(Hypertension. 1996;28:488-493.)
© 1996 American Heart Association, Inc.
Articles |
Nitrotyrosine Residues in Placenta
Evidence of Peroxynitrite Formation and Action
the Departments of Obstetrics and Gynecology (L.M., R.B.R., A.L.W.E., D.E.B.), Pediatrics (L.M.), and Molecular and Cellular Physiology (L.M.), University of Cincinnati (Ohio) College of Medicine, and Department of Obstetrics and Gynecology, University of Glasgow (UK), Royal Infirmary (I.G., F.L.).
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Abstract |
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The interaction of nitric oxide and superoxide produces peroxynitrite anion, a strong, long-lived oxidant with pronounced deleterious effects that may cause vascular damage. The formation and action of peroxynitrite can be detected by immunohistochemical localization of nitrotyrosine residues. We compared the presence and localization of nitrotyrosine and of the endothelial isoform of nitric oxide synthase in placental villous tissue from normotensive pregnancies (n=5) with pregnancies complicated by preeclampsia (n=5), intrauterine growth restriction (n=5), and preeclampsia plus intrauterine growth restriction (n=4), conditions characterized by increases in fetoplacental vascular resistance, fetal platelet consumption, and fetal morbidity and mortality. In all tissues, absent or faint nitrotyrosine immunostaining but prominent nitric oxide synthase immunostaining were found in syncytiotrophoblast. In tissues from normotensive pregnancies, faint nitrotyrosine immunostaining was found in vascular endothelium, and nitric oxide synthase was present in stem villous endothelium but not in the terminal villous capillary endothelium. In contrast, in preeclampsia and/or intrauterine growth restriction, moderate to intense nitrotyrosine immunostaining was seen in villous vascular endothelium, and immunostaining was also seen in surrounding vascular smooth muscle and villous stroma. The intensity of nitrotyrosine immunostaining in preeclampsia (with or without intrauterine growth restriction) was significantly greater than that of controls. Intense nitric oxide synthase staining was seen in endothelium of stem villous vessels and the small muscular arteries of the terminal villous region in these tissues and may be an adaptive response to the increased resistance. The presence of nitrotyrosine residues, particularly in the endothelium, may indicate the formation and action of peroxynitrite, resulting in vascular damage that contributes to the increased placental vascular resistance.
Key Words: placenta • nitric oxide • preeclampsia • fetal growth restriction • immunohistochemistry
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Introduction |
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The NO radical is recognized as a potent bioregulator exhibiting a diverse array of physiological and pathophysiological effects. In the human fetoplacental circulation, NO appears to maintain low vascular resistance and attenuates the action of vasoconstrictors in vitro.1 2 The endothelial or type III isoform of NOS (eNOS) has been characterized in the human placenta and immunohistochemically localized to the endothelium of umbilical cord, chorionic plate, and stem villous vessels, but it is absent from the endothelium of the terminal villous capillary network.3 eNOS is also localized in the syncytiotrophoblast, where NO may act to prevent platelet and neutrophil adhesion to the trophoblast surface and aggregation in the intervillous space, thus ensuring adequate blood flow to the placenta.
Approximately 7% of pregnancies are complicated by preeclampsia, a maternal condition characterized by maternal hypertension, proteinuria, and/or edema and which is associated with an increased incidence of IUGR. Preeclampsia is a major cause of perinatal and maternal morbidity and mortality.4 Infants who survive IUGR have an increased risk of physical and mental handicap and an increased risk of mortality from cardiovascular disease in later life.5 Preeclampsia is also described as a state of endothelial "dysfunction."6 In pregnancies complicated by preeclampsia and/or IUGR, abnormalities in fetoplacental blood flow, which are characterized by abnormal umbilical blood flow velocity waveforms, indicative of increased placental resistance, are seen. Interestingly, in preeclampsia, measurements of plasma nitrate concentrations, which are an index of NO synthesis, show either no change7 8 or a slight reduction9 of maternal NO synthesis. Surprisingly, however, a significant increase in fetal nitrate concentrations has been reported in preeclampsia.8 We have previously examined the distribution and intensity of immunostaining for eNOS in placentas complicated by preeclampsia, IUGR, or preeclampsia plus IUGR compared with normotensive controls. A significantly more basal distribution of eNOS within the syncytiotrophoblast of placentas complicated by preeclampsia or preeclampsia plus IUGR was seen10 that was not apparent in placentas complicated by IUGR alone. When examining the fetoplacental vasculature from these pregnancies, we noticed that a feature of all the pathological specimens (preeclampsia and/or IUGR) was the increased intensity of staining for eNOS in stem villous vessels and the appearance of eNOS staining in the endothelium of small vessels with narrow lumens and muscular walls in the terminal regions of the villous tree.10 The presence of such vessels is consistent with the increased placental resistance seen, and the increased eNOS expression in these vessels is associated with increased concentrations of nitrate measured in fetal blood from preeclamptic pregnancies8 and may therefore be an adaptive response to the altered placental vascular anatomy.
The relative activity of NO in the placenta depends on its site and rate of synthesis, its half-life, and its site of action. The interaction of NO with superoxide anion causes its inactivation.11 Conversely, the activity of NO is prolonged in the presence of superoxide dismutase, which removes superoxide. However, the interaction of NO and superoxide produces the peroxynitrite anion, a strong, relatively long-lived oxidant, which is cytotoxic because it inhibits mitochondrial electron transport,12 oxidizes sulfhydryl groups in proteins, initiates lipid peroxidation without a requirement for transition metals,13 and nitrates aromatic amino acids such as tyrosine,14 thus affecting signal transduction pathways. Hence, the metabolism of a "beneficial" molecule, NO, can potentially give rise to a molecule, peroxynitrite, with profound deleterious effects. Peroxynitrite has also been shown to be a vasodilator of the dog aorta15 and the isolated perfused rat heart16 and to aggregate human platelets.17 In this latter study, peroxynitrite administration also resulted in tachyphylaxis and inhibited the activity of other vasodilators, thus showing that although perhaps initially having a beneficial vasodilator effect, peroxynitrite can also induce a vascular dysfunction.
We have previously shown that in the perfused human placental cotyledon, infusion of superoxide dismutase was able to vasodilate the preconstricted vasculature,18 consistent with its ability to prolong the half-life of endogenously synthesized NO. Paradoxically, when we generated superoxide in the preconstricted cotyledon by coinfusion of purine and xanthine oxidase, a significant vasodilation was also observed.19 This vasodilator effect of superoxide was abolished by infusion of an NOS inhibitor, leading us to speculate that the interaction of NO and superoxide in the perfused placental cotyledon produced a vasodilator, possibly peroxynitrite.19 The production of peroxynitrite can be indirectly localized by the presence of nitrotyrosine residues. The presence of nitrotyrosine residues has been demonstrated in human atherosclerotic plaques,20 where it is taken to indicate the cytotoxic effects of peroxynitrite on endothelial cells, and in lung sections of humans and animals with acute lung injury.21
Our objective in this study was to use immunohistochemical techniques to localize nitrotyrosine residues in the human placenta as an index of peroxynitrite synthesis and also to determine whether expression of nitrotyrosine residues was altered in placentas from pregnancies complicated by preeclampsia and/or IUGR, conditions associated with endothelial dysfunction and altered vascular function. Consecutive sections were immunostained for eNOS for determination of its relative expression in these sections and its relationship to the appearance of nitrotyrosine.
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Methods |
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We used immunohistochemistry for visualization of nitrotyrosine and eNOS in placental tissue. Villous tissue samples were taken from placentas of normotensive control subjects (n=5) and subjects with preeclampsia (n=5), IUGR (n=5), or preeclampsia plus IUGR (n=4), snap-frozen in liquid nitrogen, and stored at -70°C. Preeclampsia was defined as a blood pressure of 140/90 mm Hg on at least two occasions at least 6 hours apart occurring after the 20th week of gestation accompanied by proteinuria (>300 mg/L in a 24-hour urine collection), edema, or both. IUGR was defined as a fetal weight less than the fifth percentile using standardized Scottish birth weight tables. At the time of sampling, none of the subjects had any clinical indication of infection. The study was approved by the ethics committee of the Glasgow Royal Infirmary and the Institutional Review Board, University of Cincinnati Medical Center.
Serial sections from the four groups of placentas were cut at 7 µm and stored at -70°C before staining. Sections were immunostained for nitrotyrosine residues (indicative of peroxynitrite activity) with a monoclonal anti-nitrotyrosine antibody (Upstate Biotechnology, Inc) at a dilution of 1:250 using the Vectastain Elite ABC staining method (Vector Laboratories). Two pairs of slides from each tissue sample were thawed and dried at room temperature before staining followed by rehydration in phosphate-buffered saline. Hydrogen peroxide, used to quench endogenous peroxidase activity, was diluted to 0.88 mol/L in water, and the tissue sections were incubated for 3 minutes. The Vectastain Elite ABC staining protocol was followed except for the following modifications: Primary antibody was diluted in blocking serum. Half of the diluted nitrotyrosine antibody was preabsorbed with a 10-fold excess of 3-nitro-L-tyrosine antigen, which served as the control. One slide of each pair was incubated with diluted antibody and the other with preabsorbed antibody (control). After the incubation with the normal (blocking) serum, the incubation with the primary antibody and preabsorbed antibody was performed overnight at 4°C. All other procedures were performed according to the ABC Elite protocol. Aminoethylcarbazole, which forms a red precipitate, was used as the peroxidase substrate and allowed to develop for 35 minutes. Slides were then counterstained in hematoxylin and mounted in 1:9 phosphate-buffered saline/glycerol. Consecutive sections of each tissue sample were concurrently immunostained for eNOS as described in our previous studies.3 10 Omission of the primary antibody served as the negative control for eNOS immunostaining. Each section was examined by three investigators who were blinded to the identity of the tissue. The section was scored for intensity (absent, faint, moderate, or intense [0 through 3]) of immunostaining in syncytiotrophoblast, vascular endothelium, and surrounding smooth muscle or mesenchyme. The modal value for each section was then determined and the mean value for each group of subjects calculated. Subject groups were compared by Kruskal-Wallis ANOVA, with the significance of differences between groups determined with the Wilcoxon rank sum test for nonparametric data.
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Results |
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Subject characteristics are shown in Table 1
. The gestational age of all subjects in the pathological groups was less than 37 weeks; therefore, by necessity, the control group was preterm and matched to the group with the earliest gestation (preeclampsia plus IUGR). The indications for delivery in the control group were elective delivery for a previous history of preterm abruption (n=1), emergency cesarean section for ruptured membranes (n=1), placental previa (n=1), and abruption hemorrhage (n=2). The gestational age in the subjects with IUGR alone or preeclampsia alone was significantly greater than that of the control group. However, we have not seen an increase in eNOS expression with differing gestational ages in the placental vasculature across the range of gestational ages included in the present study. The fetal and placental weights were significantly less than control values in the preeclampsia plus IUGR group. Immunostaining for eNOS and nitrotyrosine residues in villous tissue from a normotensive pregnancy is shown in Fig 1. In the absence of primary antibody (Fig 1D) or in incubations in which nitrotyrosine antibody had been preabsorbed with nitrotyrosine antigen (Fig 1C), no peroxidase immunostaining was evident. In agreement with our previous observations, eNOS immunostaining was seen predominantly throughout the syncytiotrophoblast in villous tissue of the normotensive control (Fig 1A). No eNOS immunostaining was evident in the endothelium of terminal villous vessels. When nitrotyrosine immunostaining was examined in a consecutive section of the same tissue (Fig 1B), essentially no peroxidase staining was seen in vascular endothelium and only faint diffuse staining was seen in the perivascular region, suggesting that little nitrotyrosine was present in this tissue. Examination of tissues from five normotensive control subjects (Table 2) showed that syncytiotrophoblast nitrotyrosine immunostaining was mostly faint (three tissues) or moderate (two tissues).
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Sections of villous tissue from a subject with preeclampsia are shown in Fig 2. Again, with no primary antibody or with preabsorbed nitrotyrosine antibody, no peroxidase staining was evident (Fig 2C). Examination for eNOS immunostaining (Fig 2A) showed immunostaining present in syncytiotrophoblast, with an obvious increase in intensity along the basal border. eNOS immunostaining was also evident in the endothelial cells of villous vessels in this tissue. In contrast, nitrotyrosine immunostaining ranging from moderate to intense (Table 2
) was also present in the endothelium of these vessels (example in the consecutive section, Fig 2B) but was only faint or absent in the syncytiotrophoblast layer (Table 2).
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Examination of villous tissue from a pregnancy complicated by IUGR showed a similar picture. In the absence of primary antibody or with preabsorbed nitrotyrosine antibody, no peroxidase staining was evident (Fig 3C). The narrow villous vessels displayed strong eNOS immunostaining in their endothelium, but immunostaining of the syncytiotrophoblast (Fig 3A) was no different from that in the normotensive pregnancy. Examination of the consecutive section immunostained for nitrotyrosine revealed intense staining of the villous vascular endothelium, together with diffuse immunostaining of the surrounding vascular smooth muscle (Fig 3B), whereas immunostaining was very faint or absent in syncytiotrophoblast in most samples. Examination of the intensity of nitrotyrosine immunostaining in the villous endothelium of this group (Table 2) showed that the intensity ranged from faint (n=1) to intense (n=3). However, staining was seen in both endothelium and underlying smooth muscle and stroma (Fig 3B).
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A higher-power view of a stem villous vessel from a pregnancy complicated by preeclampsia plus IUGR showed that eNOS immunostaining was confined to the endothelial cells in the vessel (Fig 4A). In contrast, nitrotyrosine immunostaining was found in the vascular endothelium (Fig 4B) but also diffusely throughout the smooth muscle and mesenchyme surrounding the vascular endothelium (Fig 4B). Table 2 shows that in these tissues, a high overall intensity of nitrotyrosine staining (moderate [n=3] to intense [n=1]) was found in the vascular endothelium.
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Statistical analysis of data on the intensity of immunostaining (Table 2) showed no differences between groups in the intensity of staining in syncytiotrophoblast. In contrast, a significant difference in villous endothelial immunostaining between control, IUGR, and preeclampsia (with or without IUGR) was apparent (P=.048, Kruskal-Wallis). Post hoc testing (Wilcoxon rank sum) revealed that the intensity was significantly greater than control (P=.014) in the sections from subjects with preeclampsia (with or without IUGR). Although moderate to intense staining was seen in the vascular endothelium of the IUGR group (Table 2), this was not significantly different from control (P=.077).
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Discussion |
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Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality,4 yet its causes are poorly understood. There is, however, increasing evidence for endothelial cell injury or dysfunction in preeclampsia,6 perhaps resulting in poor perfusion of many organs, including the placenta. Although preeclampsia is primarily thought of as a maternal condition, there is substantial fetoplacental pathology and associated fetal morbidity and mortality. Whether these fetal effects arise from the same insult affecting the maternal vasculature or as a consequence of the maternal uteroplacental pathology remains to be established. In both preeclampsia and IUGR, abnormal Doppler blood flow velocity waveforms are seen in the umbilical artery, indicating increased resistance to placental blood flow.22 Changes in placental vascular architecture, including a reduced number of villous vessels, narrower lumens, and increased thickness of smooth muscle walls, have been described in preeclampsia and IUGR.23
This study confirms our previous findings10 that preeclampsia and IUGR are associated with an apparent increased expression of NOS in the endothelium of the villous vessels, perhaps as an adaptive response to increased placental resistance, whereby increased flow or shear stress over the endothelial cells in these narrower vessels upregulates eNOS expression. Using a monoclonal antibody, we were able to visualize nitrotyrosine residues in sections of villous tissue from both normal and pathological pregnancies. Nitrotyrosine is not formed by the action of hydrogen peroxide, superoxide, or hydroxyl radical24 ; therefore, its appearance is presumably indicative of the action of peroxynitrite in the vascular endothelial cells of the placenta. Immunostaining was not present in the absence of primary antibody and was abolished by preabsorption of the primary antibody with the nitrotyrosine antigen, demonstrating specificity of nitrotyrosine immunostaining. Immunostaining in vascular endothelium was generally faint in sections taken from uncomplicated normotensive pregnancies. In the pathological pregnancies, the intensity of villous vascular endothelial nitrotyrosine immunostaining was not significantly greater than in controls in these tissues from subjects with IUGR alone but was significantly greater than controls in those with preeclampsia either with or without IUGR. The variability among tissues of the same group may reflect intersubject variations or differences in the extent of vascular damage that has occurred, in keeping with the range of severity of clinical presentation and the fetal consequences seen.4 Unlike the eNOS immunostaining, which was confined to the vascular endothelium, nitrotyrosine immunostaining, although predominantly seen in endothelium, was also observed in the surrounding vascular smooth muscle and villous stroma, but we were not able with this number of samples to show any differences in smooth muscle or stromal staining among the groups (data not shown). This suggests either that peroxynitrite is locally generated in the smooth muscle or stroma or that peroxynitrite produced in the vascular endothelium may diffuse into the underlying smooth muscle and stroma. The diffusion distance of peroxynitrite (5 µm) is 10-fold greater than that of superoxide (0.4 µm) but less than that of NO itself (100 µm).25 Peroxynitrite may therefore diffuse up to several cell diameters in distance, attacking cell membrane lipids and protein sulfhydryls and hence altering cell function. Therefore, increased nitrotyrosine formation in pathological pregnancies may not simply be reflected by an increased intensity of immunostaining but by a greater area of immunostaining.
Abnormal endothelium-dependent vascular relaxation is seen in numerous disease processes, including hypercholesterolemia, atherosclerosis, ischemia/reperfusion injury, hypertension, diabetes, and preeclampsia.6 The presence of nitrotyrosine residues in the villous endothelium of these pathological pregnancies may be an indication that vascular damage is occurring that contributes to the increased placental vascular resistance seen. Peroxynitrite formation is the result of the interaction of NO and superoxide. Clearly, the villous vascular endothelium produces NO, and eNOS expression in these cells increases in pathological pregnancies.10 Increased concentrations of nitrate, a breakdown product of NO, are found in umbilical plasma of such pregnancies,8 suggesting that this increased eNOS expression leads to greater NO synthesis. Superoxide is produced intracellularly by mitochondrial electron transfer processes and also by the enzymes NADPH oxidase and xanthine oxidase. Xanthine oxidase can be released by damaged tissues and bind to the endothelium, thus providing an extracellular source of superoxide. However, the action of superoxide per se is limited by its low lipid solubility and limited membrane transport. It remains to be determined whether superoxide production is increased in the villous vessels in pathological pregnancies and interacts with the NO to give peroxynitrite. However, maternal neutrophil superoxide release is increased by a serum factor in preeclamptic mothers,26 suggesting that increased superoxide formation may be occurring. Tissues such as macrophages and epithelial, endothelial, and interstitial cells may be induced to simultaneously produce both NO and superoxide to form peroxynitrite in a concentrated and localized manner by inflammatory stimuli, sepsis, and ischemia/reperfusion. Hence, the appearance of nitrotyrosine residues may reflect such a component in these placental pathologies. As peroxynitrite formation is proportional to the product of NO and superoxide concentrations, small increases in NO and superoxide concentrations will lead to large increases in peroxynitrite.25 27 In addition to interaction with superoxide to produce nitrotyrosine, increased NO synthesis may serve a protective function by direct interaction of NO with intermediates occurring during lipid peroxidation, hence inhibiting lipid peroxidation reactions.28 The relative concentrations of individual reactive species are central to the pro-oxidant versus antioxidant outcome.
The relatively weak staining for nitrotyrosine in syncytiotrophoblast of the pathological pregnancies contrasts strongly with the intense staining seen in the villous vascular endothelium of the same tissues. Syncytiotrophoblast expresses eNOS and thus presumably synthesizes NO. Either relatively little superoxide is generated in the region of syncytiotrophoblast, hence providing little substrate to make peroxynitrite, or there is an abundance of superoxide dismutase present in syncytiotrophoblast that efficiently scavenges superoxide. However, the rate constant for superoxide removal by superoxide dismutase (2x109 mol/L per second) is less than that for the interaction of NO and superoxide (6.7x109 mol/L per second),27 suggesting that as superoxide production increases, peroxynitrite formation would be favored. In preliminary immunohistochemical staining for both copper/zinc and manganese isoforms of superoxide dismutase, we find both forms to be present in syncytiotrophoblast, but expression is relatively weak.
The deleterious effects of free radicals have been studied and established in many systems. NO converts superoxide, a mild reductant, to peroxynitrite, a potent and long-lived oxidant. In the process, any beneficial effect of NO is lost and replaced by the deleterious effect of peroxynitrite. Haddad et al24 have shown that the extent of nitrotyrosine formation in surfactant protein A caused by peroxynitrite treatment correlated with the degree of functional injury of this protein. Peroxynitrite may be the initial oxidant involved in the development of atherosclerosis, in which extensive nitrotyrosine immunoreactivity is seen in foamy macrophages and the endothelium around atheroma.20 Interestingly, in the hypercholesterolemic and atherosclerotic rabbit aorta, NO synthesis is increased but NO degradation is accelerated because of increased endothelial superoxide production,29 probably via xanthine oxidase activation. Such data highlight the importance of the relative production rates of NO and superoxide in the determination of vascular responses in diseased vessels but also the potential for NO and superoxide to form toxic species such as peroxynitrite. In these pathological pregnancies, peroxynitrite formation may be similarly increased in the fetoplacental vasculature and result in vascular damage and the increased platelet aggregation seen in this circulation.30 Recently, Akar et al31 have shown that basal NO release is increased from umbilical vessels of preeclamptic pregnancies but that NO release from arteries is reduced in response to certain stimuli, perhaps suggesting endothelial dysfunction. We have shown that both eNOS expression10 and nitrate production8 are increased in the fetoplacental vasculature in preeclampsia and/or IUGR, implying that NO synthesis is increased locally. Metabolism of this NO may then be increased by interaction with superoxide.
A cause-and-effect relationship remains to be established among peroxynitrite, nitrotyrosine, and vascular damage in the villous vasculature of these pathological pregnancies, which characteristically have increased placental vascular resistance. An equally intriguing question concerns the absence or presence of nitrotyrosine residues in the maternal vasculature in preeclampsia, a condition described as a state of endothelial dysfunction.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Institutes of Health grant HL-47860 (L.M.) and by a grant from Action Research (I.A.G. and F.L.).
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Footnotes |
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Reprint requests to L. Myatt, PhD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, PO Box 670526, Cincinnati, OH 45267-0526. E-mail leslie.myatt @uc.edu.
Received November 6, 1995;
first decision December 11, 1995; first decision April 18, 1996;
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References |
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H. H. Kay, S. Tsoi, K. Grindle, and R. R. Magness Markers of Oxidative Stress in Placental Villi Exposed to Ethanol Reproductive Sciences, February 1, 2006; 13(2): 118 - 121. [Abstract] [PDF]
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R. E. Gandley, V. A. Tyurin, W. Huang, A. Arroyo, A. Daftary, G. Harger, J. Jiang, B. Pitt, R. N. Taylor, C. A. Hubel, et al. S-Nitrosoalbumin-Mediated Relaxation Is Enhanced by Ascorbate and Copper: Effects in Pregnancy and Preeclampsia Plasma Hypertension, January 1, 2005; 45(1): 21 - 27. [Abstract] [Full Text] [PDF]
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M. Noris, M. Todeschini, P. Cassis, F. Pasta, A. Cappellini, S. Bonazzola, D. Macconi, R. Maucci, F. Porrati, A. Benigni, et al. L-Arginine Depletion in Preeclampsia Orients Nitric Oxide Synthase Toward Oxidant Species Hypertension, March 1, 2004; 43(3): 614 - 622. [Abstract] [Full Text] [PDF]
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 P. F. Speake, J. D. Glazier, P. T.-Y. Ayuk, M. Reade, C. P. Sibley, and S. W. D'Souza L-Arginine Transport across the Basal Plasma Membrane of the Syncytiotrophoblast of the Human Placenta from Normal and Preeclamptic Pregnancies J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4287 - 4292. [Abstract] [Full Text] [PDF]
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 R. Dechend, C. Viedt, D. N. Muller, B. Ugele, R. P. Brandes, G. Wallukat, J.-K. Park, J. Janke, P. Barta, J. Theuer, et al. AT1 Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase Circulation, April 1, 2003; 107(12): 1632 - 1639. [Abstract] [Full Text] [PDF]
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 S. Mateev, A. H. Sillau, R. Mouser, R. E. McCullough, M. M. White, D. A. Young, and L. G. Moore Chronic hypoxia opposes pregnancy-induced increase in uterine artery vasodilator response to flow Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H820 - H829. [Abstract] [Full Text] [PDF]
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J. M. Roberts, G. Pearson, J. Cutler, and M. Lindheimer Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy Hypertension, March 1, 2003; 41(3): 437 - 445. [Abstract] [Full Text] [PDF]
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 T.-H. Hung, J. N. Skepper, D. S. Charnock-Jones, and G. J. Burton Hypoxia-Reoxygenation: A Potent Inducer of Apoptotic Changes in the Human Placenta and Possible Etiological Factor in Preeclampsia Circ. Res., June 28, 2002; 90(12): 1274 - 1281. [Abstract] [Full Text] [PDF]
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 A. Ceriello, L. Quagliaro, M. D'Amico, C. Di Filippo, R. Marfella, F. Nappo, L. Berrino, F. Rossi, and D. Giugliano Acute Hyperglycemia Induces Nitrotyrosine Formation and Apoptosis in Perfused Heart From Rat Diabetes, April 1, 2002; 51(4): 1076 - 1082. [Abstract] [Full Text] [PDF]
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 L. Sanchez de Miguel, M. a M. Arriero, J. Farre, P. Jimenez, A. Garcia-Mendez, T. de Frutos, A. Jimenez, R. Garcia, F. Cabestrero, J. Gomez, et al. Nitric oxide production by neutrophils obtained from patients during acute coronary syndromes: expression of the nitric oxide synthase isoforms J. Am. Coll. Cardiol., March 6, 2002; 39(5): 818 - 825. [Abstract] [Full Text] [PDF]
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 T.-H. Hung, J. N. Skepper, and G. J. Burton In Vitro Ischemia-Reperfusion Injury in Term Human Placenta as a Model for Oxidative Stress in Pathological Pregnancies Am. J. Pathol., September 1, 2001; 159(3): 1031 - 1043. [Abstract] [Full Text] [PDF]
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 J. C. Chambers, L. Fusi, I. S. Malik, D. O. Haskard, M. De Swiet, and J. S. Kooner Association of Maternal Endothelial Dysfunction With Preeclampsia JAMA, March 28, 2001; 285(12): 1607 - 1612. [Abstract] [Full Text] [PDF]
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 M. Noris, M. Todeschini, S. Zappella, S. Bonazzola, C. Zoja, D. Corna, F. Gaspari, F. Marchetti, S. Aiello, and G. Remuzzi 17beta -Estradiol corrects hemostasis in uremic rats by limiting vascular expression of nitric oxide synthases Am J Physiol Renal Physiol, October 1, 2000; 279(4): F626 - F635. [Abstract] [Full Text] [PDF]
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W. Kossenjans, A. Eis, R. Sahay, D. Brockman, and L. Myatt Role of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1311 - H1319. [Abstract] [Full Text] [PDF]
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R. Figueroa, E. Martinez, R. P. Fayngersh, N. Tejani, K. M. Mohazzab-H., and M. S. Wolin Alterations in relaxation to lactate and H2O2 in human placental vessels from gestational diabetic pregnancies Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H706 - H713. [Abstract] [Full Text] [PDF]
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A. Many, C. A. Hubel, S. J. Fisher, J. M. Roberts, and Y. Zhou Invasive Cytotrophoblasts Manifest Evidence of Oxidative Stress in Preeclampsia Am. J. Pathol., January 1, 2000; 156(1): 321 - 331. [Abstract] [Full Text] [PDF]
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 C. A. Hubel Oxidative Stress in the Pathogenesis of Preeclampsia Experimental Biology and Medicine, December 1, 1999; 222(3): 222 - 235. [Abstract] [Full Text]
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 M. J. S. Miller and M. Sandoval III. A molecular prelude to intestinal inflammation Am J Physiol Gastrointest Liver Physiol, April 1, 1999; 276(4): G795 - G799. [Abstract] [Full Text] [PDF]
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A. M. Roggensack, Y. Zhang, and S. T. Davidge Evidence for Peroxynitrite Formation in the Vasculature of Women With Preeclampsia Hypertension, January 1, 1999; 33(1): 83 - 89. [Abstract] [Full Text] [PDF]
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 B. A. Banks, H. Ischiropoulos, M. McClelland, P. L. Ballard, and R. A. Ballard Plasma 3-Nitrotyrosine Is Elevated in Premature Infants Who Develop Bronchopulmonary Dysplasia Pediatrics, May 1, 1998; 101(5): 870 - 874. [Abstract] [Full Text] [PDF]
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 L. Myatt, A. L.W. Eis, D. E. Brockman, W. Kossenjans, I. A. Greer, and F. Lyall Differential Localization of Superoxide Dismutase Isoforms in Placental Villous Tissue of Normotensive, Pre-eclamptic, and Intrauterine Growth-restricted Pregnancies J. Histochem. Cytochem., October 1, 1997; 45(10): 1433 - 1438. [Abstract] [Full Text] [PDF]
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 C.-L. M. Cooke and S. T. Davidge Peroxynitrite increases iNOS through NF-kappa B and decreases prostacyclin synthase in endothelial cells Am J Physiol Cell Physiol, February 1, 2002; 282(2): C395 - C402. [Abstract] [Full Text] [PDF]
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