Open access peer-reviewed chapter

Selected Endothelial Responses after Ionizing Radiation Exposure

Written By

Bjorn Baselet, Raghda Ramadan, Abderrafi Mohammed Benotmane, Pierre Sonveaux, Sarah Baatout and An Aerts

Submitted: May 8th, 2017 Reviewed: November 10th, 2017 Published: December 20th, 2017

DOI: 10.5772/intechopen.72386

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Abstract

Along with the development of novel chemotherapeutic agents, radiation therapy has revolutionized the prognosis of patients with various cancers. However, with a longer life expectancy, radiation treatment-related comorbidity, like cardiovascular diseases (CVDs), becomes an issue for cancer survivors. In addition, exposure to X-rays for medical diagnostics is dramatically increasing at the present times. A pressing question is whether or not exposure to these very low doses can cause health damage. Below 0.5 gray (Gy), an increased risk cannot be evidenced by epidemiology alone, and in vitro and in vivo mechanistic studies focused on the elucidation of molecular signaling pathways are needed. Given the critical role of the endothelium in normal vascular functions, a complete understanding of radiation-induced endothelial dysfunction is crucial. In this way, the current radiation protection system could be refined if needed, making it possible to more accurately assess the cardiovascular risk in the low-dose region. Finally, radiation-induced CVD, like CVD in general, is a progressive disorder that may take years to decades to manifest. Therefore, experimental studies are warranted to fulfill the urgent need to identify noninvasive biomarkers for an early detection and potential interventions—together with a healthy lifestyle—that may prevent or mitigate these adverse effects.

Keywords

  • ionizing radiation
  • radiation therapy
  • X-ray diagnostics
  • cardiovascular disease
  • atherosclerosis
  • endothelial dysfunction
  • inflammation
  • DNA damage
  • apoptosis
  • cell cycle
  • oxidative stress
  • mitochondrial dysfunction and metabolic changes
  • premature senescence
  • intercellular communication

1. Introduction

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. It accounts for nearly one-third of all deaths worldwide. There are multiple contributory risk factors for heart disease. Some are of a controllable nature, such as lifestyle, dietary factors, and metabolic disorders, such as high cholesterol levels and hypertension. Others are noncontrollable risk factors, such as gender, age, and genetic predisposition [1, 2]. In addition, there are environmental factors affecting the risk of CVD, ionizing radiation being one such factor.

It has been known for a long time that high doses of radiation, such as those delivered during radiotherapy, cause damage to the heart and vasculature and thus increase the risk of CVD. Data from animal experiments have strongly supported this observation [3, 4, 5, 6]. However, for doses <0.5 gray (Gy), epidemiological data are suggestive rather than persuasive. Therefore, the magnitude of CVD risk in the low-dose region where issues of radiation protection usually operate is not clear [3, 4, 5, 6].

Various issues, such as occupational radiation exposure, future of nuclear power, manned space flights, and threat of radiological terrorism, call for a thorough understanding of low-dose health risks [7]. The main concern is, however, an increasing use of ionizing radiation for diagnostic medical purposes (Figure 1) [8]. For instance, since 1993, the number of computed tomography (CT) scans has increased four times in the United States, and a similar trend is observed in Europe [9]. Medical radiation is the largest source of radiation exposure in Western countries, accounting for a mean effective dose of 3.0 millisievert (mSv) on average per capita per year from diagnostic procedures only, corresponding to a radiological risk of 30 chest X-rays [10]. Of note, doses from therapeutic procedures are not taken into account in this number. Although the health benefits of these improved diagnostic procedures are huge, concerns are raised regarding “overuse” and potential associated health risks [11].

Figure 1.

Average annual effective dose per person received in 1980 (left panel) and in 2006 (right panel) in the United States. The large increase in the use of ionizing radiation for medical purposes, in the period 1980–2006, contributed to a total increase from 3.0 mSv in 1980 to 6.2 mSv in 2006. Similar trends are observed in other industrialized countries [1].

1.1. What is ionizing radiation?

From natural to manufactured sources, life on earth is exposed on a daily basis to ionizing radiation. Defined as a type of energy released by atoms that travel in the form of electromagnetic or particles, this energy can eject tightly bound electrons from the orbit of an atom, causing the atom to become ionized [12]. In nature, one can distinguish three main types of ionizing radiation: alpha (α), beta (β) particles, and gamma (γ) rays. They are all produced by naturally occurring substances with unstable nuclei (e.g., cobalt-60 and cesium-137) that spontaneously undergo radioactive decay. During the decay process, energy is lost via emission of ionizing radiation in the form of electromagnetic γ-rays and/or charged particles (e.g., α- and β-particles) [13]. One of the most common manufactured forms of ionizing radiation is X-ray radiation. X-rays are in most aspects similar to γ-rays but differ in origin. While γ-rays are derived from the natural decay of radioactive elements, X-rays are artificially produced in X-ray generators by directing a stream of high-speed electrons at a target material, such as gold or tungsten [14]. When electrons interact with atomic particles of the target, X-radiation is produced [12]. In addition to the most common forms listed above, there are many other forms of ionizing radiation of human or natural origin. Examples are neutrons, accelerated ions and fission fragments [15, 16]. These less common forms can have different biological effects, which can be exploited, for example, in hadron therapy for cancer treatment [17].

1.2. Radiation metrics

Biological effects of ionizing radiation are related to energy deposition in matter. To assess the impact of ionizing radiation on human health and to set guidelines in radioprotection, units to measure a dose and its biological effects are required.

The absorbed dose is defined as the amount of energy, originating from any type of ionizing radiation and any irradiation geometry that is absorbed per unit mass of material. The international SI unit for absorbed dose is gray (Gy). One Gy represents the absorption of 1 joule of energy in 1 kilogram of mass (1 J/kg). This definition is pure physical, as it does not consider the quality of the ionizing radiation type and the extent of biological damage it inflicts to certain tissues and/or organs. As a result, the terms equivalent dose and effective dose have been introduced [18].

The equivalent dose takes into account the ability of a particular kind of ionizing radiation to cause damage. It is obtained by multiplying the absorbed dose (Gy) with a radiation-weighting factor (wR) attributed to each different radiation type (e.g., the wR of photons and electrons is 1, the wR of protons and charged ions is 2, and the wR of α particles and fission fragments is 20). The international SI unit for equivalent dose is the sievert (Sv) [18].

The effective dose is defined as the weighted sum of all tissue and organ equivalent doses multiplied by their respective tissue-weighting factor (wT). It expresses the biological effect that a certain type of ionizing radiation has on the human body. wT values have been defined to represent the contributions of individual organs and tissues to overall radiation effects on the human body. Similar to the equivalent dose, the effective dose has sievert (Sv) as international SI unit. Care should be taken with wT values because they constitute an average over both genders and adult ages to reflect the radiation burden to an average human adult [18, 19]. Examples of effective doses associated with different sources of ionizing radiation are presented in Table 1.

SourceEffective dose (mSv)*
Dental X-ray0.005
Radiography of the chest0.1
One return flight (New York-London)0.1
Radiography of the abdomen1.2
CT of the head2
Natural background (per year)2.4
Mammography3
CT of the chest7
CT of the abdomen6–10
CT of the pelvis8–10
Coronary CT angiography12
Myocardial perfusion study10–29
Myocardial viability study14–41
Annual occupational dose limit20
Radiotherapy (delivered in fractions)40,000–70,000

Table 1.

Representative effective doses associated with different sources of ionizing radiation.

Doses are whole-body doses, except those of medical exposure, which are delivered to a specific organ. CT, computed tomography; Sv sievert [7, 19, 20, 21, 22, 23]


1.3. Protection against radiation exposure

Short after the discovery of ionizing radiation by Röntgen in 1895, its detrimental effects became apparent, and people tried to protect themselves [24]. Nowadays, the International Committee on Radiological Protection (ICRP) and the US National Council on Radiation Protection and Measurements (NCRP) aim to protect people by advising means for achieving this, e.g., regulatory and guidance limits [18, 25].

The major question that keeps radiation protection bodies busy and that became the foundation of radiation protection guidelines worldwide is “How much is harmful?” This question is particularly relevant for low-dose exposures for which health impact is not yet fully elucidated. Although a large number of epidemiological and radiobiological studies have been performed to date in order to investigate the effects of low doses of ionizing radiation [26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47], accurate risk assessment is not yet available [18]. Current guidelines for protection against low-dose radiation are based on cancer risk estimates from epidemiological studies. As discussed further, cohorts include atomic bomb survivors, occupationally exposed people, patients (diagnostics or therapeutics), and environmentally exposed people [48]. In general, an excess cancer risk can be statistically evidenced for doses above 100 mGy. Nevertheless, doses below 100 mGy are inconclusive due to two practical limits of epidemiological studies: low statistical power that generates random errors and demography that gives rise to systematic errors. Due to a high natural incidence of cancer, a lifetime follow-up of larger cohorts would be needed to quantify excess cancer risks due to a low dose of ionizing radiation. This is practically infeasible. Furthermore, confounding factors, such as lifestyle risk factors for CVD, can hamper accuracy to confidently detect a small increase in cancer mortality (discussed in Section 2.4). Any inadequacy in matching between control and study groups may give rise to a bias that cannot be merely reduced by expanding the size of the groups [49]. As a consequence, risk assessment in the low-dose region (<100 mGy) is based on extrapolations made from high-dose risk estimates [50]. For cancer, it is widely accepted that the tumorigenic risk increases with radiation dose without the presence of a threshold (the stochastic linear non-threshold [LNT] model). This assumption implies that no dose is absolutely safe, resulting in implementation of the “as low as reasonably achievable” principle [51, 52].

In contrast to cancer, non-cancer diseases have for long not been considered as health risks following exposure to low doses of ionizing radiation. Consequently, they were believed to have a threshold dose below which no significant adverse risks are induced (deterministic linear threshold model) [18, 53]. This idea has been challenged by epidemiological findings showing an excess risk of non-cancer diseases following exposure to doses lower than previously thought [34, 54]. Epidemiological evidence suggests an excess risk of CVD mortality above 0.5 Gy [34, 54]. For doses below 0.5 Gy, the dose-risk relationship is still unclear. However, if the relationship proves to be without a threshold, this may have a considerable impact on the current radiation protection system, since the overall excess mortality risk following low-dose exposure could double [55].

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2. Radiation-induced cardiovascular disease

2.1. Epidemiology of radiation-induced CVD

Current predictions indicate that in Western countries almost one of three people will develop cancer during their lifetime [56]. About 50–60% of all cancer patients will undergo radiotherapy with radiation doses averaging 1.8–2 Gy per fraction [57]. During the radiotherapeutic treatment of tumors located in the mediastinal region of the human body (breast, lung, and esophageal cancers), the heart and its blood vessels incidentally receive a part of the radiation dose [46]. Exposure of the cardiovascular system to these therapeutic doses is known to be associated with CVDs. The first epidemiological evidence of this association came from radiation-treated Hodgkin’s lymphoma survivors in the 1960s. In a study of 258 Hodgkin’s disease patients followed for a median of 14.2 years (range 0.7–26.2) after radiotherapy, cumulative risk for ischemic event increased from 6.4% (95% confidence interval (CI), 3.8 ± 10.7) at 10 years to 21.2% (95% CI, 15 ± 30) at 20–25 years after radiotherapy treatment. Risk for myocardial infarction was 3.4% (95% CI, 1.6 ± 7.0) at 10 years and 14.2% (95% CI, 9 ± 22) at 20–25 years, and risk for ischemic cardiac mortality was 2.6% (95% CI, 1.1 ± 6.1) at 10 years and 10.2% (95% CI, 5.3 ± 19) at 25 years (Figure 2A) [58]. Cardiac fibrosis, which causes cardiac dysfunction, arrhythmias, and heart failure, is also seen in Hodgkin’s lymphoma survivors but is rather the result of the use of anthracyclines [59]. Radiation-induced cardiovascular disorders are based rather on the damage to the blood vessels. Later, in the study of Darby et al., 2168 breast cancer patients were followed between 5 and more than 20 years after radiotherapy. It was found that women irradiated for left breast cancer (estimated mean heart dose 6.6 Gy) had higher rates of major coronary events than women irradiated for right breast cancer (estimated mean heart dose 2.9 Gy; P = 0.002). Excess relative risk (ERR), a measure that quantifies how much the level of risk among persons with a given level of exposure exceeds the risk of nonexposed persons [60] for major coronary events was 7.4% per Gy (95% CI, 2.9–14.5) when all follow-up times and all breast cancer patients were included (Figure 2B) [54].

Figure 2.

Epidemiological evidence for an increased risk of CVDs after exposure to ionizing radiation. (A) Cumulative risk curves for the occurrence of cardiac events in Hodgkin’s lymphoma survivors [58]. (B) Rate of major coronary events according to mean radiation dose to the heart given during breast cancer radiotherapy, as compared with the estimated rate with no radiation exposure to the heart [54]. (C) Excess relative risk for death from heart disease in Japanese atomic bomb survivors. Shaded area is the 95% confidence region for the fitted lines [34].

Additional proofs of increased risk of CVDs after high-dose exposure were provided during the follow-up of Japanese atomic bomb survivors. During a 53-year follow-up of 86,611 members of the Life Span Study cohort, excess relative risk of death from heart disease per Gy was 0.14 (95% CI 0.06–0.23) (Figure 2C) [34]. Although there is a large number of epidemiological studies showing a clear excess of CVD risk above 0.5 Gy, they are of limited use for quantitative risk assessment, because individual dosimetry has yet to be performed [35]. In addition, even if an adverse effect can be evidenced at relatively high doses of ionizing radiation, mechanisms by which therapeutic doses affect the cardiovascular system are still not completely understood [28].

When the heart receives a radiation dose lower than 0.5 Gy, epidemiological evidence is less strong than that for higher doses. The most informative cohort in this respect is composed of Japanese atomic bomb survivors. It is of high value for low-dose epidemiology as a source for risk estimation due to its large size, the presence of both sexes and all ages, and because irradiated people have well-characterized individual dose estimates [36]. Studies in occupationally exposed individuals are also of interest as they generally involve relatively low doses received during repeated exposures. Examples of such cohorts are nuclear industry workers from 15 countries (the 15-country study) [37], the UK National Registry for Radiation Workers [38], the National Dose Registry of Canada [39], the Chernobyl liquidator cohort [40], and the Mayak cohort [41, 42, 43]. The last cohort is composed of workers from Mayak PA, the first and largest Russian nuclear factory for plutonium production where the majority of workers were exposed to ionizing radiation during the first period of operation [61]. In addition, data can also be acquired from environmentally exposed groups, such as settlements located at the vicinity of the Techa River [44] and the Semipalatinsk nuclear test area [45].

When taking into account all epidemiological data on CVD effects of ionizing radiation, a small but highly statistically significant ERR of 0.09 per Gy (95% CI, 0.07–0.12) was observed at doses higher than 0.5 Gy [35]. In addition, ERR of CVD mortality was estimated at 0.08 (95% CI, 0.04–0.12). In other words, receiving 1 Gy of ionizing radiation to the heart and its blood vessels increases the risk of CVD mortality with 8% in comparison to nonexposed people. This assumed risk is rather large and may therefore have serious implications for public health. Indeed, considering the high background rate of CVD, the absolute number of excess cases could be substantial [62]. In order to find an association between low-level radiation exposure and CVD risk in a general unselected population, this meta-analysis was extended by Little et al. [55]. When taking into account 717,660 individuals from the Japanese atomic bomb survivor and occupational and environmental exposure studies listed above, a statistically significant ERR coefficient of 0.10 (95% CI, 0.05–0.15) for coronary artery disease was observed as a result of exposure to low-level radiation more than 5 years prior to death [55]. A linear association between ERR and radiation dose was assumed even in the low-dose range, because there was little evidence of nonlinearity in the dose-response curves for CVD in Japanese atomic bomb survivors [34, 63] and in Mayak workers [41]. Authors further argued that the consistency of ERR/Gy between Japanese atomic bomb survivors with moderate radiation doses [34, 63] and occupational cohorts with low doses could be used to support the notion of a linear relationship between ERR of CVD mortality and low doses of ionizing radiation [55]. In a recent third analysis of the Life Span Study cohort of atomic bomb survivors with 105,444 subjects, the shape of the dose-response curve for solid cancer incidence was found significantly different among males and females (P = 0.02). For females, dose-response was consistent with linearity, but for males dose-response best fitted a linear-quadratic model [64]. If this were to be confirmed, the overall excess risk of CVD-associated mortality after exposure to low doses of radiation would be about twice that associated to radiation-induced cancers, which ranges from 4.2% to 5.6% per Sv for the cohort populations discussed above [55, 65] and would even be different between both sexes.

2.2. Pathophysiology of radiation-induced CVD

Following radiotherapy of the thoracic part of the human body for mediastinal lymphoma, breast, lung, and esophageal cancers, the heart incidentally receives a part of the therapeutic dose [46]. As indicated in the epidemiology section, high-dose radiation exposure of the heart and its vessels is associated with a risk of radiation-induced CVD [34, 54, 55]. In this context, coronary artery disease is considered to be the major cardiovascular complication [28, 30, 54]. Two studies provide molecular and cellular mechanisms accounting for increased morbidity and mortality of coronary artery disease following radiation exposure. First, radiation can influence the pathogenesis of age-related atherosclerosis, thereby accelerating the development of atherosclerosis in coronary arteries [28]. Growing atherosclerotic plaques narrow the blood vessel and hamper the blood stream (Figure 3). Second, damage to the heart microvasculature can reduce blood flow to the myocardium, causing myocardial ischemia, which promotes acute infarction [30]. Because endothelial activation and dysfunction are major causes of atherosclerosis, much of the current radiobiological research is exploring the molecular and phenotypic effects of ionizing radiation in endothelial cells in the context of radiation-induced CVD [66, 67]. It should be noted, however, that there are also other clinical manifestations of radiation-related CVD, such as pericarditis, congestive heart failure, and heart fibrosis [30, 68, 69]. Radiation-induced pericarditis is caused by damage to the cardiac microvascular network in combination with fibrosis of cardiac venous and lymphatic channels. This ultimately leads to accumulation of a fibrin-rich exudate in the pericardium, causing pericardial tamponade. Congestive heart failure is attributed to radiation-induced fibrosis of the myocardium, which ultimately leads to decreased elasticity and extensibility of cardiac walls, thereby reducing the ejection fraction [70]. To learn more about putative mechanisms, the interested reader is referred to some excellent recent reviews [69, 71].

Figure 3.

Longitudinal cut of a normal, healthy blood vessel (left) and of a blood vessel with an atherosclerotic plaque hampering the blood stream (right). Damage to the endothelium is an important trigger of atherosclerosis, itself a main cause of CVD.

2.3. Gaps in the current knowledge of radiation-induced CVD

Available epidemiological studies have limited statistical power to detect a possible excess risk of CVD following exposure to radiation doses lower than 0.5 Gy. Limited power is due both to the high background level of CVD in studied populations and to the existence of many potentially confounding risk factors. For example, occupational studies have to deal with the “healthy worker” effect, and the study of A-bomb survivors has to deal with the “healthy survivor” effect. Both selection effects occur when healthy individuals with lower mortality and morbidity rates are selectively retained at a specific site (work and living area, respectively) where they accumulate higher doses and therefore confound the dose-risk relationship [37]. Other potential confounders in epidemiological studies are lifestyle risk factors for CVD (e.g., smoking, alcohol consumption, obesity, diabetes, hypertension) [35, 55] prognosis of cancer treatment regimens [30], distribution of the dose range, accuracy of dosimetry, duration of follow-up after exposure, and correct assignment of the cause of mortality [62]. For these reasons, the number of people needed to quantify the excess risk of a dose <0.5 Gy is unfeasibly high. In the context of radiation-related cancer, for example, a cohort of 5 million people would be needed to quantify the excess risk of a 10 mGy dose, assuming that the excess risk is in proportion to the dose [7]. Moreover, CVD may occur a long time after exposure to doses below 30 Gy (approx. 10–30 year lag) [30, 72, 73]. As a result, a long follow-up period of time is needed to determine the nature and magnitude of risks following individual exposure to lower doses.

Despite the fact that epidemiological studies have led to significant insights in radiation-related CVD risk, there are still many uncertainties that need to be addressed. Does CVD risk occur only above a specific radiation dose? Is the latency of CVD development dependent on the dose? Which are the sensitive targets in the heart and vasculature (e.g., fibroblasts, vascular smooth muscle cells, and endothelial cells)? Does radiation exposure affect CVD incidence or progression or both? Is there a difference between single dose and fractionated and chronic exposure? How does the time interval between two consecutive dose fractionations play a role in the induction of damage? These questions need to be answered to provide a more accurate dose risk assessment in order to improve the current radiation protection system.

Classical epidemiological studies are not adapted to provide answers to these questions. There is, therefore, a clear need for more detailed epidemiological studies that would be capable of addressing potential confounding factors and selection biases that could influence results. Furthermore, there is a particular need for a better understanding of the biological and molecular mechanisms responsible for the association between ionizing radiation and CVD [6]. Hence, a more directed approach is required, such as molecular epidemiology that integrates epidemiology and biology [55]. Radiobiological research is thus essential for understanding the radiation-related CVD risks, both at high and low doses. In other words, accurate risk estimation will be possible only based on comprehensive biological and molecular understanding of what ionizing radiation does to the cardiovascular system. To date, the induction of radiation-related CVD risks is believed to be the result of endothelial dysfunction, which will be discussed in the next section [30].

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3. Endothelial cell responses after ionizing radiation exposure

The endothelium could be a critical target in ionizing radiation-related CVD [74]. The endothelium is a single layer of cells that lines the interior of the vascular system and of the heart and has thus a strategic position between the blood and the surrounding tissues. It is a highly active organ system that is constantly sensing and responding to changes of the extracellular environment to maintain a normal function of the vascular system [75]. Endothelial cells are involved in a wide range of physiological processes, such as regulation of vascular tone, vascular permeability, blood coagulation/fibrinolysis, and inflammation, which are needed to maintain proper vascular functioning (Figure 4) [76]. Endothelial dysfunction has been observed in patients with atherosclerosis and in patients that exhibit CVD risk factors such as smoking, dyslipidemia, obesity, and diabetes mellitus [77] and is considered to be one of the first predictive indicators of cardiovascular morbidity and mortality [78].

Figure 4.

Overview of the major physiological functions of the arterial endothelium. (A) The endothelium (ECs, endothelial cells) forms a selective barrier regulating solute flux and fluid permeability between the blood and surrounding tissues [78]. (B) Formation of a thrombus or blood clot is referred to as intravascular coagulation, and the breakdown of a thrombus is referred to as fibrinolysis. Normal endothelium has antithrombotic and profibrinolytic properties and actively represses platelet adhesion and aggregation. Vessel damage or exposure to pro-inflammatory molecules shifts the balance toward more prothrombic/antifibrinolytic activities [75,109]. (C) To regulate the vascular tone, the endothelium releases various vasodilatory agents, such as nitric oxide (NO) and endothelial-derived hyperpolarizing factor (EDHF), or vasoconstrictive agents, such as endothelin-1 (ET-1), which modify vascular smooth muscle cell (VSMC) contractility [110]. (D) In the case of inflammation, endothelial permeability is increased. Endothelial cells recruit immune cells via the expression of adhesion molecules and mediate their transmigration toward the inner vascular wall [75,76] .

A dysfunctional endothelium is characterized by inflammation, DNA damage, oxidative stress, alterations of coagulation and platelet pathways, senescence, and cell death, all of which are observed after radiation doses above 1–2 Gy, as shown in many in vitro and in vivo studies [6, 28, 79, 80, 81]. Comparatively, both protective and detrimental effects have been reported for low-dose exposure, suggesting that multiple mechanisms may influence radiation-induced atherosclerosis [6, 62]. Increasing evidence also suggests a role of intercellular communication in the endothelial cell response to ionizing radiation [82]. All of these endpoints are briefly discussed in the following paragraphs. In addition, other pathological effects of ionizing radiation on the endothelium are observed like impaired endothelial regulation of vascular tone [8387], loss of the endothelial monolayer integrity [88, 89, 90, 91, 92], and procoagulant and prothrombic conditions [28, 93108].

3.1. Inflammation

Endothelial expression of adhesion molecules plays an important role in recruiting inflammatory cells from the bloodstream into the vessel intima where they transform into foam cells, elements of the atherosclerotic plaque. Radiation has been shown to upregulate several of such adhesion molecules. For instance, exposure of endothelial cells to 5 Gy increases the expression of intercellular adhesion molecule-1 (ICAM-1) and E-selectin 6 h after irradiation [111]. Platelet endothelial cell adhesion molecule-1 (PECAM-1), ICAM-1 and ICAM-2, and vascular cellular adhesion molecule-1 (VCAM-1) were also observed to increase in mouse heart cells 10 weeks after local thorax irradiation with 8 Gy [112]. Interestingly, ICAM-1 and VCAM-1 remained upregulated 20 weeks after irradiation. Besides induction of adhesion molecules, the expression of cytokines, such as interleukin (IL)-6 and IL-8, and other inflammatory molecules such as transforming growth factor-β (TGF-β) was shown to increase after high and moderate irradiation doses in human endothelial cell cultures [113, 114]. In this context, the Japanese atomic bomb survivors’ cohort also showed signs of a generally increased inflammation state, with increased levels of IL-6 and C-reactive protein (CRP) [115].

3.2. DNA damage and apoptosis

Ionizing radiation is known to induce a wide range of DNA lesions, of which double-strand breaks (DSBs) are most severe in a direct manner but also indirectly through the formation of reactive oxygen species (ROS) [116, 117]. Upon DNA damage, a response is initiated, and cells activate cell cycle checkpoints that slow down or stop cell cycle progression [118]. This gives them time to repair damaged DNA or to prevent division when chromosomes are damaged or incompletely replicated. If cells fail to repair their DNA, they undergo programmed cell death, apoptosis, or premature senescence (described below) [119]. Consequently, DSB leads to a high lethality of the affected cells.

Whereas high doses are known to induce apoptosis in endothelial cells [120], less is known about the effect of low radiation doses. A subtle but significant increase in DSBs was observed in human umbilical vein endothelial cells (HUVEC) and EA.hy926 endothelial cells 30 min after exposure to 0.05 Gy. In addition, irradiation with 0.05 Gy and 0.1 Gy induced relatively more DSB/Gy in comparison to 0.5 Gy and 2 Gy [121]. This observation could be caused either by an underestimation due to DNA damage spot merging [122] or by the induction of a global chromatin reorganization at low doses of ionizing radiation [123]. Furthermore, a dose-dependent increase in the number of apoptotic cells was observed, down to 0.5 Gy in HUVEC and 0.1 Gy in EA.hy926 cells [121]. Another study showed no increase in the number of apoptotic endothelial cells after exposure to 0.2 Gy, whereas apoptosis was observed after exposure to 5 Gy [124].

3.3. Oxidative stress, mitochondrial dysfunction, and metabolic changes

Mitochondria are often regarded as the powerhouse of the cell by generating the ultimate energy transfer molecule, adenosine triphosphate or ATP. Mitochondrial dysfunction is part of both normal and premature agings, but it can also contribute to inflammation, cell senescence, oxidative stress, and apoptosis. Increasing evidence indicates that mitochondrial damage and dysfunction occur in atherosclerosis and may contribute to the multiple pathological processes underlying the disease [125].

An increased accumulation of mitochondrial DNA damage was observed in several human fibroblast cell lines after exposure to doses as low as 0.1 Gy [126]. Furthermore, functional impairment of mitochondria (reduced mitochondrial respiration and electron transport chain activity) and alterations of the mitochondrial proteome were observed in isolated cardiac mouse mitochondria 4 and 40 weeks after a 2 Gy local heart irradiation. Only a few alterations of the mitochondrial proteome and no effect on mitochondrial function were observed with 0.2 Gy [127, 128]. Finally, alterations of energy and lipid metabolism and perturbations of the insulin/insulin growth factor—phosphatidylinositol-4,5-bisphosphate 3-kinase—RAC-alpha serine/threonine-protein kinase (IGP-PI3K-Akt) signaling pathway were suggested in proteomic studies using cell lines or cells isolated from mice after irradiation with doses ranging from 3 to 16 Gy [129131].

Water radiolysis instantly causes the formation of ROS (e.g., •OH, •O2, H2O2). However, cellular oxidative stress can also be observed long after irradiation, due to an increase in endogenous cellular ROS production [132]. Mitochondria are believed to be the major source of radiation-induced secondary ROS. For instance, Leach et al. have demonstrated that between 1 and 10 Gy, the amount of ROS-producing cells increased with the dose, which they suggested was dependent on radiation-induced propagation of mitochondrial permeability transition via a Ca2+-dependent mechanism [133, 134]. It has further been suggested that ROS can be transferred from cell to cell by gap junctions and paracrine communication pathways in order to propagate radiation-induced biological effects at the intercellular level. This phenomenon is commonly referred to as the radiation-induced “bystander effect” [135]. Multiple molecular signaling mechanisms involving oxidative stress, various kinases, inflammatory molecules, and Ca2+ are postulated to contribute to this effect [136].

3.4. Premature senescence

The culprit of radiation-induced premature senescence is most likely severe irreparable DSB [137], even if accelerated telomere shortening has also been suggested [138]. Furthermore, oxidative stress is seen as a major player in radiation-induced senescence and is involved in both radiation-induced DNA damage and accelerated telomere attrition [138140].

In several in vitro studies, it has been demonstrated that ionizing radiation induces endothelial cell senescence, mainly with exposure to higher radiation doses [141, 142, 143, 144]. An interesting study was carried out to examine the effect of chronic low-dose rate irradiation (1.4, 2.4, and 4.1 mGy/h) during 10 weeks [145, 146]. Exposure to 1.4 mGy/h did not accelerate the onset of senescence, whereas exposure to 2.4 mGy/h and 4.1 mGy/h did. Remarkably, a senescent profile was observed when the accumulated doses received by the cells reached 4 Gy. Proteomic analysis revealed a role for radiation-induced oxidative stress and DNA damage, resulting in induction of the p53/p21 pathway. Also, a role for the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway was suggested. In a related transcriptomic study, authors suggested that premature senescence resulted from an early stress response with p53 signaling, cell cycle changes, DNA repair, and apoptosis observed after 1 week of exposure and an inflammation-related profile observed after 3 weeks. In addition, a possible role of insulin-like growth factor-binding protein 5 (IGFBP-5) signaling, known to be involved in the regulation of cellular senescence, was suggested for the induction of premature senescence after chronic low-dose rate irradiation [147].

Oxidative stress, inflammation, and cellular senescence are all consequences of a normal aging process but are observed early in irradiated tissues, including the heart, suggesting an intensification and acceleration of these molecular processes [71].

3.5. Intercellular communication

Traditionally, it was accepted that exposure to ionizing radiation only directly affects irradiated cells. However, in 1992, it was found that irradiation of 1% cells with α-particles leads to genetic damage in more than 30% of cells [148]. Exposure of cells to ionizing radiation results in significant biological effects occurring in both irradiated and non-irradiated cells through the radiation-induced bystander effect [149, 150]. Although the mechanisms of this effect are not fully elucidated yet, oxidative stress, different cytokines (e.g., TNF-α, IL-1, and IL-6), Ca2+, and kinases play a role in the damage to non-irradiated cells.

Intercellular communication through gap junctions and paracrine signaling through hemichannels have been suggested to mediate bystander responses. Gap junctions and hemichannels are composed of multimeric transmembrane structures made of connexin (Cx) [150, 151]. In human, 21 Cx proteins have been identified, which are present in most organs, and display a tissue/cellular specificity [152, 153]. There are three different Cx isotypes expressed in endothelial cells of major arteries, namely, Cx37, Cx40, and Cx43 [154156]. Cxs have important physiological roles (e.g., they support longitudinal and radial cell-cell communication in the vascular wall), and changes of their expression patterns have been observed during atherosclerosis. Although healthy endothelial cells mainly express Cx37 and Cx40, both Cxs are lost in the endothelium covering advanced atherosclerotic plaques. On the contrary, Cx43 is detectable at specific regions of advanced atherosclerotic plaques [157]. The mechanisms responsible for modification of the Cx expression pattern in atherosclerosis are not fully understood. However, it has been recently demonstrated that Cx37 is a regulator of endothelial NO synthase (eNOS) [158]. The altered Cx37 expression level could be responsible for decreased eNOS activity and decreased NO bioavailability, which may cause endothelial cell dysfunction and increased susceptibility to atherosclerosis. Therefore, Cx37 may play a protective role against atherosclerosis. In addition, Cx40 may play a similar role, as endothelial-specific deletion of Cx40 was reported to promote atherosclerosis by increasing CD73-dependent leukocyte adhesion to the endothelium [155]. In contrast to the atheroprotective effects of Cx37 and Cx40, Cx43 has been suggested to be pro-atherosclerotic. Indeed, downregulation of Cx43 expression inhibited monocyte-endothelial adhesion by decreasing the expression levels of cell adhesion proteins, whereas its upregulation enhanced the adhesion of monocytes to endothelial cells [159]. Besides their roles in atherosclerosis, Cxs were reported to be highly sensitive to ionizing radiation [156]. Indeed, it was observed that a low-dose irradiation exposure induced activation of Cx43 in a time- and dose-dependent manner in human neonatal foreskin fibroblasts [160]. Moreover, upregulation of Cx43 was noticed after 5 Gy of X-ray exposure in mouse primary endothelial cells [161].

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4. Conclusion

Research regarding CVD risk related to ionizing radiation is an important way forward to complement epidemiological data with the underlying biological and molecular mechanisms. This is especially important for doses <0.5 Gy, for which epidemiological data are suggestive rather than persuasive. Indeed, due to limited statistical power, the dose-risk relationship is undetermined below 0.5 Gy, but if this relationship proves to be without a threshold, it may have a considerable impact on current low-dose health risk estimates. In this regard, a complete understanding of the pathological effects of ionizing radiation regarding endothelial dysfunction is needed. In addition, it will help in the identification of protective strategies as well as a set of predictive biomarkers for radiation-induced cardiovascular disorders.

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Acknowledgments

This review is written in the context of a study that was funded by EU FP7 DoReMi (grant agreement 249689) on “low dose research towards multidisciplinary integration,”, by EU FP7 ProCardio project (grant agreement 295823) and by the Federal Agency of Nuclear Control (FANC-AFCN, Belgium) (grant agreement: CO-90-13-3289-00). R. Ramadam and B. Baselet are recipients of a doctoral SCK•CEN/Ghent University grant and of a doctoral SCK•CEN/Université catholique de Louvain grant, respectively. P. Sonveaux is a Senior Research Associate of the Belgian National Fonds de la Recherche Scientifique.

References

  1. 1. UNSCEAR United Nations Scientific Committee on the Effects of Atomic Radiation. Annex B. Epidemiological evaluation of cardiovascular disease and other non-cancer diseases following radiation exposure. UNSCEAR Report Vol 1. 2006
  2. 2. Montgomery JE, Brown JR. Metabolic biomarkers for predicting cardiovascular disease. Vascular Health and Risk Management. 2013;9:37-45
  3. 3. AGIR–Advisory Group on Ionising Radiation. Circulatory Disease Risk. Report of the independent Advisory Group on Ionizing Radiation. London: Health Protection Agency; 2010
  4. 4. Authors of behalf of ICRP SF, Akleyev AV, Hauer-Jensen M, Henddy JH, Kleiman NJ, Macvittie TJ, Aleman BM, Edgar AB, Mabuchi K, Muirhead CR, et al. ICRP publication 118. ICRP statement on tissue reactions and early and late effects of radiation in normal tissue and organ—Threshold doses for tissue reactions in a radiation protection context. Annals of the ICRP. 2012;41:322
  5. 5. Little MP. Radiation and circulatory disease. Mutation Research. 2016;770(Pt B):299-318
  6. 6. Baselet B, Rombouts C, Benotmane AM, Baatout S, Aerts A. Cardiovascular diseases related to ionizing radiation: The risk of low-dose exposure (review). International Journal of Molecular Medicine. 2016;38(6):1623-1641
  7. 7. Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, et al. Cancer risks attributable to low doses of ionizing radiation: Assessing what we really know. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(24):13761-13766
  8. 8. UNSCEAR. Sources and effects of ionizing radiation. Annex A: medical radiation exposures. Report to the General Assembly with annexes. New york, NY: United Nations. 2008
  9. 9. Hall EJ, Brenner DJ. Cancer risks from diagnostic radiology. The British Journal of Radiology. 2008;81(965):362-378
  10. 10. Picano E, Vano E, Rehani MM, Cuocolo A, Mont L, Bodi V, et al. The appropriate and justified use of medical radiation in cardiovascular imaging: A position document of the ESC associations of cardiovascular imaging, percutaneous cardiovascular interventions and electrophysiology. European Heart Journal. 2014;35(10):665-672
  11. 11. Shapiro BP, Mergo PJ, Snipelisky DF, Kantor B, Gerber TC. Radiation dose in cardiac imaging: How should it affect clinical decisions? American Journal of Roentgenology. 2013;200(3):508-514
  12. 12. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 7th ed. Philadelphia: Lippincott, Williams & Wilkins; 2012
  13. 13. Martin A, Harbison S, Beach K, Cole P. An Introduction to Radiation Protection. 6th ed. London: Hodder Arnold; 2012. 256 p
  14. 14. Dendy PP, Heaton B. Physics for Diagnostic Radiology. 3rd ed. Taylor & Francis Inc: Bosa Roca, US; 2012. 695 p
  15. 15. Kudriashov IB, Kudriashov YB. Radiation Biophysics (Ionizing Radiations). 1st ed. New York: Nova Science Publishers Inc; 2008. 327 p
  16. 16. Maalouf M, Durante M, Foray N. Biological effects of space radiation on human cells: History, advances and outcomes. Journal of Radiation Research. 2011;52(2):126-146
  17. 17. Durante M, Loeffler JS. Charged particles in radiation oncology. Nature Reviews. Clinical Oncology. 2010;7(1):37-43
  18. 18. ICRP. The 2007 recommendations of the international commission on radiological protection. ICRP publication 103. Annals of the ICRP. 2007;37(2-4):1-332
  19. 19. Einstein AJ. Effects of radiation exposure from cardiac imaging: How good are the data? Journal of the American College of Cardiology. 2012;59(6):553-565
  20. 20. Lin EC. Radiation risk from medical imaging. Mayo Clinic Proceedings. 2010;85(12):1142-1146 quiz 6
  21. 21. Mullenders L, Atkinson M, Paretzke H, Sabatier L, Bouffler S. Assessing cancer risks of low-dose radiation. Nature Reviews. Cancer. 2009;9(8):596-604
  22. 22. Paterick TE, Jan MF, Paterick ZR, Tajik AJ, Gerber TC. Cardiac imaging modalities with ionizing radiation: The role of informed consent. JACC: Cardiovascular Imaging. 2012;5(6):634-640
  23. 23. Fazel R, Krumholz HM, Wang Y, Ross JS, Chen J, Ting HH, et al. Exposure to low-dose ionizing radiation from medical imaging procedures. The New England Journal of Medicine. 2009;361(9):849-857
  24. 24. Thariat J, Hannoun-Levi JM, Sun Myint A, Vuong T, Gerard JP. Past, present, and future of radiotherapy for the benefit of patients. Nature Reviews. Clinical Oncology. 2013;10(1):52-60
  25. 25. Walker JS. Permissible dose : a history of radiation protection in the twentieth century. Berkeley: University of California Press; 2000. xii, 168 pp
  26. 26. Stewart JR, Fajardo LF. Radiation-induced heart disease. Clinical and experimental aspects. Radiologic Clinics of North America. 1971;9(3):511-531
  27. 27. Stewart FA. Mechanisms and dose-response relationships for radiation-induced cardiovascular disease. Annals of the ICRP. 2012;41(3-4):72-79
  28. 28. Schultz-Hector S, Trott KR. Radiation-induced cardiovascular diseases: Is the epidemiologic evidence compatible with the radiobiologic data? International Journal of Radiation Oncology, Biology, Physics. 2007;67(1):10-18
  29. 29. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;366(9503):2087-2106
  30. 30. Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, et al. Radiation-related heart disease: Current knowledge and future prospects. International Journal of Radiation Oncology, Biology, Physics. 2010;76(3):656-665
  31. 31. Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: Prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncology. 2005;6(8):557-565
  32. 32. McGale P, Darby SC, Hall P, Adolfsson J, Bengtsson NO, Bennet AM, et al. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiotherapy and Oncology. 2011;100(2):167-175
  33. 33. Carr ZA, Land CE, Kleinerman RA, Weinstock RW, Stovall M, Griem ML, et al. Coronary heart disease after radiotherapy for peptic ulcer disease. International Journal of Radiation Oncology, Biology, Physics. 2005;61(3):842-850
  34. 34. Shimizu Y, Kodama K, Nishi N, Kasagi F, Suyama A, Soda M, et al. Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003. BMJ. 2010;340:b5349
  35. 35. Radiation AGoI, editor. Circulatory Disease Risk. Report of the Independent Advisory Group on Ionising Radiation. Health Protection Agency; 2010
  36. 36. Takahashi I, Abbott RD, Ohshita T, Takahashi T, Ozasa K, Akahoshi M, et al. A prospective follow-up study of the association of radiation exposure with fatal and non-fatal stroke among atomic bomb survivors in Hiroshima and Nagasaki (1980-2003). BMJ Open. 2012;2(1):e000654
  37. 37. Vrijheid M, Cardis E, Ashmore P, Auvinen A, Bae JM, Engels H, et al. Mortality from diseases other than cancer following low doses of ionizing radiation: Results from the 15-country study of nuclear industry workers. International Journal of Epidemiology. 2007;36(5):1126-1135
  38. 38. Muirhead CR, O’Hagan JA, Haylock RG, Phillipson MA, Willcock T, Berridge GL, et al. Mortality and cancer incidence following occupational radiation exposure: Third analysis of the National Registry for Radiation Workers. British Journal of Cancer. 2009;100(1):206-212
  39. 39. Ashmore JP, Krewski D, Zielinski JM, Jiang H, Semenciw R, Band PR. First analysis of mortality and occupational radiation exposure based on the National Dose Registry of Canada. American Journal of Epidemiology. 1998;148(6):564-574
  40. 40. Ivanov VK, Maksioutov MA, Chekin SY, Petrov AV, Biryukov AP, Kruglova ZG, et al. The risk of radiation-induced cerebrovascular disease in Chernobyl emergency workers. Health Physics. 2006;90(3):199-207
  41. 41. Azizova TV, Muirhead CR, Druzhinina MB, Grigoryeva ES, Vlasenko EV, Sumina MV, et al. Cardiovascular diseases in the cohort of workers first employed at Mayak PA in 1948-1958. Radiation Research. 2010;174(2):155-168
  42. 42. Azizova TV, Day RD, Wald N, Muirhead CR, O’Hagan JA, Sumina MV, et al. The “clinic” medical-dosimetric database of Mayak production association workers: Structure, characteristics and prospects of utilization. Health Physics. 2008;94(5):449-458
  43. 43. Azizova TV, Muirhead CR, Moseeva MB, Grigoryeva ES, Vlasenko EV, Hunter N, et al. Ischemic heart disease in nuclear workers first employed at the Mayak PA in 1948-1972. Health Physics. 2012;103(1):3-14
  44. 44. Krestinina LY, Epifanova S, Silkin S, Mikryukova L, Degteva M, Shagina N, et al. Chronic low-dose exposure in the Techa River Cohort: Risk of mortality from circulatory diseases. Radiation and Environmental Biophysics. 2013;52(1):47-57
  45. 45. Grosche B, Lackland DT, Land CE, Simon SL, Apsalikov KN, Pivina LM, et al. Mortality from cardiovascular diseases in the Semipalatinsk historical cohort, 1960-1999, and its relationship to radiation exposure. Radiation Research. 2011;176(5):660-669
  46. 46. Chargari C, Riet F, Mazevet M, Morel E, Lepechoux C, Deutsch E. Complications of thoracic radiotherapy. Presse Médicale. 2013;42(9 Pt 2):e342-e351
  47. 47. Mancuso M, Pasquali E, Braga-Tanaka I 3rd, Tanaka S, Pannicelli A, Giardullo P, et al. Acceleration of atherogenesis in ApoE−/− mice exposed to acute or low-dose-rate ionizing radiation. Oncotarget. 2015;6(31):31263-31271
  48. 48. United Nations. Scientific Committee on the Effects of Atomic Radiation. Sources and Effects of Ionizing Radiation : United Nations Scientific Committee on the Effects of Atomic Radiation : UNSCEAR 2008 Report to the General Assembly, with Scientific Annexes. New York: United Nations; 2010
  49. 49. United Nations. Scientific Committee on the Effects of Atomic Radiation. Sources and Effects of Ionizing Radiation : United Nations Committee on the Effects of Atomic Radiation : UNSCEAR 1993 Report to the General Assembly, with Scientific Annexes. New York: United Nations; 1993. 922 p
  50. 50. Committee to assess Health Risks from Exposure to Low Levels of Ionizing Radiation Research NRC. Health risks from exposure to low levels of ionizing radiation: BEIR VII—Phase 2. 2006
  51. 51. Martin CJ. The LNT model provides the best approach for practical implementation of radiation protection. The British Journal of Radiology. 2005;78:14-16
  52. 52. Martin CJ, Sutton DG, West CM, Wright EG. The radiobiology/radiation protection interface in healthcare. Journal of Radiological Protection: Official Journal of the Society for Radiological Protection. 2009;29:A1-A20
  53. 53. Hildebrandt G. Non-cancer diseases and non-targeted effects. Mutation Research. 2010;687(1-2):73-77
  54. 54. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. The New England Journal of Medicine. 2013;368(11):987-998
  55. 55. Little MP, Azizova TV, Bazyka D, Bouffler SD, Cardis E, Chekin S, et al. Systematic review and meta-analysis of circulatory disease from exposure to low-level ionizing radiation and estimates of potential population mortality risks. Environmental Health Perspectives. 2012;120(11):1503-1511
  56. 56. Dale RG, Jones B, Carabe-Fernandez A. Why more needs to be known about RBE effects in modern radiotherapy. Applied Radiation and Isotopes. 2009;67(3):387-392
  57. 57. Gottfried K-LD, Penn G. U.S. Nuclear Regulatory Commission. Medical Use Program., Institute of Medicine (U.S.). Committee for Review and Evaluation of the Medical Use Program of the Nuclear Regulatory Commission. Radiation in Medicine : A Need for Regulatory Reform. Washington, D.C.: National Academy Press; 1996. 308 p
  58. 58. Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, van Putten WL, Levendag PC. Ischemic heart disease after mantlefield irradiation for Hodgkin’s disease in long-term follow-up. Radiotherapy and Oncology. 1999;51(1):35-42
  59. 59. Ng AK, van Leeuwen FE. Hodgkin lymphoma: Late effects of treatment and guidelines for surveillance. Seminars in Hematology. 2016;53(3):209-215
  60. 60. Lee WC. Excess relative risk as an effect measure in case-control studies of rare diseases. PLoS One. 2014;10(4):e0121141
  61. 61. Azizova TV, Grigorieva ES, Hunter N, Pikulina MV, Moseeva MB. Risk of mortality from circulatory diseases in Mayak workers cohort following occupational radiation exposure. Journal of Radiological Protection. 2015;35(3):517-538
  62. 62. Borghini A, Gianicolo EA, Picano E, Andreassi MG. Ionizing radiation and atherosclerosis: Current knowledge and future challenges. Atherosclerosis. 2013;230(1):40-47
  63. 63. Yamada M, Wong FL, Fujiwara S, Akahoshi M, Suzuki G. Noncancer disease incidence in atomic bomb survivors, 1958-1998. Radiation Research. 2004;161(6):622-632
  64. 64. Grant EJ, Brenner A, Sugiyama H, Sakata R, Sadakane A, Utada M, et al. Solid cancer incidence among the life span study of atomic bomb survivors: 1958-2009. Radiation Research. 2017;187(5):513-537
  65. 65. Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K. Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950-1997. Radiation Research. 2003;160(4):381-407
  66. 66. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317-325
  67. 67. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circulation Research. 2014;114(12):1852-1866
  68. 68. Adams MJ, Lipshultz SE, Schwartz C, Fajardo LF, Coen V, Constine LS. Radiation-associated cardiovascular disease: Manifestations and management. Seminars in Radiation Oncology. 2003;13(3):346-356
  69. 69. Taunk NK, Haffty BG, Kostis JB, Goyal S. Radiation-induced heart disease: Pathologic abnormalities and putative mechanisms. Frontiers in Oncology. 2015;5:39
  70. 70. Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE. Radiation-associated cardiovascular disease. Critical Reviews in Oncology/Hematology. 2003;45(1):55-75
  71. 71. Tapio S. Pathology and biology of radiation-induced cardiac disease. Journal of Radiation Research. 2016;57(5):439-448
  72. 72. Little MP, Lipshultz SE. Low dose radiation and circulatory diseases: A brief narrative review. Cardio-Oncology. 2015;1(1):1-10
  73. 73. Simonetto C, Azizova TV, Grigoryeva ES, Kaiser JC, Schollnberger H, Eidemuller M. Ischemic heart disease in workers at Mayak PA: Latency of incidence risk after radiation exposure. PLoS One. 2014;9(5):e96309
  74. 74. Baselet B, Rombouts C, Benotmane AM, Baatout S, Aerts A. Cardiovascular diseases related to ionizing radiation: The risk of low-dose exposure (review). International Journal of Molecular Medicine. 2016
  75. 75. Michiels C. Endothelial cell functions. Journal of Cellular Physiology. 2003;196(3):430-443
  76. 76. Hirase T, Node K. Endothelial dysfunction as a cellular mechanism for vascular failure. American Journal of Physiology. Heart and Circulatory Physiology. 2012;302(3):H499-H505
  77. 77. Flammer AJ, Luscher TF. Three decades of endothelium research: From the detection of nitric oxide to the everyday implementation of endothelial function measurements in cardiovascular diseases. Swiss Medical Weekly. 2010;140:w13122
  78. 78. Triggle CR, Samuel SM, Ravishankar S, Marei I, Arunachalam G, Ding H. The endothelium: Influencing vascular smooth muscle in many ways. Canadian Journal of Physiology and Pharmacology. 2012;90(6):713-738
  79. 79. Hendry JH, Akahoshi M, Wang LS, Lipshultz SE, Stewart FA, Trott KR. Radiation-induced cardiovascular injury. Radiation and Environmental Biophysics. 2008;47(2):189-193
  80. 80. Little MP, Tawn EJ, Tzoulaki I, Wakeford R, Hildebrandt G, Paris F, et al. A systematic review of epidemiological associations between low and moderate doses of ionizing radiation and late cardiovascular effects, and their possible mechanisms. Radiation Research. 2008;169(1):99-109
  81. 81. Bhatti P, Sigurdson AJ, Mabuchi K. Can low-dose radiation increase risk of cardiovascular disease? Lancet. 2008;372(9640):697-699
  82. 82. Decrock E, Hoorelbeke D, Ramadan R, Delvaeye T, De Bock M, Wang N, et al. Calcium, oxidative stress and connexin channels, a harmonious orchestra directing the response to radiotherapy treatment? Biochimica et Biophysica Acta. 2017;1864(6):1099-1120
  83. 83. Lerman A, Burnett JC Jr. Intact and altered endothelium in regulation of vasomotion. Circulation. 1992;86(6 Suppl):III12-III19
  84. 84. Tousoulis D, Kampoli AM, Tentolouris C, Papageorgiou N, Stefanadis C. The role of nitric oxide on endothelial function. Current Vascular Pharmacology. 2012;10(1):4-18
  85. 85. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: A marker of atherosclerotic risk. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23(2):168-175
  86. 86. Mombouli JV, Vanhoutte PM. Endothelial dysfunction: From physiology to therapy. Journal of Molecular and Cellular Cardiology. 1999;31(1):61-74
  87. 87. Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease—A 30th anniversary update. Acta Physiologica (Oxford, England). 2017;219(1):22-96
  88. 88. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nature Protocols 2006;1(5):2315-2319
  89. 89. Park MT, ET O, Song MJ, Lee H, Park HJ. Radio-sensitivities and angiogenic signaling pathways of irradiated normal endothelial cells derived from diverse human organs. Journal of Radiation Research. 2012;53(4):570-580
  90. 90. Riquier H, Wera AC, Heuskin AC, Feron O, Lucas S, Michiels C. Comparison of X-ray and alpha particle effects on a human cancer and endothelial cells: Survival curves and gene expression profiles. Radiotherapy and Oncology. 2013;106(3):397-403
  91. 91. Haimovitz-Friedman A, Kan CC, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z, et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. The Journal of Experimental Medicine. 1994;180(2):525-535
  92. 92. Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene. 2003;22(37):5897-5906
  93. 93. Verheij M, Dewit LG, van Mourik JA. The effect of ionizing radiation on endothelial tissue factor activity and its cellular localization. Thrombosis and Haemostasis. 1995;73(5):894-895
  94. 94. Wang J, Zheng H, Ou X, Albertson CM, Fink LM, Herbert JM, et al. Hirudin ameliorates intestinal radiation toxicity in the rat: Support for thrombin inhibition as strategy to minimize side-effects after radiation therapy and as countermeasure against radiation exposure. Journal of Thrombosis and Haemostasis. 2004;2(11):2027-2035
  95. 95. van Kleef E, Verheij M, te Poele H, Oussoren Y, Dewit L, Stewart F. In vitro and in vivo expression of endothelial von Willebrand factor and leukocyte accumulation after fractionated irradiation. Radiation Research. 2000;154(4):375-381
  96. 96. Boerma M, Kruse JJ, van Loenen M, Klein HR, Bart CI, Zurcher C, et al. Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation. Strahlentherapie und Onkologie. 2004;180(2):109-116
  97. 97. Stewart FA, Te Poele JA, Van der Wal AF, Oussoren YG, Van Kleef EM, Kuin A, et al. Radiation nephropathy—The link between functional damage and vascular mediated inflammatory and thrombotic changes. Acta Oncologica. 2001;40(8):952-957
  98. 98. Sporn LA, Rubin P, Marder VJ, Wagner DD. Irradiation induces release of von Willebrand protein from endothelial cells in culture. Blood. 1984;64(2):567-570
  99. 99. Jahroudi N, Ardekani AM, Greenberger JS. Ionizing irradiation increases transcription of the von Willebrand factor gene in endothelial cells. Blood. 1996;88(10):3801-3814
  100. 100. McManus LM, Ostrom KK, Lear C, Luce EB, Gander DL, Pinckard RN, et al. Radiation-induced increased platelet-activating factor activity in mixed saliva. Laboratory Investigation. 1993;68(1):118-124
  101. 101. Wang J, Zheng H, Ou X, Fink LM, Hauer-Jensen M. Deficiency of microvascular thrombomodulin and up-regulation of protease-activated receptor-1 in irradiated rat intestine: Possible link between endothelial dysfunction and chronic radiation fibrosis. The American Journal of Pathology. 2002;160(6):2063-2072
  102. 102. Zhou Q, Zhao Y, Li P, Bai X, Ruan C. Thrombomodulin as a marker of radiation-induced endothelial cell injury. Radiation Research. 1992;131(3):285-289
  103. 103. Hosoi Y, Yamamoto M, Ono T, Sakamoto K. Prostacyclin production in cultured endothelial cells is highly sensitive to low doses of ionizing radiation. International Journal of Radiation Biology. 1993;63(5):631-638
  104. 104. Leigh PJ, Cramp WA, MacDermot J. Identification of the prostacyclin receptor by radiation inactivation. The Journal of Biological Chemistry. 1984;259(20):12431-12436
  105. 105. Eldor A, Vlodavsky I, Riklis E, Fuks Z. Recovery of prostacyclin capacity of irradiated endothelial cells and the protective effect of vitamin C. Prostaglandins. 1987;34(2):241-255
  106. 106. Henderson BW, Bicher HI, Johnson RJ. Loss of vascular fibrinolytic activity following irradiation of the liver—An aspect of late radiation damage. Radiation Research. 1983;95(3):646-652
  107. 107. Svanberg L, Astedt B, Kullander S. On radiation-decreased fibrinolytic activity of vessel walls. Acta Obstetricia et Gynecologica Scandinavica. 1976;55(1):49-51
  108. 108. Ts’ao CH, Ward WF, Port CD. Radiation injury in rat lung. III. Plasminogen activator and fibrinolytic inhibitor activities. Radiation Research. 1983;96(2):301-308
  109. 109. van Hinsbergh VW. Endothelium—Role in regulation of coagulation and inflammation. Seminars in Immunopathology. 2012;34(1):93-106
  110. 110. Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. Open Cardiovascular Medicine Journal. 2010;4:302-312
  111. 111. Hildebrandt G, Maggiorella L, Rodel F, Rodel V, Willis D, Trott KR. Mononuclear cell adhesion and cell adhesion molecule liberation after X-irradiation of activated endothelial cells in vitro. International Journal of Radiation Biology. 2002;78(4):315-325
  112. 112. Sievert W, Trott KR, Azimzadeh O, Tapio S, Zitzelsberger H, Multhoff G. Late proliferating and inflammatory effects on murine microvascular heart and lung endothelial cells after irradiation. Radiotherapy & Oncology. 2015;117(2):376-381
  113. 113. Van Der Meeren A, Squiban C, Gourmelon P, Lafont H, Gaugler MH. Differential regulation by IL-4 and IL-10 of radiation-induced IL-6 and IL-8 production and ICAM-1 expression by human endothelial cells. Cytokine. 1999;11(11):831-838
  114. 114. Milliat F, Francois A, Isoir M, Deutsch E, Tamarat R, Tarlet G, et al. Influence of endothelial cells on vascular smooth muscle cells phenotype after irradiation: Implication in radiation-induced vascular damages. The American Journal of Pathology. 2006;169(4):1484-1495
  115. 115. Hayashi T, Morishita Y, Khattree R, Misumi M, Sasaki K, Hayashi I, et al. Evaluation of systemic markers of inflammation in atomic-bomb survivors with special reference to radiation and age effects. The FASEB Journal. 2012;26(11):4765-4773
  116. 116. Jeggo P, Lobrich M. Radiation-induced DNA. damage responses. Radiation Protection Dosimetry. 2006;122(1-4):124-127
  117. 117. Bolus NE. Basic review of radiation biology and terminology. Journal of Nuclear Medicine Technology. 2001;29(2):67-73 test 6-7
  118. 118. Norbury CJ, Hickson ID. Cellular responses to DNA damage. Annual Review of Pharmacology and Toxicology. 2001;41:367-401
  119. 119. Clarke PR, Allan LA. Cell-cycle control in the face of damage—A matter of life or death. Trends in Cell Biology. 2009;19(3):89-98
  120. 120. Langley RE, Bump EA, Quartuccio SG, Medeiros D, Braunhut SJ. Radiation-induced apoptosis in microvascular endothelial cells. British Journal of Cancer. 1997;75(5):666-672
  121. 121. Rombouts C, Aerts A, Beck M, De Vos WH, Van Oostveldt P, Benotmane MA, et al. Differential response to acute low dose radiation in primary and immortalized endothelial cells. International Journal of Radiation Biology. 2013;89(10):841-850
  122. 122. Neumaier T, Swenson J, Pham C, Polyzos A, Lo AT, Yang P, et al. Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(2):443-448
  123. 123. Costes SV, Chiolo I, Pluth JM, Barcellos-Hoff MH, Jakob B. Spatiotemporal characterization of ionizing radiation induced DNA damage foci and their relation to chromatin organization. Mutation Research. 2010;704(1-3):78-87
  124. 124. Pluder F, Barjaktarovic Z, Azimzadeh O, Mortl S, Kramer A, Steininger S, et al. Low-dose irradiation causes rapid alterations to the proteome of the human endothelial cell line EA.hy926. Radiation and Environmental Biophysics. 2011;50(1):155-166
  125. 125. Yu E, Mercer J, Bennett M. Mitochondria in vascular disease. Cardiovascular Research. 2012;95(2):173-182
  126. 126. Schilling-Toth B, Sandor N, Kis E, Kadhim M, Safrany G, Hegyesi H. Analysis of the common deletions in the mitochondrial DNA is a sensitive biomarker detecting direct and non-targeted cellular effects of low dose ionizing radiation. Mutation Research. 2011;716(1-2):33-39
  127. 127. Barjaktarovic Z, Schmaltz D, Shyla A, Azimzadeh O, Schulz S, Haagen J, et al. Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays. PLoS One. 2011;6(12):e27811
  128. 128. Barjaktarovic Z, Shyla A, Azimzadeh O, Schulz S, Haagen J, Dorr W, et al. Ionising radiation induces persistent alterations in the cardiac mitochondrial function of C57BL/6 mice 40 weeks after local heart exposure. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology. 2013;106(3):404-410
  129. 129. Azimzadeh O, Scherthan H, Sarioglu H, Barjaktarovic Z, Conrad M, Vogt A, et al. Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation. Proteomics. 2011;11(16):3299-3311
  130. 130. Azimzadeh O, Sievert W, Sarioglu H, Merl-Pham J, Yentrapalli R, Bakshi MV, et al. Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction. Journal of Proteome Research. 2015;14(2):1203-1219
  131. 131. Azimzadeh O, Sievert W, Sarioglu H, Yentrapalli R, Barjaktarovic Z, Sriharshan A, et al. PPAR alpha: A novel radiation target in locally exposed Mus musculus heart revealed by quantitative proteomics. Journal of Proteome Research. 2013;12(6):2700-2714
  132. 132. Yamamori T, Yasui H, Yamazumi M, Wada Y, Nakamura Y, Nakamura H, et al. Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint. Free Radical Biology & Medicine. 2012;53(2):260-270
  133. 133. Bernardi P. The mitochondrial permeability transition pore: A mystery solved? Frontiers in Physiology. 2013;4:95
  134. 134. Leach JK, Van Tuyle G, Lin PS, Schmidt-Ullrich R, Mikkelsen RB. Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Research. 2001;61(10):3894-3901
  135. 135. Marin A, Martin M, Linan O, Alvarenga F, Lopez M, Fernandez L, et al. Bystander effects and radiotherapy. Reports of Practical Oncology and Radiotherapy. 2015;20(1):12-21
  136. 136. Decrock E, Hoorelbeke D, Ramadan R, Delvaeye T, De Bock M, Wang N, et al. Calcium, oxidative stress and connexin channels, a harmonious orchestra directing the response to radiotherapy treatment? Biochimica et Biophysica Acta. 2017;1864(6):1099-1120
  137. 137. Vavrova J, Rezacova M. The importance of senescence in ionizing radiation-induced tumour suppression. Folia Biologica. 2011;57(2):41-46
  138. 138. Sabatino L, Picano E, Andreassi MG. Telomere shortening and ionizing radiation: A possible role in vascular dysfunction? International Journal of Radiation Biology. 2012;88(11):830-839
  139. 139. Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. Journal of Cell Science. 2004;117(Pt 11):2417-2426
  140. 140. Campisi J, d’Adda di Fagagna F. Cellular senescence: When bad things happen to good cells. Nature Reviews Molecular Cell Biology. 2007;8(9):729-740
  141. 141. CW O, Bump EA, Kim JS, Janigro D, Mayberg MR. Induction of a senescence-like phenotype in bovine aortic endothelial cells by ionizing radiation. Radiation Research. 2001;156(3):232-240
  142. 142. Panganiban RA, Mungunsukh O, Day RM. X-irradiation induces ER stress, apoptosis, and senescence in pulmonary artery endothelial cells. International Journal of Radiation Biology. 2013;89(8):656-667
  143. 143. Igarashi K, Sakimoto I, Kataoka K, Ohta K, Miura M. Radiation-induced senescence-like phenotype in proliferating and plateau-phase vascular endothelial cells. Experimental Cell Research. 2007;313(15):3326-3336
  144. 144. Kim KS, Kim JE, Choi KJ, Bae S, Kim DH. Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells. International Journal of Radiation Biology. 2014;90(1):71-80
  145. 145. Yentrapalli R, Azimzadeh O, Barjaktarovic Z, Sarioglu H, Wojcik A, Harms-Ringdahl M, et al. Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma-radiation. Proteomics. 2013;13(7):1096-1107
  146. 146. Yentrapalli R, Azimzadeh O, Sriharshan A, Malinowsky K, Merl J, Wojcik A, et al. The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation. PLoS One. 2013;8(8):e70024
  147. 147. Rombouts C, Aerts A, Quintens R, Baselet B, El-Saghire H, Harms-Ringdahl M, et al. Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation. International Journal of Radiation Biology. 2014;90(7):560-574
  148. 148. Nagasawa H, Little JB. Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Cancer Research. 1992;52(22):6394-6396
  149. 149. Mancuso M, Pasquali E, Leonardi S, Tanori M, Rebessi S, Di Majo V, et al. Oncogenic bystander radiation effects in patched heterozygous mouse cerebellum. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(34):12445-12450
  150. 150. Wang N, De Bock M, Decrock E, Bol M, Gadicherla A, Vinken M, et al. Paracrine signaling through plasma membrane hemichannels. Biochimica et Biophysica Acta. 2013;1828(1):35-50
  151. 151. Herve JC, Derangeon M. Gap-junction-mediated cell-to-cell communication. Cell and Tissue Research. 2013;352(1):21-31
  152. 152. Laird DW. Life cycle of connexins in health and disease. The Biochemical Journal. 2006;394(Pt 3):527-543
  153. 153. Sohl G, Willecke K. An update on connexin genes and their nomenclature in mouse and man. Cell Communication & Adhesion. 2003;10(4-6):173-180
  154. 154. Wong CW, Christen T, Roth I, Chadjichristos CE, Derouette JP, Foglia BF, et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Nature Medicine. 2006;12(8):950-954
  155. 155. Chadjichristos CE, Scheckenbach KE, van Veen TA, Richani Sarieddine MZ, de Wit C, Yang Z, et al. Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion. Circulation. 2010;121(1):123-131
  156. 156. Azzam EI, de Toledo SM, Little JB. Expression of CONNEXIN43 is highly sensitive to ionizing radiation and other environmental stresses. Cancer Research. 2003;63(21):7128-7135
  157. 157. Kwak BR, Mulhaupt F, Veillard N, Gros DB, Mach F. Altered pattern of vascular connexin expression in atherosclerotic plaques. Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22(2):225-230
  158. 158. Pfenniger A, Derouette JP, Verma V, Lin X, Foglia B, Coombs W, et al. Gap junction protein Cx37 interacts with endothelial nitric oxide synthase in endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30(4):827-834
  159. 159. Yuan D, Sun G, Zhang R, Luo C, Ge M, Luo G, et al. Connexin 43 expressed in endothelial cells modulates monocyteendothelial adhesion by regulating cell adhesion proteins. Molecular Medicine Reports. 2015;12(5):7146-7152
  160. 160. Glover D, Little JB, Lavin MF, Gueven N. Low dose ionizing radiation-induced activation of connexin 43 expression. International Journal of Radiation Biology. 2003;79(12):955-964
  161. 161. Banaz-Yasar F, Tischka R, Iliakis G, Winterhager E, Gellhaus A. Cell line specific modulation of connexin43 expression after exposure to ionizing radiation. Cell Communication & Adhesion. 2005;12(5-6):249-259

Written By

Bjorn Baselet, Raghda Ramadan, Abderrafi Mohammed Benotmane, Pierre Sonveaux, Sarah Baatout and An Aerts

Submitted: May 8th, 2017 Reviewed: November 10th, 2017 Published: December 20th, 2017