrepalli et al., 2013b). After mouse aorta were irradiated with 18 Gy X-rays, the number of apoptotic cells were determined over 84 days. The number of apoptotic cells was significantly higher than the controls after 3, 7, 14, 28, and 84 days, but was highest (5-fold higher than control) after 7 days followed by a linear decrease (Shen et al., 2018).
Similarly, rabbit thoracic aortas irradiated with 6 Gy gamma rays and exposed to ACh showed a 0.5-fold decrease in maximum relaxation after both 9 and 30 days (Soloviev et al., 2003). When rats were irradiated with 1 Gy 56Fe ions, ACh-induced relaxation in the aorta decreased 0.25-fold compared to controls 4 months after irradiation, and went from a 67.5% relaxation response in the control group to 59% in the irradiated group after 6 months (although this change was not statistically significant). Relaxation response to ACh remained non-significant at 8 months post-irradiation (Soucy et al., 2011). Young (2012) observed a transient, significant decrease in the monolayer resistance 3 hours after irradiation with 5 Gy of γ rays. In another study, a significant 6-fold transient decrease was observed in transmonolayer resistance at 3 hours post irradiation with 5 Gy of γ rays (Young & Smilenov, 2011).
Essentiality
Endothelial dysfunction can be triggered in response to an injury or a stressor. Therefore, with a reduction in stressor severity, there should be less endothelial dysfunction. As deposition of energy is a physical stressor, it cannot be blocked/decreased using chemicals; however, it can be shielded, though currently no available data used shielding of radiation and measured the impact on endothelial dysfunction. Since deposited energy initiates events immediately, the removal of deposited energy also supports the essentiality of the key event. Studies that do not deposit energy are observed to have no downstream effects.
Uncertainties and Inconsistencies
- Much evidence for this relationship comes from high dose studies (>2 Gy); further work is needed at varying doses and dose rates to better understand the relationship.
Known modulating factors
Modulating factor |
Details |
Effects on the KER |
References |
Drug |
Oxypurinol (Oxp) (a xanthine oxidase inhibitor) |
Treatment led to increased endothelial relaxation response to ACh after irradiation. |
(Soucy et al., 2011) |
Drug |
Vitamin C |
Treatment increased the relaxation response to ACh after irradiation. |
(On et al., 2001) |
Drug |
MnTBAP |
Treatment restored vasodilation ability after irradiation. |
(Hatoum et al., 2006) |
Drug |
Tempol |
Treatment restored vasodilation ability after irradiation. |
(Hatoum et al., 2006) |
Drug |
Human bone marrow stem cells |
Both low and high doses decreased apoptosis after irradiation. |
(Shen et al., 2018) |
Quantitative Understanding of the Linkage
Examples of quantitative understanding of the relationship are shown in the table below. All data represented is statistically significant unless otherwise indicated.
Response-response Relationship
Dose Concordance
Reference |
Experiment Description |
Result |
Baselet et al., 2017 |
In vitro. X-ray radiation was delivered to human endothelial cells at a dose rate of 0.5 Gy/min for total doses of 0.05, 0.1, 0.5 and 2 Gy. SA-β-gal activity was used as a marker for senescence and endothelial dysfunction and was measured 14 days post exposure. |
SA-β-gal activity for all radiation doses was significantly elevated above the non-irradiated control and increased with an increase in radiation dose. At the highest dose of 2 Gy, there was a 1.7-fold increase compared to control. |
Soucy et al., 2011 |
In vivo. 3-4 months-old rats were whole body irradiated with 0.5 or 1 Gy of 56Fe ions before their aortas were harvested and the endothelium dependent vasodilation response to ACh was evaluated at 4 months post-irradiation. |
A 0.5 Gy dose did not show significant changes to maximum relaxation response to ACh compared to non-irradiated control. Following a 1 Gy dose there was a 0.8-fold decrease in maximum relaxation response to ACh compared to non-irradiated control. |
Soucy et al., 2010 |
In vivo. 4-months-old rats were irradiated with 5 Gy of 137Cs, and the endothelium dependent vasodilation response to ACh of harvested aortas was evaluated. |
There was a 0.6-fold decrease in maximum relaxation response to ACh in the aorta compared to the non-irradiated control. |
Soloviev et al., 2003 |
In vivo. The endothelium dependent vasorelaxation response to ACh of aortas from rabbits exposed to 6 Gy of 60Co whole body irradiation was evaluated 9 days post exposure. Furthermore, endothelium dependent relaxation response following exposure to 1, 2, and 4 Gy on the 7th day post exposure were also evaluated. |
9 days after exposure to 6 Gy, there was a 0.5-fold decrease in maximum relaxation response to ACh. At 7 days post irradiation, maximum relaxation response to ACh decreased with an increase in radiation dose, with 60% maximum relaxation at 0 Gy dropping down to 30% after 4 Gy. |
Shen et al., 2018 |
In vivo. 18 Gy of X-ray radiation was delivered to 8-week-old mice. Apoptosis was evaluated using TUNEL assays at 3-, 7-, 14-, 28- and 84-days post irradiation. |
Apoptosis levels in 18 Gy irradiated groups were significantly elevated above sham irradiated control at all time points tested. The difference peaked 7-days post irradiation at a 5-fold increase compared to control. |
Hatoum et al., 2006 |
In vivo. Rats were whole body irradiated with up to 2250 cGy via 9 fractions of 250 cGy X-rays at a dose rate of 243 cGy/min. Endothelium dependent vasodilation response to ACh of harvested submucosal vessels was evaluated at various radiation doses. |
After the final dose (total 22.5 Gy) there was a 0.03-fold decrease in maximum relaxation response to ACh in irradiated rat microvessels compared to non-irradiated controls. Following dose 1 and 2 (250 cGy and 500 cGy total dose), maximum dilation remained similar to non-irradiated control (~90% maximum dilation). However, following the third dose (750 cGy total), maximum dilation dropped below 10% and remained significantly below non-irradiated control levels for all remaining doses tested. |
Time-scale
Time Concordance
Reference |
Experiment Description |
Result |
Yentrapalli et al., 2013a |
In vitro. Chronic gamma irradiation (137Cs) was delivered to human umbilical vein endothelial cells (HUVECs) at a dose rate of 1.4 mGy/h or 2.4 mGy/h. SA-β-gal activity was used as a marker for premature endothelial cell senescence and was evaluated at 1-, 3-, 6-, 10- and 12-weeks post irradiation. |
Between 1 to 6 weeks post irradiation no significant differences were observed between either of the irradiated groups and the sham irradiated control. At the 10- and 12-week time points, the 1.4 mGy/h exposure continued to show no significant changes from control, while the 2.4 mGy/h group showed a 1.7-fold increase at 10-weeks and 1.9-fold increase at 12-weeks. |
Yentrapalli et al., 2013b |
In vitro. Chronic gamma (137Cs) irradiation was delivered to human umbilical vein endothelial cells (HUVECs) at a dose rate of 4.1 mGy/h for up to 6 weeks for final doses of 0.69, 2.07 and 4.13 Gy. SA-β-gal activity was used as a marker for premature endothelial cell senescence and was evaluated at 1-, 3- and 6-weeks post exposure. |
No significant changes in SA-β-gal activity were observed between irradiated and sham irradiated groups in the first week. SA-β-gal activity was significantly elevated in irradiated HUVECs at the 3- and 6-week timepoints, showing a 2-fold and 3-fold elevation above control respectively. |
Soucy et al., 2011 |
In vivo. 3-4 months-old rats were whole body irradiated with 0.5 or 1 Gy of 56Fe ions before their aortas were harvested and the endothelium dependent vasodilation response to ACh was evaluated. |
At 4 months post radiation there was a 0.8-fold decrease in maximum relaxation response to ACh with a return to control levels by 6 months. |
Soloviev et al., 2003 |
In vivo. The maximum endothelium dependent vasorelaxation response to ACh of aortas from rabbits having been whole body irradiated to 6 Gy 60Co gamma-rays was evaluated 9- and 30-days post exposure. |
At both 9- and 30-days post-irradiation there was a ~0.5-fold decrease in maximum relaxation response to ACh compared to non-irradiated control. There was no significant difference in maximum relaxation between the 9- and 30-day timepoints. |
Shen et al., 2018 |
In vivo. 18 Gy of X-ray radiation was delivered to 8-week-old mice with apoptosis levels being measured for up to 84 days post-irradiation in the aorta. |
There was a significant increase of 3-fold in apoptosis as soon as 3 days post-irradiation with a peak of 7-fold after 7 days. There was a gradual return to a 3-fold increase by 84 days. |
Young, 2012 |
In vitro. Human umbilical vein endothelial cell (HUVEC) were exposed to 0 and 5 Gy of 137Cs γ rays at a dose rate of 0.79 Gy/min. Endothelial permeability and resistance changes were measured with Electric Cell Substrate Impedance Sensing (ECIS) technology and evaluated up to 8 hours post-irradiation. |
A transient, significant decrease in the monolayer resistance 3 hours after irradiation with 5.0 Gy compared to the control. |
Young & Smilenov, 2011 |
In vitro. Human coronary arterial endothelial cells (HCAECs) were exposed to 0 and 5 Gy of 137Cs γ rays at a dose rate of 0.79 Gy/min. Endothelial permeability and resistance changes were measured with Electric Cell Substrate Impedance Sensing (ECIS) technology and evaluated up to 15 hours post-irradiation. |
A significant 6-fold transient decrease was observed the in transmonolayer resistance at 3 hours post irradiation with 5 Gy compared to the control. |
Known Feedforward/Feedback loops influencing this KER
Not identified
Domain of Applicability
The evidence for the taxonomic applicability to humans is low as the majority of the evidence is from in vitro human-derived cells. The relationship is supported by both sexes of mouse, rat, and rabbit models. The in vivo studies were mostly undertaken in adolescent or adult rats and mice. In addition, the relationship is likely at any life stage.
References
Baselet, B. et al. (2019), “Pathological effects of ionizing radiation: endothelial activation and dysfunction”, Cellular and Molecular Life Science, Vol. 76, Springer, New York, https://doi.org/10.1007/s00018-018-2956-z.
Baselet, B. et al. (2017), “Functional Gene Analysis Reveals Cell Cycle Changes and Inflammation in Endothelial Cells Irradiated with a Single X-ray Dose”, Frontiers in pharmacology, Vol. 8, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphar.2017.00213.
Bonetti, P. O., L. O. Lerman and A. Lerman (2003), “Endothelial dysfunction: a marker of atherosclerotic risk”, Arteriosclerosis, thrombosis, and vascular biology, Vol. 23/2, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.atv.0000051384.43104.fc .
Bouten, R. M. et al. (2021), “Chapter Two - Effects of radiation on endothelial barrier and vascular integrity”, Tissue Barriers in Disease, Injury and Regeneration, Elsevier, Amsterdam, https://doi.org/10.1016/B978-0-12-818561-2.00007-
Deanfield, J. E., J. P. Halcox and T. J. Rabelink (2007), “Endothelial Function and Dysfunction”, Circulation, Vol. 115/10, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/CIRCULATIONAHA.106.652859.
Donaubauer, A. J. et al. (2020), “The Influence of Radiation on Bone and Bone Cells-Differential Effects on Osteoclasts and Osteoblasts”, International journal of molecular sciences, Vol. 21/7, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms21176377.
Guipaud, O. et al. (2018), “The importance of the vascular endothelial barrier in the immune-inflammatory response induced by radiotherapy”, The British journal of radiology, Vol.91/1089, Oxford University Press, Oxford. https://doi.org/10.1259/bjr.20170762
Hatoum, O. A. et al. (2006), “Radiation Induces Endothelial Dysfunction in Murine Intestinal Arterioles via Enhanced Production of Reactive Oxygen Species”, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26/2, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.ATV.0000198399.40584.8c
Hughson, R.L., A. Helm and M. Durante (2018), “Heart in space: Effect of the extraterrestrial environment on the cardiovascular system”, Nature Reviews Cardiology, Vol. 15/3, Nature Portfolio, London, https://doi.org/10.1038/nrcardio.2017.157.
Konukoglu, D., and H. Uzun (2017), “Endothelial Dysfunction and Hypertension”, Advances in experimental medicine and biology, Vol. 956, Springer, New York, https://doi.org/10.1007/5584_2016_90.
Korpela, E., and S. K. Liu (2014), “Endothelial perturbations and therapeutic strategies in normal tissue radiation damage”, Radiation oncology, Vol. 9, BioMed Central, London, https://doi.org/10.1186/s13014-014-0266-7.
Krüger-Genge, A. et al. (2019), “Vascular Endothelial Cell Biology: An Update”, International Journal of Molecular Sciences, Vol. 20/18, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/IJMS20184411.
On, Y. K. et al. (2001), “Vitamin C prevents radiation-induced endothelium-dependent vasomotor dysfunction and de-endothelialization by inhibiting oxidative damage in the rat”, Clinical and experimental pharmacology & physiology, Vol. 28/10, Wiley-Blackwell, Hoboken, https://doi.org/10.1046/j.1440-1681.2001.03528.x.
Ramadan, R. et al. (2021), “The role of connexin proteins and their channels in radiation-induced atherosclerosis”, Cellular and molecular life sciences: CMLS, Vol. 78/7, Springer, New York, https://doi.org/10.1007/s00018-020-03716-3.
Shen, Y. et al. (2018), “Transplantation of bone marrow mesenchymal stem cells prevents radiation-induced artery injury by suppressing oxidative stress and inflammation”, Oxidative Medicine and Cellular Longevity, Vol. 2018, Hindawi, London, https://doi.org/10.1155/2018/5942916.
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.
Soloviev, A. I. et al. (2003), “Mechanisms of endothelial dysfunction after ionized radiation: selective impairment of the nitric oxide component of endothelium-dependent vasodilation”, British journal of pharmacology, Vol. 138/5, Wiley, https://doi.org/10.1038/sj.bjp.0705079
Soucy, K. G. et al. (2011), “HZE 56Fe-Ion Irradiation Induces Endothelial Dysfunction in Rat Aorta: Role of Xanthine Oxidase”, Radiation Research, Vol. 176/4, Radiation Research Society, Bozeman, https://doi.org/10.1667/RR2598.1.
Soucy, K. G. et al. (2010), “Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta”, Journal of Applied Physiology, Vol. 108/5, American Physiological Society, Rockville, https://doi.org/10.1152/japplphysiol.00946.2009.
Sylvester, C. B. et al. (2018), “Radiation-Induced Cardiovascular Disease: Mechanisms and Importance of Linear Energy Transfer”, Frontiers in Cardiovascular Medicine, Vol. 5, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fcvm.2018.00005.
Verma, S., M. R. Buchanan and T. J. Anderson (2003), “Endothelial function testing as a biomarker of vascular disease”, Circulation, Vol. 108/17, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.CIR.0000089191.72957.ED.
Wang, Y., M. Boerma and D. Zhou (2016), “Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases”, Radiation research, Vol. 186/2, Radiation Research Society, Bozeman, https://doi.org/10.1667/RR14445.1.
Yentrapalli, R. et al. (2013a), “The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation”, PloS one, Vol. 8/8, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0070024.
Yentrapalli, R. et al. (2013b), “Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation”, Proteomics, Vol. 13/7, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/pmic.201200463.
Young, E. F. (2012), “Transient impedance changes in venous endothelial monolayers as a biological radiation dosimetry response”, Journal of Electrical Bioimpedance, Vol. 3/1, Sciendo, Warsaw, https://doi.org/10.1667/rr2665.1
Young, E. F. and L. B. Smilenov (2011), “Impedance-based surveillance of transient permeability changes in coronary endothelial monolayers after exposure to ionizing radiation”, Radiation research, Vol. 176/4, BioOne, Washington, https://doi.org/10.1667/rr2665.1