the role of the l-arginine-nitric oxide pathway in preeclampsia

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DOI: 10.1177/1753944708092277

2008 2: 261Ther Adv Cardiovasc DisPatricio López-Jaramillo, William D. Arenas, Ronald G. García, Melvin Y. Rincon and Marcos López

Review: The role of the L-arginine-nitric oxide pathway in preeclampsia

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Therapeutic Advances in Cardiovascular Disease Review

Therapeutic Advances inCardiovascular Disease

(2008) 2(4) 261–275

DOI: 10.1177/1753944708092277

©SAGE Publications 2008Los Angeles, London,New Delhi and Singapore

The role of the L-arginine-nitric oxide pathwayin preeclampsiaPatricio López-Jaramillo, William D. Arenas, Ronald G. García, Melvin Y. Rincon and Marcos López

Abstract: Preeclampsia (PE) is a major cause of maternal and perinatal mortality, especially indeveloping countries. Its etiology involves multiple factors, but no specific cause has beenidentified. Evidence suggests that clinical manifestations are caused by endothelialdysfunction. Nitric oxide (NO), which is synthesized from L-arginine in endothelial cells by theendothelial nitric oxide synthase (eNOS), provides a tonic dilator tone and regulates theadhesion of white blood cells and platelet aggregation. Alterations in the L-arginine-NOpathway have been associated with the development of PE. Various studies, reportingdecreased, elevated or unchanged levels of nitrite (NO2) and nitrate (NO3), two end products ofNO metabolism, have been published. Our group contributed to those contradictory reportsdescribing cases of PE with both elevated and decreased levels of NO2 and NO3. Apparently,diminished levels of NO could be related to deficiencies in the ingestion of dietary calciumassociated to low levels of plasma ionic calcium, which is crucial to the eNOS’ activity. Also, lowlevels of NO could be associated with the presence of eNOS polymorphisms or the presence ofincreased levels of ADMA, the endogenous inhibitor of NO. High levels of NO associated to lowlevels of cGMP suggest a decreased bioactivity of NO, which is probably related to an increaseddegradation of NO caused by a high production of superoxide in states of infection andinflammation. The present article analyses and reviews the reported paradoxical roles of theL-arginine-NO pathway in PE and gives a possible explanation for these results.

Keywords: preeclampsia, endothelium, nitric oxide, inflammation, infection

IntroductionHypertensive pregnancy disorders are the maincause of maternal and perinatal morbidity andmortality. Preeclampsia (PE) is the most impor-tant among these pathologies [WHO, 2004;Walker, 2000] Preeclampsia, defined as the onsetof hypertension and proteinuria after 20 weeksof gestation in previously normotensive non-proteinuric pregnant women [Walker, 2000], isa multiorgan disease, affecting the liver, kid-neys, brain, and blood clotting system. Despiteits importance, the etiology of PE is not welldefined and multiple risk factors have beenidentified [Lopez-Jaramillo et al. 2001; Lopez-Jaramillo, 2000]. The impact of each of themvaries in different populations, with considerabledifferences between developed and developingcountries [Lopez-Jaramillo et al. 2005]. In LatinAmerica, the high frequency of risk factors,such as inappropriate nutrition, young mater-nal age, and inadequate prenatal care pro-grams, is reflected in the high incidence of

PE [WHO, 2004, 1987] and elevated maternal Correspondence to:Patricio López–JaramilloVILANO Group. ResearchInstitute, FundaciónCardiovascular deColombia, Floridablanca,Santander, Colombia andResearch Department,Medical School,Universidad de Santander(UDES), Bucaramanga,[email protected];[email protected]

William D. Arenas,Ronald G. García,Melvin Y. RinconVILANO Group. ResearchInstitute, FundaciónCardiovascular deColombia, Floridablanca,Santander, Colombia

Marcos LópezFree Radical ResearchCenter, Department ofBiophysics, MedicalCollege of Wisconsin,Milwaukee, WI, USA

mortality, which is 10–20 times higher thanin developed countries [WHO InternationalCollaborative Study of Hypertensive Disorders ofPregnancy, 1998].

Pregnancy is a physiological state in whichthere are important hemodynamic adaptationsthat are maintained by an increased peripheralvasodilation [Lopez-Jaramillo, 1996]. The vas-cular endothelial cells provide a tonic dilatortone, which is mainly maintained not only bythe production of NO, but also by prostacyclinand endothelium-derived hyperpolarizing factor(EDHF). Furthermore, these substances inhibitthe adhesion and migration of leukocytes andplatelets to the vascular wall [Sladek et al. 1997;Moncada et al. 1991].

Nitric oxide is synthesized from the amino acidL-arginine by a family of enzymes denominatedNO synthases (NOS). The endothelial NOS

http://tac.sagepub.com 261

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Therapeutic Advances in Cardiovascular Disease

(eNOS) is a NADPH and Ca2+ dependentenzyme [Moncada et al. 1991]. Moreover, wehave demonstrated the crucial role of extracel-lular calcium concentrations in the productionof endothelial NO and in the control of vas-cular tone [Lopez-Jaramillo et al. 1990]. NOacts as a potent vasodilator via the activation ofcGMP [Sladek et al. 1997] (Figure 1). eNOSis expressed in human placental syncytiotro-phoblasts and extravillous trophoblasts [Sladeket al. 1997]. NO is inactivated when react-ing with superoxide (O−

2 ) to form peroxynitrite(ONOO−) a potent oxidant responsible for thelipid peroxidation and the nitration of tyrosine.An increased production of O−

2 during pregnancyhas been reported, especially in case of infectionand/or inflammation. Moreover, O−

2 is producedby eNOS when there is a deficiency of tetrahydro-biopterin (BH4) [Ronson et al. 1999; Moncadaet al. 1991].

The aim of the present review was to evaluatethe role of the L-arginine-NO pathway in normalpregnancy, and to analyze the conflicting resultsreported in the literature about the role of NOin PE. We searched PubMed for articles pub-lished between 1990 and 2005. The keywordsused were ‘Preeclampsia,’ ‘nitric oxide,’ ‘nitrites/nitrates,’ ‘cyclic guanosine monophosphate,’ and

‘L-arginine.’ We also searched the bibliographiesof the articles retrieved for further relevantreferences. Reports, letters to the editor andpapers not specifically focused on this topic wereexcluded. Because of the large number of articlesidentified, the decision on which to include wasbased on personal judgment.

Hemodynamic changes in normal pregnancyNormal pregnancy is characterized by pro-found anatomical, physiological, and biochemicalchanges to support growth and development ofthe fetus [Heilmann, 1987; Taylor and Lind,1979; Chesley, 1972; Lund and Donovan, 1967].The hemodynamic changes observed duringpregnancy are: increased blood volume, heartrate, cardiac output, and a decreased periph-eral vascular resistance [Moutquin et al. 1985;Metcalfe and Ueland, 1974; Lees et al. 1967].This decrease in resistance is achieved by bothperipheral vasodilatation and reduction in bloodviscosity [Heilmann, 1987].

In normal pregnancy, plasma volume increasesto about 40% above pre-pregnancy levels at30-week gestation [Chesley, 1972; Lund andDonovan, 1967]. Furthermore, during gesta-tion red cell mass increases linearly to reach atterm, a level 25% higher than before pregnancy

Endothelialcell

Receptoragonist

Shearstress

Inhibits plateletahesion andaggregation Inhibits monocytes

adhesion andmigrationCa2+

Ca2+/Calmodulin - Bh4

NOS

NO

NO

L-Citruline

NO

SGC

cGMPGTP

Vasodilation

R R

Smoothmusclecell

L-Arginine + O2

Figure 1. Regulation of the production of NO in the vascular endothelium and antithrombotic, antiatherogenicand vasodilation actions. SGC: Soluble guanylate cyclase. GTP: Guanosine 5′-triphosphate. cGMP: Cyclicguanosine monophosphate.

262 http://tac.sagepub.com




Review

[Taylor and Lind, 1979; Chesley, 1972; Lundand Donovan, 1967], besides cardiac output risesfrom 30 to 40% compared with nonpregnantresting stage [Lees et al. 1967]. The increase incardiac output occurs as early as the twelvethweek, probably as a result of afterload due toperipheral vasodilation [Metcalfe and Ueland,1974]. Despite these increases in cardiac outputand plasma volume, blood pressure falls duringnormal pregnancy [Moutquin et al. 1985]. Thereasons for the fall in peripheral vascular resis-tance have not been completely established buthave been associated with an increased produc-tion of prostacyclin and NO [Lopez-Jaramilloet al. 1995; Felix et al. 1991].

An important body of evidence suggests that anincreased endothelial NO production is impli-cated in normal pregnant vasodilation [Williamset al. 1997]. Table 1 summarizes some of thestudies demonstrating that the production of NO,evaluated by the plasma and serum levels ofNO2 and NO3 [Schiessl et al. 2006; Teran et al.2006; D’Anna et al. 2004; Diejomaoh et al. 2004;Makkonen et al. 2002; Vural, 2002; Yoneyamaet al. 2002; Nishikawa et al. 2000; Shaamashet al. 2000; Conrad et al. 1999; Egerman et al.1999; Hata et al. 1999; Lopez-Jaramillo et al.1992], the bioactivity of NO evaluated by cGMPlevels in biological fluids or in platelets [Baksuet al. 2005; Teran et al. 2004; Shaamash et al.2000; Conrad et al. 1999; Lopez-Jaramillo et al.1996; Schneider et al. 1996;] and, the biologicaleffect of NO in the vasculature, evaluated by flow-mediated vasodilation (FMD) [Saarelainen et al.2006; Sierra-Laguado et al. 2006;Yamamoto et al.2005; Savvidou et al. 2000; Dorup et al. 1999;Cockell and Poston, 1997], are all increased innormal pregnant women, in relation with nor-motensive nonpregnant women. Thus, nowadays,there is no doubt that an increased productionof NO in the vascular endothelium and a normalbioactivity of NO are the critical mechanisms thatexplain the hemodynamical adaptations duringpregnancy.

Alterations of the L-arginine-nitric oxidepathway in PEThe most characteristic alteration of PE is ageneralized peripheral vasoconstriction [Walker,2000]. It has been proposed that an altered pro-duction of endothelial NO could be the reasonfor vasoconstriction in PE [Schiessl et al. 2006;Baksu et al. 2005; Xiang et al. 2005; Yamamotoet al. 2005; Aydin et al. 2004; D’Anna et al. 2004;

Diejomaoh et al. 2004; Teran et al. 2004, 2006;Celik et al. 2003a,b; Var et al. 2003; Makkonenet al. 2002; Vural, 2002; Yoneyama et al. 2002;Nishikawa et al. 2000; Shaamash et al. 2000;Conrad et al. 1999; Egerman et al. 1999; Hataet al. 1999; Dorup et al. 1999; Mutlu-Turkogluet al. 1999; Norris et al. 1999; Ranta et al. 1999;Cockell and Poston, 1997; Begum et al. 1996;Davidge et al. 1996; Lopez-Jaramillo et al. 1996;Schneider et al. 1996; Silver et al. 1996; Seligmanet al. 1994; Lopez-Jaramillo et al. 1992, 1998].In animal models, the inhibition of NO produc-tion leads to findings similar to those reported inhuman PE, including hypertension, proteinuria,and fetal growth restriction [Deng et al. 1996].

Several approaches have been used to study therole of NO in PE. NO is a molecule, which isquickly removed by its rapid diffusion throughtissues into red blood cells. This limits the bio-logical half-life of NO in vivo to less than asecond.The existing analytical methods have sev-eral limitations in the measurement of NO [Yaoet al. 2004]. The most used method to studyNO production has been the quantification ofNO2/NO3 levels in plasma and serum [Selig-man et al. 1994]. The results from several reportsof the NO2/NO3 levels in preeclamptic womenare summarized in Table 2. However, most ofthe reports involved a small sample number, andused different methods to quantify NO2/NO3.

These studies showed paradoxical results withelevated, decreased, or unchanged NO2/NO3

levels in preeclamptic women, compared withcontrols. These inconsistent results were alsoreported by our group in patients from the samepopulation [Lopez-Jaramillo et al. 1998, 1992].The initial confusion caused by these results waslater clarified by reports showing that indepen-dent of NO2/NO3 levels, the concentration ofcGMP, determined in plasma, urine, or platelets,was always consistently lower in women withPE (Table 3) [Baksu et al. 2005; Teran et al.2004; Lopez-Jaramillo et al. 1996; Schneider et al.1996;]. These results suggested that in somepatients with PE, there is a decreased produc-tion of NO expressed by low NO2/NO3 lev-els and cGMP, but in other cases there is anormal or increased production of NO, deter-mined by normal or high NO2/NO3 levels anda decreased bioactivity of NO, expressed by thelow levels of cGMP [Lopez-Jaramillo et al. 2005].Moreover, in all the studies [Yamamoto et al.2005; Takata et al. 2002; Yoshida et al. 2000;





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Table 2. Levels of NO metabolites in biological fluids of preeclamptic women compared to women with normalpregnancy.

Similar levels

Author/Year Method n

Davidge et al. [1996] Spectrophotometric – Griess reaction 13Silver et al. [1996] Chemiluminescence 21Hata et al. [1999] Fluorometric assay 13Conrad et al. [1999] Griess reaction 15Egerman et al. [1999] Spectrophotometric 12Yanik et al. [2001] Spectrophotometer 38Diejomaoh et al. [2004] Liquid chromatography 34Schiessl et al. [2006] Griess reaction 13McCord et al. [2006] DAF-FM DA fluorescent dye 10

Decreased levels


Lopez-Jaramillo et al. [1992] Spectrophotometric 9Begum et al. [1996] Griess reaction 12Mutlu-Türkoglu et al. [1999] Griess reaction 20Celik et al. [2003] Spectrophotometric 21Celik et al. [2003] Griess reaction 20Var et al. [2003] Griess reaction 19Aydinl et al. [2004] Colorimetric assay 34Xiang et al. [2005] Nitrate reductase method 11Teran et al. [2006] Chemioluminiscence 30

Increased levels


Lopez-Jaramillo [1998] Spectrophotometric 10Ranta et al. [1999] Griess reaction 20Norris et al. [1999] Griess reaction 16Nishikawa et al. [2000] Spectrophotometric 17Shaamash et al. [2000] Griess reaction 31Makkonen et al. [2002] Colorimetric assay 20Yoneyama et al. [2002] Griess reaction 25Vural [2002] The Grisham’s method 19D’Anna et al. [2004] Chemiluminescence detection 30Pasaoglu et al. [2004] Spectrophotometric 40

n = Number of patients.

Cockell and Poston, 1997] that reported FMDin women with PE, there was a decreased vasodi-lating response to hyperemia (Table 3).

All these results reveal that PE is characterized bya decreased bioavailability of NO, which explainsthe peripheral vasoconstriction, the endothelialdysfunction, and the clinical manifestations ofthis disease. Furthermore, these results supportthe proposal of multicausality of the disease withdifferent mechanisms conducting alterations inthe activity of NO [Lopez-Jaramillo et al. 2001;Lopez-Jaramillo, 2000].

In the case of PE with low production ofNO (low NO2/NO3 levels) some alterations inthe L-arginine-NO pathway have been described(Figure 2):

1. Deficiency in the substrate L-arginine or inits transport [McCord et al. 2006; Neri et al.2000].

2. Deficiency in the cofactors needed for thenormal activity of eNOS, such as ionic cal-cium [Herrera et al. 2006; Steinert et al. 2002;Lopez-Jaramillo et al. 2001] and BH4 [Varet al. 2003; Toth, 2002].






Tabl

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cGM

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656

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Aut

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nN

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Review

Synthesis

PRMT

Protein

eNOS

NO

Citruline

eNOS

NOSpolymorphism

Proteolysis

Methil arginines

Asimmetricdimethilarginine

DDAH IDDAH II

L-Arginine

Calciumdeficience

BH4deficience

Figure 2. Different factors that can affect the production of NO in the vascular endothelium duringpregnancy. DDAH: Dimethylarginine dimethylaminohydrolase. PRMT: Protein arginine methyltransferase.BH4: tetrahydrobiopterin.

3. Accumulation of asymmetric dimethylarginine(ADMA), an endogenous inhibitor of eNOS[Slaghekke et al. 2006].

4. Presence of polymorphic alterations of theeNOS that results in a lower enzymatic activity[Serrano et al. 2004].

In the case of PE with normal or high productionof NO and normal or increased NO2/NO3 levelsbut with lower bioactivity of NO, an increaseddegradation of NO has been proposed. Due tothe high reactivity of NO with O−

2 to form perox-initrite, increased oxidative stress in PE has beenreported as the cause of the rapid degradation ofNO [Sharma et al. 2006; Myatt and Cui, 2004;Lowe, 2000; Sagol et al. 1999].

Table 4 summarizes the results of several stud-ies using different methods to evaluate thestate of oxidative stress in PE. It is clear that,regardless of the method used to quantify oxy-gen reactive species, most of the studies foundan increased superoxide production in preg-nant women with PE [Biri et al. 2007; Chamyet al. 2006; Sharma et al. 2006; Myatt and Cui,2004; Pasaoglu et al. 2004; Serdar et al. 2002;Diedrich et al. 2001; Yanik et al. 2001; Kharb,2000; Lowe, 2000; Sagol et al. 1999; Madazliet al. 1999]. Below are some of the causesdescribed to explain the reduced bioavailability

of NO and the increased state of oxidativestress in PE.

1. Presence of antibodies anti receptors AT1 ofangiotensin II [Dechend et al. 2000; Xia et al.2003].

2. Early abnormal placentation with placentalischemia and hypoxia [Gilbert et al. 2007].

3. Alterations in the metabolism of carbohy-drates and lipids associated to insulin resis-tance, overweight, and obesity [Joffe et al.1998].

4. Subclinical infections in the vagina, urinarytract system, and periodontal disease [Herreraet al. 2001, 2007; Trogstad et al. 2001; Hillet al. 1986].

A defective placentation has been proposedas the primary cause of preeclampsia [Gilbertet al. 2007]. An inadequate trophoblastic inva-sion of uterine spiral arteries results in placen-tal ischaemia, oxidative stress, inflammation, andalteration of maternal endothelial cell function[Sankaraligam et al. 2006]. It has been sug-gested that a reduced formation of NO couldbe responsible for the abnormal placental per-fusion in PE [Lowe et al. 2000]. However,there is accumulating evidence that supports thatpreeclamptic placenta has a normal capacity tosynthesize NO [Baylis et al. 1998]. Moreover, as






Tabl

e4.

Oxi

dativ

est

ress

inpr

eecl

ampt

icw

omen

com

pare

dto

wom

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Review

we previously mentioned, the concentration ofcGMP in placental circulation is lower thannormal [Kovasc et al. 1994], suggesting thatPE is a condition of normal placental pro-duction of NO, but with a reduced activityof this substance. One mechanism, by whichNO bioavailability is reduced in PE, could bethe increased production of oxygen free rad-icals, which scavenge this potent vasodilator[Sankaraligam et al. 2006]. Another pathwaythat might result in reduced NO bioavailabil-ity involves arginase, an enzyme that cataly-ses the conversion of L-arginine to L-ornithineand urea [Li et al. 2001]. There are two iso-forms of arginase (arginase I and II) that arelocated in the cytosol and mitochondria, respec-tively. Noris et al. [2004] found that arginaseII m RNA expression was more than 4-foldhigher in villous tissue of preeclamptic than innormal pregnant women. In addition, levels ofarginase II mRNA in villous tissue correlatedinversely with fetal L-arginine concentration, sug-gesting excess consumption of the substrate.Since L-arginine is also a substrate for NOS,arginase reciprocally regulates NOS [Berkowitzet al. 2003]. Higher than normal expressionof arginase II causes that less L-arginine beavailable for eNOS in trophoblast cells thanin the villous endothelium. A decrease in theL-arginine concentrations could result in uncou-pling of eNOS, thus increasing the generationof O−

2 [Kuzkaya et al. 2003]. This might resultin increased scavenging of NO by superoxide togenerate peroxynitrite [Xia et al. 1996]. Markersof oxidative stress are increased in placenta ofwomen with PE, and nitrotyrosine staining, amarker of peroxynitrite, has been found in thepreeclamptic placenta [Myatt et al. 1996; Manyet al. 2000]. The peroxynitrite is an anion thatinhibits mitochondrial electron transport, oxi-dizes proteins, initiates lipid peroxidation, nitratesaromatic amino acids, and decreases prosta-cyclin synthase expression, producing periph-eral vasoconstriction and increasing maternalblood pressure [Radi et al. 1991]. Peroxynitritealso activates pro-inflammatory transcription fac-tors such as NF-κB, which controls expres-sion of adhesion molecules and other inflam-matory factors [Li and Karin, 1999]. Thusperoxynitrite contributes to the establishmentof the generalized intravascular inflammatoryreaction that produces endothelial dysfunctionearly in pregnancy and predisposes women to ahigher risk of developing PE [Sankaraligam et al.2000].

The upregulation of arginase II in PE, provides apotential rational for L-arginine supplementation.A preclinical study performed in rats, showedthat L-arginine attenuates the hypertension pro-duced in response to a chronic reduction inuterine perfusion pressure in the pregnant rat,suggesting that L-arginine supplementation maybe beneficial in attenuating the hypertension inPE [Alexander et al. 2004]. In humans, adminis-tration of L-arginine improves uterine-placentalcirculation [Neri et al. 1996], lowers maternalblood pressure [Facchinetti et al. 1999], andreduces platelet aggregation [Neri et al. 1998].However, few studies have evaluated the effectsof L-arginine supplementation on clinical out-comes of women with PE. Staff et al. [2004]evaluated the effects of oral administration of12 g of L-arginine or placebo on preeclampticwomen with gestational length ranging from 28to 36 weeks. They found no significant effectson diastolic blood pressure values, time of deliv-ery, or mean birth weight between the groups.However, this study was limited by the smallsample size (15 subjects in each group) andthe short-term treatment (two days). Recently,Facchineti et al. [Facchinetti et al. 2007] in astudy with a larger sample size demonstrated thatthe daily intravenous administration of L-arginine(20 g/500 ml), for five days followed by 4 g/dayorally administered for two weeks, prolongedpregnancy and reduced blood pressure in womenwith gestational hypertension in comparison withplacebo. Despite these promising results, theeffectiveness of L-arginine in preventing thedevelopment of PE remains to be determined.

Because oxidative stress has been proposed asa key factor involved in the development ofendothelial dysfunction and PE, supplementa-tion with antioxidants, like vitamin C and E,during pregnancy has also been proposed as apossible strategy to prevent or delay the onsetof PE. Recently, a systematic review performedby Rumbold et al. [2007] involving seven tri-als with 6082 women, found that supplementingwomen with any antioxidant during pregnancycompared with control or placebo was associatedwith a reduced risk of developing preeclamp-sia (RR 0.61; 95% CI 0.50–0.75) or having asmall-for-gestational-age infant (RR 0.64; 95%CI 0.47–0.87). However, the reviewers mentionthat these results should be interpreted with cau-tion, and results of larger studies are neededbefore antioxidants can be recommended forclinical practice.






In addition to an increased oxidative stress, it hasbeen suggested that placenta-derived circulatingfactors may induce endothelial dysfunction lead-ing to preeclampsia [Maynard et al. 2003]. Ithas been demonstrated that high levels of cir-culating sFlt1 (soluble fms-like tyrosine kinase)of placental origin, bind to and neutralize theproangiogenic actions of vascular endothelialgrowth factor (VEGF) and placental growth fac-tor (PIGF). Thus, by preventing the binding ofVEFG to Flt1 receptor in cytotrophoblast cells,the excessive production of sFlt1 in placental tro-phoblast could be responsible for the defectivecytotrophoblast differentiation and abnormal pla-centation of PE [Noris et al. 2005]. High concen-trations of sFlt1 along with decreased free VEGFare observed before the onset of clinical symp-toms in women with PE [Levine et al. 2004].VEGF also induces endothelial cell productionof vasodilatory NO and prostacyclin [Brockelsbyet al. 1999], and may be important in the reg-ulation of vascular tone. It has been suggestedthat the induction of hypertension by placenta-derived sFlt1could be related with the impair-ment of VEGF-dependent activation of eNOS[Maynard et al. 2003]. Recently, it has beenfound that Endoglina (sEng) or CD105, a cell-surface coreceptor for transforming growth factor(TGF)-β1 and TGF-β3 isoforms, is also elevatedin the sera of preeclamptic women. The concen-tration of this molecule correlates with the diseaseseverity and diminishes after delivery [Venkateshaet al. 2006]. sEng impairs binding of TGF-b1 toits receptors and downstream signaling includingeffects on activation of eNOS and vasodilation,suggesting that sEng leads to dysregulated TGF-b signaling in the vasculature, contributing tothe endothelial dysfunction characteristic of PE[Venkatesha et al. 2006].

Besides the placental factors already explained,there are environmental factors such as insulinresistance and subclinical infections that couldalso contribute to an increased inflammatoryresponse early in pregnancy, and consequently tothe development of endothelial dysfunction andPE. Recently, in two nested case-control stud-ies that involved an important sample of womenwith PE [Garcia et al. 2007; Sierra-Laguadoet al. 2007] we reported increased levels ofC-reactive protein (CRP), leukocytes count andinsulin resistance using the homeostatic modelassessment (HOMA); risk factors that precedethe development of the clinical manifestationsof PE. These alterations were evident as early

as in the first trimester of gestation. Moreover,both, high CRP and increased HOMA were asso-ciated with a decreased FMD; which suggeststhat inflammation associated to infection and/orinsulin resistance might also be an importantcause of the endothelial dysfunction that precedesthe development of PE.

Implications in the management of PESince huge differences in the PE incidence andmortality are observed between developed anddeveloping countries, the understanding of thedifferent mechanisms that result in an alterationin the L-arginine-NO pathway and endothelialdysfunction is highly important because of itsimplications in the preventive and therapeuticalapproaches. For instance, the maternal mortal-ity by PE in UK is about 10/100,000 deliveriesand in Colombia is about 176/100,000 deliver-ies [Lopez-Jaramillo, 2000; WHO InternationalCollaborative Study of Hypertensive Disordersof Pregnancy, 1998]. These enormous differ-ences are probably related with the quality ofprenatal care, and with the demonstration thatin developing countries the nutritional deficien-cies and the subclinical chronic infections inpregnant women have a higher prevalence thanin developed countries [Lopez-Jaramillo et al.2005]. This situation has been already solved indeveloped countries where the major risk fac-tors for the PE are genetic and immunologi-cal alterations [Lopez-Jaramillo et al. 2005]. Insupport of this proposal, we have demonstratedthat ADMA, in our population, has no respon-sibility in the development of PE [Maas et al.2004; Lopez-Jaramillo et al. 1996]. However, indeveloped countries, it is an important factorthat inhibits the endothelial production of NO[Savvidou et al. 2003; Ellis et al. 2001; Holdenet al. 1998; Fickling et al. 1993]. This contradic-tory situation may be related with the fact thatthe high incidence of infection dilutes the role ofADMA in our population [Lopez-Jaramillo et al.2005]. Preventive interventions to decrease therisk of PE, such as supplementation with calcium[Lopez-Jaramillo, 1996; Lopez-Jaramillo et al.1997, 1995, 1990, 1989], conjugated linoleic acid[Herrera et al. 2005], early diagnosis, and treat-ment of infections [Herrera et al. 2001], seemto be more determining in clinical trials con-ducted in developing countries. It is possible thatby improving the prenatal care system in undevel-oped countries, the prevalence of PE comes to besimilar to that observed in developed countries.Therefore, to demonstrate this proposal, an





Review

international collaborative study comparing thesimilarities and differences in the incidence ofthe risk factors for PE between developed andundeveloped countries is necessary. Moreover,such a study will provide further insights aboutthe role of the L-arginine-NO pathway in theetiology of PE.

ConclusionsDuring pregnancy the adaptative hemodynamicchanges are mediated by a higher productionof NO and bioactivity of the L-arginine-NOpathway. To guarantee the correct production ofNO, different factors such as nutrition, infections,genetic alteration, metabolism, placentation, andmaybe ethnical aspects must be considered. Analteration in the NO production or its activityis associated with the development of PE. Boththe understanding of the etiology of PE and therole played by the differences in the environ-mental factors between developed and developingcountries, should be a research priority.

AcknowledgmentWe would like to thank Jean Noël Guillemot forhis contribution to the correction of the Englishstyle.

The authors would like to acknowledge Colcien-cias for the financial support to the VILANOGroup (Grant N. 6566-04-18061). MelvinRincón received a young investigator grant forColciencias.

Conflict of interest statementNone declared.

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the role of the l-arginine-nitric oxide pathway in preeclampsia

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