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Received: 2012.11.12Accepted: 2012.01.25

Published: 2013.06.05

3313 1 3 43

A comparison of maternal serum levels ofendothelial nitric oxide synthase, asymmetric

dimethylarginine, and homocysteine in normaland preeclamptic pregnancies ABCDEFG 1 Marzena Laskowska CDEF 2 Katarzyna Laskowska CEF 3 Mahfoz Terbosh BCEG 1 Jan Oleszczuk

Corresponding Author: Marzena Laskowska, e-mail:[email protected] Source of support: Departmental sources

Background: The aim of this study was to determine the maternal serum concentrations of eNOS, ADMA, and homocyste-ine in preeclamptic pregnancies.

Material/Methods: The study was carried out on 62 patients with pregnancy complicated by early onset and 53 patients with lateonset preeclampsia. The control group consisted of 65 healthy normotensive pregnant patients. The serumeNOS, ADMA and homocysteine concentrations were determined using ELISA assays.

Results: Our study revealed elevated levels of homocysteine and ADMA in the serum of women with preeclampsia.The highest levels were observed in patients with early onset preeclampsia, but the differences between bothgroups of preeclamptic patients with early and late onset of preeclampsia were not statistically signicant.Both groups of preeclamptic women had slightly lower levels of maternal serum endothelial nitric oxide syn-

thase than in normotensive pregnant women, but these differences were not statistically signicant. Conclusions: The higher levels of homocysteine and ADMA observed in patients with early onset preeclampsia may sug-

gest that higher levels of maternal serum homocysteine and ADMA correlate with the severity, and may deter-mine the earlier clinical onset of the disease. The elevated levels of ADMA and the unchanged levels of eNOSin preeclamptic pregnancies suggest that NO deciency in this pregnancy disorder results not from a reducedlevel or activity of eNOS, but from elevated levels of ADMA, an endogenous eNOS inhibitor. The lowering ofincreased levels of homocysteine and ADMA may be helpful in therapy of vascular disturbances occurring inpreeclampsia.

Key words: preeclampsia homocysteine ADMA eNOS

Full-text PDF: http://www.medscimonit.com/download/index/idArt/883932

Authors Contribution:Study Design A

Data Collection B Statistical Analysis CData Interpretation D

Manuscript Preparation E Literature Search FFunds Collection G

1 Chair and Department of Obstetrics and Perinatology, Medical University ofLublin, Lublin, Poland

2 Chair and Department of Gastroenterology University Hospital in Lublin, Lublin,Poland

3 Chair and Department of Obstetrics and Perinatology University Hospital inLublin, Lublin, Poland

e-ISSN 1643-3750 Med Sci Monit, 2013; 19: 430-437

DOI: 10.12659/MSM.883932

430Indexed in: [Current Contents/Clinical Medicine] [SCI Expanded] [ISI Alerting System][ISI Journals Master List] [Index Medicus/MEDLINE] [EMBASE/Excerpta Medica][Chemical Abstracts/CAS] [Index Copernicus]

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This work is licensed under a Creative CommonsAttribution-NonCommercial-NoDerivs 3.0 Unported License

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Background

Preeclampsia, a unique human pregnancy disorder, is charac-

terized by the development of new hypertension and protein-uria after 20 weeks of gestation in patients free from any clin-ical disease. But it is not only hypertension and proteinuria;preeclampsia is a multiorgan disease in which the target or-gans are the endothelium, brain, liver, kidneys (glomerular en-dotheliosis) and the coagulation system. Delivery still remainsthe only curative treatment in cases of severe preeclampsia,but is not always advantageous for the fetus. Managementdecisions concerning patients with preeclampsia must be in-dividualized and should balance the maternal risks of contin-ued pregnancy against the fetal risks associated with inducedpreterm delivery [1,2].

Preeclampsia is a major cause of maternal and fetal mortalityand morbidity, and remains amongst the biggest challenges inobstetrics, but its precise etiopathogenesis is still unclear [3,4].It has been suggested that the root cause of preeclampsia isthe placenta [5,6]. The placenta, as the interface between themother and fetus, regulates fetal growth and development. Itsfunctions are determined by vascular development and bloodow, which depend on proper trophoblast growth and differ-entiation [6,7]. According to the most recent hypothesis, pre-eclampsia results from impaired placentation early in the be-ginning of the pregnancy, leading to placental hypoxia and

dysfunction [3,7,8]. There are differences between the placen-tal ndings in early and late onset preeclampsia, but it is diffi-cult to determine whether these are qualitative, indicating dif-ferent diseases, or simply quantitative differences within thesame disease [5]. It has been suggested that the onset, clini-cal manifestations, severity, and progression of preeclampsiaare affected by the maternal response to placentally derivedantiangiogenic factors that lead to the imbalance between an-giogenic and antiangiogenic factors [3,4]. Nitric oxide (NO) reg-ulates the placental blood ow and actively participates in tro-phoblast invasion and placental development [9]. One theory(of many) suggests that clinical manifestations of preeclamp-sia caused by failure of the placental vasculature and endo-thelial malfunction, including insufficient nitric oxide synthe-sis or NO bioavailability, may contribute to increased bloodpressure, systemic vascular resistance, and sensitivity to thepressors [4,1013].

Nitric oxide, initially described as an endothelium-derived re-laxant factor (EDRF) is the smallest biologically active moleculeproduced by endothelial cells, and plays many important func-tions in basic life processes [14]. Nitric oxide is the key trans-mitter for the endothelium-dependent regulation of the vas-cular tone and it regulates blood pressure, abolishes the toxicactivity of superoxide ions, inhibits the adhesion and activa-tion of platelet aggregation, and acts as an anticoagulant and

antiatherogenic substance [10,14]. Nitric oxide contributes tothe vasodilatation of blood vessels and to the decrease in vas-cular resistance observed during normal pregnancy [10,13,15].

Nitric oxide is produced in intact endothelial cells by endothe-lial NO synthase (eNOS) as the key enzyme from L-arginine[14,15]. Preeclampsia is associated with impaired uteropla-cental adaptations during pregnancy and abnormalities in theendothelial nitric oxide synthase (eNOS)-nitric oxide pathway.However, the mechanism associated with the alteration of nitricoxide formation in pregnancies complicated by preeclampsiais not well understood. It is also unknown whether eNOS de-ciency plays a causal role in preeclampsia [16]. Animal stud-ies suggest that hyperhomocysteinemia affects the blood ves-sel wall and causes a change in the endothelium and smoothmuscle proliferation [17]. Hyperhomocysteinemia is a risk fac-

tor of cardiovascular diseases and vasculopathy. It may be acause of changes and lesions in endothelial cells due to vas-cular brosis, which results in the activation of thrombogene-sis, alterations in the coagulation system, and enhanced plate-let activation changes that are noted in preeclampsia [17].It has also been postulated that hyperhomocysteinemia maycontribute to the development of placental microvascular dis-eases and preeclampsia, which adversely affect the endotheli-um [18]. Asymmetric dimethylarginine (ADMA), an endogenousinhibitor of endothelial NO synthase (NOS), has been linkedto endothelial dysfunction [11,19,20]. In addition, preliminaryevidence has suggested that hyperhomocysteinemia leads to

endothelial dysfunction and an accumulation of ADMA [21,22].These observations were the inspiration for the present study.

The aim of the present study was to evaluate the alterationsof maternal serum concentrations of endothelial nitric oxidesynthase (eNOS), asymmetric dimethylarginine (ADMA), andhomocysteine in women with pregnancies complicated by earlyand late onset severe preeclampsia in comparison to healthynormotensive pregnant women.

Material and Methods

In total, 115 pregnant patients diagnosed with severe pre-ec-lampsia according to the criteria published in the National HighBlood Pressure Education Program Working Group Report onHigh Blood Pressure in Pregnancy (ACOG 2002) [23], and 65healthy normotensive women with uncomplicated pregnanciesin their 3rd trimester were included in the study. Preeclampticpatients were divided into early onset preeclampsia (before34+0 weeks of gestation; the ePRE group, n=62) and late on-set preeclampsia (after 34+0 weeks of gestation; the lPREgroup, n=53) groups.

Preeclampsia was diagnosed by an increased blood pressure of>140 mmHg systolic and >90 mmHg diastolic in women who


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were normotensive before 20 weeks of gestation accompaniedby proteinuria, dened as the urinary excretion of >0.3 g pro-tein in a 24-h specimen. Severe preeclampsia was diagnosed

based on the following criteria: systolic blood pressure >160mmHg, diastolic blood pressure >110 mmHg, and proteinuria>5 g/in a 24-h period. In addition, patients were considered tohave severe preeclampsia if they had 1 or more of the follow-ing clinical manifestations: renal abnormalities (oliguria), he-matologic abnormalities (thrombocytopenia and microangio-pathic hemolysis), HELLP syndrome (hemolysis, elevated liverenzymes, low platelet count and right-upper quadrant pain),or neurologic symptoms (headache, visual disturbances andseizures). None of the pregnant patients with preeclampsiawere affected by chronic hypertension or renal disorders and/or proteinuria before pregnancy, and all were normotensive

before the 20th

week of pregnancy. Preeclamptic patients wereadmitted to the Department of Obstetrics and Perinatology inthe University Hospital in Lublin because of the symptoms ofthe disease, but without signs of labor.

The control group consisted of 65 healthy normotensive preg-nant patients with singleton uncomplicated pregnancies, with-out any renal, cardiac, or vascular diseases, with normal labo-ratory tests and appropriate-for-gestational-age weight infants(the Control group).

All arterial blood pressure measurements in the Control

group of pregnant patients were normal and did not exceed135/85mmHg, and none of the patients had proteinuria.

No participants smoked, used caffeine or alcohol, or had ahistory of endocrinological disease, diabetes, pre-pregnan-cy cardiovascular disease, or hypertension. Pregnant womenwith multiple pregnancies were also excluded from this study.

The blood pressure (BP) of all the participants was measured atrest. The body mass index (BMI) of the patients was calculatedas kg/m2. Serum samples were collected from patients immedi-ately after the diagnosis, before administering any medication,and from controls at their routine visits. The research protocol,including the consent form, was approved by the institutionalEthics Committee for the Protection of Human Subjects fromthe Medical University in Lublin, and informed consent for pe-ripheral blood sampling was obtained from all participants.

Homocysteine endothelial nitric oxide synthase (eNOS)and asymmetric dimethylarginine (ADMA) determination

Blood samples collected from the patients were allowed to clotand then were centrifuged at 1500g for 15 min and the se-rum samples were stored at 70C until assayed. Commerciallyavailable enzyme-linked immunosorbent assay (ELISA) sys-tem kits (Human Sandwich ELISA kit, Axis-Shield Diagnostics

Ltd, UK) were used according to the manufacturers recom-mendations, to determine the maternal serum homocysteineconcentrations. The endothelial NOS3 levels were measured

in the maternal serum samples using a commercially avail-able ELISA kit according to the manufacturers instructions(Human Endothelial Nitric Oxide Synthase 3 kit made by USCLife Science Inc., Wuhan, China). The asymmetric dimethyl-arginine levels from maternal serum were evaluated using asandwich ELISA assay according to the manufacturers instruc-tions (Human ADMA Sandwich ELISA kit, Immundiagnostik AG,Stubenwald-Allee Ba, Bensheim).

Statistical analysis

Data were expressed as mean SD. All calculations were car-

ried out using Statistica v.8 PL software. Analysis of variance(ANOVA) tests were used to test differences between the 3 in-dependent groups. A statistically signicant effect in ANOVAwas followed up with post-hoc Tukeys test in order to assessdifferences between groups. The level of statistical signicancewas established as p

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onset of preeclampsia were not statistically signicant. The meanvalues of maternal serum homocysteine were 11.4284.158

mol/L in the ePRE group, 10.0462.795 mol/L in lPRE group,and 7.8352.482 mol/L in the control group (Figure 1).

The mean values of maternal serum asymmetric dimethylar-ginine were 0.5830.163 mol/L in the group of early onsetof preeclampsia, 0.5550.165 mol/L in the group of late on-set of preeclampsia, and 0.4880.111 mol/L in the controlgroup (Figure 2).

One important conclusion of our study is that we did not nda statistically signicant decrease of eNOS concentrations ineither group of preeclamptic women compared to the healthywomen with uncomplicated pregnancies from the control group.The preeclamptic women had slightly lower levels of maternalserum endothelial nitric oxide synthase than in normotensivepregnant women, but these differences were not statistical-ly signicant. The mean values of maternal serum eNOS were154.327155.308 U/mL in women with pregnancies compli-cated by early onset preeclampsia, 156.247127.019 U/mL inpatients with late onset preeclampsia, and 217.744265.114U/mL in the healthy pregnant controls( Figure 3).

Discussion

During a normal pregnancy, spiral artery remodelling reducesmaternal blood ow resistance and increases uteroplacentalperfusion to meet the requirements of the fetus. It has alsobeen observed that eNOS in the mother and in the fetus con-tribute to uteroplacental vascular changes and increased uter-ine arterial blood ow [16].

Whereas preeclampsia is associated with impaired uteropla-cental adaptations during pregnancy and abnormalities in theendothelial NO synthase (eNOS)-NO pathway, it is unknownwhether eNOS deciency plays a causal role there [16]. Ithas also been suggested that disturbances in the homocys-teine-ADMA-NO pathway may be at least partly responsiblefor the etiology of preeclampsia and could be regarded asmarkers for the severity of the disease [24]. Homocysteineinhibits the expression and activity of dimethylamino di-methyl hydrolase (DDAH), the enzyme hydrolyzing and de-grading ADMA to citrulline and dimethylamine [10,21,25,26].Because of this metabolic relation, it has been suggested thatADMA is a mediator of endothelial dysfunction in hyperho-mocysteinemia [25].

Parameters

Early onsetpreeclampsia group

(the ePRE group)(n=62)

Late onsetpreeclampsia group

(the lPre group)(n=53)

The Control group

(the C group) (n=65)

ANOVA test (p value;

* statisticalsignifcance)

Post hoc test

(* statisticalsignifcance)

Age (years) 30.715.72 28.834.88 29.214.42 p=0.081492

Gravidity 1.971.48 1.590.94 1.410.68 p=0.009280* ePRE/C*

Parity 1.741.40 1.460.80 1.340.55 p=0.051795

Height (cm) 163.115.61 164.276.14 164.705.54 p=0.294651

Weight (kg) 80.4013.97 83.2815.45 78.2612.36 p=0.216629

BMI (kg/m2 ) 30.074.40 30.764.95 28.854.35 p=0.113296

SBD (mmHg) 167.4316.69 169.1318.25 113.569.60 p

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In the present study we found signicantly increased mater-nal serum concentrations of homocysteine and asymmetric di-methylarginine in pregnancies complicated by early and lateonset preeclampsia compared to uncomplicated pregnancies.The higher levels of homocysteine and ADMA in patients withearly onset preeclampsia may suggest a relationship betweenthe levels of these factors and the time of the clinical mani-festation of preeclampsia. They may also suggest that high-er levels of maternal serum homocysteine and ADMA corre-late with the severity, and may determine the earlier clinicalonset of the disease. In contrast, endothelial nitric oxide syn-thase did not show any signicant differences between nor-mal and preeclamptic pregnant women.

Our results regarding the elevated ADMA and homocysteinelevels in preeclamptic pregnancies compared to uncomplicat-ed pregnancies are in agreement with several other studies.Rizos et al. [27] observed signicantly elevated ADMA concen-trations in the second trimester in pregnancies that later de-veloped preeclampsia. Lpez-Quesada et al. [28] found signif-icantly higher homocysteine levels in preeclamptic women.

Similar ndings were observed by Wang et al. [29], who dem-onstrated elevated levels of maternal plasma homocysteine inpreeclamptic pregnancies and in pregnancies with a suspectedfetal compromise and umbilical or placental vascular disease.They concluded that elevated plasma homocysteine plays arole in the pathogenesis of the vascular disease in the utero-placental circulation in placental insufficiency, and it in turnmay suggest vascular lesions in the maternal uteroplacentalbed in preeclampsia and fetal growth restriction.

Similar results concerning higher homocysteine levels in pre-eclamptic women and their positive correlation with asymmet-ric dimethylarginine concentrations were presented by Mao etal. [24]. These authors suggested that the altered homocyste-ine-ADMA-NO signalling pathway may be responsible for theetiology of preeclampsia [24].

Our ndings are in disagreement with results from the study bySiroen et al. [30], who observed similar levels of ADMA in womenwith preeclampsia compared to normotensive pregnant wom-en. However, they observed higher ADMA levels in women witha clinical worsening of preeclampsia with impaired condition ofliver and kidneys, which are organs responsible for the elimina-tion of ADMA. Siroen et al. [30] reported increased levels of ADMAin relationship to the laboratory parameters of liver and kidneydysfunction and the clinical picture of systolic and diastolic blood

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Maternal serum homocysteine levels in studied groups of women(p

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pressure, the birth weight of infants, and the weight of the pla-centa. On the basis of these studies, Siroen et al drew far-reach-ing conclusions, suggesting a causal role of ADMA in the devel-

opment of renal failure and liver and placental insufficiency [30].

Holden et al. [19] showed that lowering blood pressure in ear-ly pregnancy is accompanied by a signicant decrease in theplasma concentrations of asymmetric dimethylarginine. Thisphenomenon was not observed in women who developed pre-eclampsia later on. However, there was an increase in circulat-ing blood levels of ADMA, and they reached higher levels thanin non-pregnant subjects [30]. Holden et al conrmed the roleof both asymmetric dimethylarginine and nitric oxide in thesequence of changes in blood pressure observed in both nor-mal and preeclamptic pregnancies [19].

Our data are similar to those of Sthlinger et al. [21], whoshowed that the homocysteine induced increase in ADMA isassociated with a reduction in DDAH activity, and that ADMAaccumulation is associated with a temporally related decline inDDAH activity. These authors observed a reduced release of NOby endothelial cells in hyperhomocysteinemia, and suggestedthat impairment of the eNOS pathway by DDAH inhibition couldhave biological implications beyond the vasculature. Yucel et al.[31] suggested that hyperhomocysteinemia is a risk factor foratherosclerosis, and is associated with endothelial dysfunction.

However, it has been observed that hyperhomocysteinemia mayalso impair endothelial function through a mechanism largelyindependent of the pathway of ADMA/DDAH, and without el-evating ADMA, probably through the inhibition of endothelialnitric oxide synthase activity by protein kinase C or oxidativeinactivation of NO, induced by dysregulation of renal cellularantioxidant enzymes [24]. Dayal et al. found that hyperhomo-cysteinemia causes tissue-specic decreases in DDAH expres-sion without altering plasma ADMA levels in mice, but withendothelial dysfunction [32].

Hyperhomocysteinemia may result in vasomotor dysfunction,because the amended structure and biomechanics of blood ves-sels and enhanced thrombosis are considered to be independentrisk factors for metabolic and cardiovascular disease [26]. Themechanism of vascular damage by homocysteine has not beenfully explained, but the importance of vascular smooth musclecell proliferation and vascular remodelling leading to thrombosisand atherosclerosis should be considered. During normal preg-nancy, physiological homocysteine levels are reduced secondaryto hormonal changes and kidney, liver, and placental metabolism.

According to De Falco et al. [33], hyperhomocysteinemia dur-ing pregnancy could be responsible for placental abnormali-ties, which may be the cause of these very serious pregnancycomplications. Steegers-Thenissen et al. [34] suggested that

hyperhomocysteinemia was associated with an approximately2- to 3-fold increased risk of pregnancy-induced hypertension,abruption of the placenta, and intrauterine growth restriction.

Elevated levels of ADMA and unchanged levels of eNOS in preg-nancies complicated by severe preeclampsia suggest that the ni-tric oxide deciency in this pregnancy disorder results not froma reduced level or activity of eNOS, but from elevated levels ofasymmetric dimethylarginine, an endogenous eNOS inhibitor.

The results of the studies of eNOS activity were inconclusive.Myatt et al. [35] observed the primary location of eNOS inthe syncytiotrophoblast of preeclamptic placenta. These au-thors also noted the lack of eNOS expression in vascular ter-minal villi and a weak expression in the endothelial cells of vil-

lous vessels in placenta from normal pregnancy. This locationshowed intense expression of eNOS in both types of vesselsin placentas from pregnancies complicated by preeclampsia.

In contrast, Beinder et al. [36] observed similar placental lev-el of eNOS activity in patients with pregnancy complicated bypreeclampsia and healthy pregnant women with pathologicaland normal blood ow in the umbilical cord. However, they ob-served a lower activity of endothelial nitric oxide synthase wherethe uterine and placental vessels meet and increased uterineartery resistance in preeclamptic women compared to healthypregnant women. Nasiell et al and Schiessl et al found signi-

cantly increased placental expression of endothelial nitric oxidesynthase in pregnancies complicated by preeclampsia [37,38].

Our ndings are also in disagreement with the results of Kimet al., who found lower expression of eNOS in the syncytiotro-phoblast, reduced concentrations of L-arginine, and unchangedADMA in the serum of women with pregnancies complicatedby preeclampsia [39]. NO synthase plays a very important rolein the physiology and pathology of the placental circulation; ni-tric oxide produced by endothelial nitric oxide synthase is animportant regulator of cardiovascular physiology [39,40]. NOappears to be an antiatherogenic agent, thus ADMA may be acommon mediator of endothelial dysfunction. In addition, stud-ies have shown that ADMA is not only a risk factor for athero-sclerosis and a marker of endothelial injury, but it can also playan important role in the progression of renal damage [4143].Homocysteine has an inhibitory effect on ADMA metabolism,leading to increased ADMA concentrations in hyperhomocyste-inemia in preeclamptic women. Finally, this study suggests thatlowering the increased homocysteine levels may be helpful inthe therapy of vascular disturbances in preeclampsia and maybe associated with the down-regulation and impaired bioavail-ability of NO that results from higher levels of ADMA, an endog-enous endothelial nitric oxide synthase inhibitor. Larger scaleprospective studies are needed to determine the impact of thera-pies aimed at decreasing serum homocysteine and ADMA levels.



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Conclusions

Our results conrm the key role of elevated levels of homocys-

teine and asymmetric dimethylarginine in the development ofpreeclampsia. The higher levels of homocysteine and ADMAobserved in patients with early onset preeclampsia may sug-gest a relationship between the levels of these factors and thetime of clinical manifestation of preeclampsia. They may alsosuggest that higher levels of maternal serum homocysteineand ADMA correlate with the severity, and may determine theearlier clinical onset of the disease.

Elevated levels of ADMA and the unchanged levels of eNOS inpregnancies complicated by severe preeclampsia lead to theconclusion that the nitric oxide deciency in this pregnancy

disorder result not from a reduced level or activity of eNOS,but rather from elevated levels of asymmetric dimethylargi-nine, an endogenous eNOS inhibitor.

Our results also suggest that ADMA and homocysteine reduc-tion may be a goal in the prevention and treatment of pre-eclampsia, but expanded studies are needed to develop newperspectives into this topic. Studies with larger populationswill yield more informative results for understanding the eti-ological determinants of preeclampsia.

Declaration of interest

The authors report no conicts of interest. The authors aloneare responsible for the content and writing of the paper.

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