MinireviewThe vascular endothelium as a target of cadmium toxicity
Introduction
The importance of Cd as an industrial and environmental pollutant has become increasingly apparent in recent years; it currently ranks 7th on the United States Environmental Protection Agency's priority list of hazardous substances (ATSDR, 2003). During the past century, Cd and its compounds have been used extensively in the smelting and electroplating industries, and in the manufacturing of batteries, dyes, paints and plastics. Large amounts of Cd have also been released into the environment through the burning of refuse materials that contain Cd and through the use of Cd-contaminated sludge and phosphate salts as fertilizers (ATSDR, 1999, Elinder, 1986, Page et al., 1986). Tobacco contains significant amounts of Cd and smoking is one of the primary sources of Cd exposure in the general population (Ellis et al., 1979, Ostergaard, 1977, Satarug and Moore, 2004, Scherer and Barkemeyer, 1983).
Exposure to Cd can result in a variety of adverse effects in humans and animals. Depending on the dose, route and duration of exposure, Cd can damage various organs including the lung, liver, kidney, bone, testis and placenta [for reviews see (Bernard and Lauwerys, 1984, Elinder and Kjellstrom, 1986, Fassett, 1975, Jarup et al., 1998)]. In addition, Cd has been shown to have teratogenic and carcinogenic activites (Degraeve, 1981, IARC, 1993, Mahalik et al., 1995, Pearson and Prozialeck, 2001, Waalkes et al., 1992). With regard to the cardiovascular system, exposure to Cd has been associated with a wide variety of cardiovascular pathologies including hemorrhagic injury (Nolan and Shaikh, 1986), atherosclerosis (Navas-Acien et al., 2005), hypertension (Tomera et al., 1994, Varoni et al., 2003) and cardiomyopathy (Jamall and Smith, 1985, Kopp et al., 1978, Kopp, 1986).
Even though Cd represents a major environmental health problem, the specific mechanisms by which it produces its adverse effects have yet to be fully elucidated. Studies to address this issue have shown that Cd can cause a variety of biochemical, metabolic and cytotoxic effects [for reviews see (Elinder and Kjellstrom, 1986, Fassett, 1975, Prozialeck, 2000)]. However, in most cases, the relationships between these effects and the specific toxic actions of Cd in various target organs have not been firmly established. In this context, the growing volume of evidence suggesting that the vascular endothelium may be an important target of Cd toxicity in various organs could be especially significant.
The vascular endothelium consists of specialized epithelial-like cells that line the lumenal surface of all blood vessels and form the capillary networks that mediate the delivery of oxygen and nutrients to tissues of the body. In addition, the vascular endothelium plays a key role in a wide variety of physiologic and pathologic processes such as blood pressure regulation (Bauersachs and Schafer, 2004, Endemann and Schiffrin, 2004, Triggle et al., 2003), angiogenesis (Aird, 2004), atherosclerosis (Davignon and Ganz, 2004, Houtman, 1993), inflammation (Galley and Webster, 2004), tumor formation and tumor metastasis (Pearson and Prozialeck, 2001).
The suggestion that the vascular endothelium may be an important target of Cd toxicity stemmed from studies during the 1950's and 1960's showing that acute exposure to Cd in many scrotal-bearing mammals resulted in edema and hemorrhaging in the testis (Gunn et al., 1961, Hoey, 1966, Kar and Das, 1960, Parizek and Zahor, 1956). Later studies showed that Cd caused the breakdown of the junctions between the endothelial cells of the capillaries and venules, resulting in an increase in vascular permeability (Sacerdote and Cavicchia, 1983), followed by edema, hemorrhage and testicular necrosis (Aoki and Hoffer, 1978, Fende and Niewenhuis, 1977, Gabbiani et al., 1974, Gunn and Gould, 1970). Additional studies showed that similar Cd-induced alterations in endothelial integrity could also occur in other tissues including: the lung (Bus et al., 1978), uterus (Peereboom-Stegeman and Jongstra-Spaapen, 1979), nervous system (Gabbiani et al., 1974), placenta (Di Sant'Agnese et al., 1983, Levin et al., 1981, Parizek, 1964) and liver (Quaife et al., 1984). In a seminal review published in this journal in 1986, Nolan and Shaikh suggested that with acute exposure to relatively high doses of Cd, the vascular endothelium may be one of the primary targets of toxicity. They suggested that the interaction of Cd with the vascular endothelium resulted in a loss of barrier integrity, and an increase in endothelial permeability which, in turn, could result in edema, hemorrhage, hypoxia, inflammation and various types of secondary injury in the specific target organs.
Studies conducted over the past 20 years have yielded further evidence that Cd can affect the vascular endothelium in a variety of ways, and they have provided important insights into the mechanisms underlying these effects. The purpose of this review is to summarize the results of these more recent studies and to discuss the implications of these findings with regard to the mechanisms of Cd toxicity in specific organ systems.
Section snippets
Routes and patterns of exposure to Cd
In considering the effects of Cd on the vascular endothelium, it is first necessary to consider the various ways in which humans and animals are exposed to Cd and to be aware of the different forms of Cd that exist in vivo. In humans, exposure usually results from the inhalation of airborne Cd (either in the workplace or through cigarette smoke) or from the ingestion of Cd-contaminated food or water (Bernard and Lauwerys, 1984, Elinder, 1986, Foulkes, 1986, Jarup et al., 1998). Each of these
Acute cytotoxic effects
Early morphologic studies had shown that while the latter stages of Cd-induced hemorrhagic injury in various tissues were sometimes associated with the death and sloughing of the vascular endothelial cells, the early stages of injury appeared to be associated with more subtle, sublethal changes in the structural organization of the cells, particularly at the cell–cell contacts (Fende and Niewenhuis, 1977, Gabbiani et al., 1974, Gunn and Gould, 1970, Sacerdote and Cavicchia, 1983). The
Cd-induced capillary leakage, hemorrhagic injury and inflammation
As was noted previously, acute exposure to moderate–high doses of Cd can cause hemorrhagic injury in organs such as the testis, uterus, placenta, lung and liver. In each of these organs, the initial effect of Cd involves an increase in microvascular permeability that results in the leakage of fluid, protein, and blood cells from the capillaries into the interstitial space. While the mechanisms underlying this effect are not known, there is evidence to suggest that this increase in macrovascular
Concluding remarks
The studies summarized in this review indicate that Cd, at toxicologically relevant concentrations, can influence endothelial function in several ways that could have important implications regarding the mechanisms of Cd toxicity in a variety of organ systems. At the molecular level, the effects of Cd on the endothelium result from actions at multiple sites including cell adhesion molecules, metal ion transporters and protein kinase signaling pathways. Obviously, identifying the mechanisms and
Acknowledgements
Portions of this work were supported by grant R01 ES006478 from the National Institute of Environmental Health Sciences to W.C.P. and NIH Grant R15 AR050985 as well as an Arthritis Foundation Investigator award to J.M.W. The authors gratefully acknowledge the excellent technical assistance of Peter C. Lamar, Karolina Klosowska and Marissa Leone and thank Victoria Sears and Mr. Lamar for their help in preparing the manuscript.
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