Placental oxidative stress: From miscarriage to preeclampsia

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REVIEW ARTICLES

Placental Oxidative Stress: From Miscarriageto Preeclampsia

Graham J. Burton, MD, and Eric Jauniaux, MD, PhD

OBJECTIVE: To review the role of oxidative stress in two common placental-related disorders ofpregnancy, miscarriage and preeclampsia.METHODS: Review of published literature.RESULTS: Miscarriage and preeclampsia manifest at contrasting stages of pregnancy, yet both have theirroots in deficient trophoblast invasion during early gestation. Early after implantation, endovasculartrophoblast cells migrate down the lumens of spiral arteries, and are associated with their physiologicalconversion into flaccid conduits. Initially these cells occlude the arteries, limiting maternal blood flow into theplacenta. The embryo therefore develops in a low oxygen environment, protecting differentiating cells fromdamaging free radicals. Once embryogenesis is complete, the maternal intervillous circulation becomes fullyestablished, and intraplacental oxygen concentration rises threefold. Onset of the circulation is normally aprogressive periphery-center phenomenon, and high levels of oxidative stress in the periphery may induceformation of the chorion laeve. If trophoblast invasion is severely impaired, plugging of the spiral arteries isincomplete, and onset of the maternal intervillous circulation is premature and widespread throughout theplacenta. Syncytiotrophoblastic oxidative damage is extensive, and likely a major contributory factor tomiscarriage. Between these two extremes will be found differing degrees of trophoblast invasion compatiblewith ongoing pregnancy but resulting in deficient conversion of the spiral arteries and an ischemia-reperfusion-type phenomenon. Placental perfusion will be impaired to a greater or lesser extent, generating commensurateplacental oxidative stress that is a major contributory factor to preeclampsia.CONCLUSION: Miscarriage, missed miscarriage, and early- and late-onset preeclampsia represent aspectrum of disorders secondary to deficient trophoblast invasion. ( J Soc Gynecol Investig 2004;11:342–52) Copyright © 2004 by the Society for Gynecologic Investigation.

KEY WORDS: Oxidative stress, placenta, pregnancy, miscarriage, preeclampsia.

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bnormalities of human placentation are associated withdisorders that are either unique to our species, such aspreeclampsia, or very rare in other species, such as

iscarriage. There is considerable evidence implicating pla-ental oxidative stress in the pathogenesis of preeclampsia,1,2

nd increasing evidence indicating that it may also contributeo early pregnancy failure.3,4 Our hypothesis is that theseisorders, although manifesting at contrasting stages of preg-ancy, represent different points on a spectrum of placentaltress induced by changes in the intraplacental oxygen concen-ration. Underlying these changes is a common deficit inrophoblast invasion during the first and early second trimestersf pregnancy, and hence incomplete conversion of the endo-etrial spiral arteries. We review here the anatomic, physio-

ogic, and pathologic evidence in support of this concept.

From the Department of Anatomy, University of Cambridge, Cambridge; and thecademic Department of Obstetrics and Gynaecology Royal Free and University Collegeondon Medical School, London, United Kingdom.This work was supported by a grant from the WellBeing Charity, London, United

ingdomThe authors are grateful to Dee Hughes for preparing the final version of Figure 4.Address correspondence and reprint requests to: Graham J. Burton, MD, Department

f Anatomy, Downing Street, Cambridge CB2 3DY, United Kingdom. E-mail:
[email protected]
opyright © 2004 by the Society for Gynecologic Investigation.ublished by Elsevier Inc.

FREE RADICALS AND REACTIVEOXYGEN SPECIES

volution from unicellular life in the oceans to multicellularife on land has been associated with remarkable metabolichanges linked to the increasing demand for energy required toive, grow, and reproduce. Energy transformation of dietaryroteins, carbohydrates, and fats occurs mainly in the mito-hondria of animal cells through a series of oxidation-reduc-ion reactions, and the energy released in these reactions is usedo phosphorylate adenosine diphosphate (ADP), thus generat-ng adenosine triphosphate (ATP). The final step of this pro-ess uses oxygen (O2) as an electron recipient, and this becameossible some 2 billion years ago with the accumulation of O2

n the atmosphere due to the photosynthetic activities ofyanobacteria.5 The entire process is known as oxidative phos-horylation, and ATP is pivotal as the storage form of thehemical energy required to drive many biochemical reactionsn the cell, in particular, protein biosynthesis, active transportf molecules through cellular membranes, ionic homeostasis,nd muscular contractions.

Most of the O2 used during the oxidation of dietary organic
olecules is converted into water through the integrated ac-
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Placental Oxidative Stress J Soc Gynecol Investig Vol. 11, No. 6, September 2004 343

ions of the enzymes of the mitochondrial respiratory chain.owever, these enzymes, in particular complex III, are not

otally efficient and electrons can “leak” onto molecular oxy-en to form the superoxide anion (O2

.�).6 A significantmount (1–2%) of the O2 we consume is diverted into theroduction of O2

.� in this way, with O2.� being formed at a

ate dependent on the prevailing oxygen tension.7 Because itossesses an unpaired electron, the superoxide anion belongs toclass of molecules termed free radicals, which along with

heir nonradical intermediates fall under the umbrella term ofeactive oxygen species (ROS). ROS are characterized byheir high reactivity, and in order to prevent damage toiomolecules an array of antioxidant defenses has evolved. Dueo its charge O2

.� is membrane impermeable, and remainsithin the mitochondrial matrix where it is detoxified by the

nzyme manganese superoxide dismutase (MnSOD). SOD isresent in all aerobic cells, and is found in the cytoplasm as thelternative copper/zinc isoform (Cu/Zn SOD). The enzymeonverts O2

.� to hydrogen peroxide (H2O2), which in turn iseduced to water by the antioxidant enzymes catalase (CAT)nd glutathione peroxidase (GPX) (Figure 1). In addition tohe antioxidant enzymes, other molecules such as thiols, cer-loplasmin, or transferrin and dietary vitamins, for example,scorbate (vitamin C) and �-tocopherol (vitamin E), play arucial role in the defense against oxygen free radicals.5

A complex homeostatic balance is thus achieved, and athysiological levels free radicals regulate a wide variety of cellunctions through their actions on redox-sensitive transcrip-ion factors.8,9 It is essential that these defenses act in concert,s an imbalance can lead to the production of other moreighly reactive radical species such as the hydroxyl (OH.),eroxyl (RO2), and hydroperoxyl (HO2

.) anions.5 If the gen-ration of these radicals exceeds the cellular defenses, thenndiscriminate damage can occur to proteins, lipids, and DNA,

igure 1. Diagrammatic representation of the main detoxificationathways for ROS. Excess production of superoxide anions (O2

.�)an lead to formation of the more dangerous hydroxyl (OH.) ionshrough the iron-catalyzed Fenton reaction. Alternatively, O2

.� mayeact with nitric oxide to form the prooxidant peroxynitrite. The rateeaction for this combination is some ten times faster than thatetween O2

.� and SOD.

esulting in cellular oxidative stress. The consequences may s

ange from the activation of stress-response proteins throughisruption of signaling mechanisms, structural damage to apo-tosis, or necrosis.10

Although under physiological conditions the main source ofntracellular ROS is as a byproduct of aerobic respiration, theyan arise from other metabolic reactions and oxidase enzymes.hese include NAD(P)H oxidase, a membrane-associated en-yme that plays an important role in oxygen sensing in endo-helial cells and myocytes,11 and that is also present in thelacenta.12,13 Under pathological conditions, however, differ-nt mechanisms may come into play, and one potentiallymportant source is the enzyme xanthine dehydrogenase/xan-hine oxidase. In the dehydrogenase form, this enzyme con-erts hypoxanthine to xanthine, and xanthine to uric acid,assing the electron released on to NAD�. During periods ofypoxia, the enzyme can be cleaved by calcium-dependentroteases to the oxidase form, which uses O2 as the electronecipient, so generating O2

.�. This conversion is responsibleor the burst of free radical production that is associated withpisodes of ischemia-reperfusion,14 and accounts for why fluc-uations in O2 concentration can be particularly damaging toells.

Fluctuations in O2 concentration may occur within theuman placenta due to the unique pattern of development ofhe maternal blood supply to the organ.

ONSET OF THE MATERNAL ARTERIAL BLOODSUPPLY TO THE PLACENTA IN

NORMAL PREGNANCIEShe definitive human placenta consists of the elaboratelyranched fetal villous tree bathed by the maternal blood cir-ulating within the intervillous space, and so is classified his-ologically as being of the hemochorial type (Figure 2). Duringmplantation the invading trophoblast erodes into capillariesnd small veins within the superficial endometrium,15 andhortly after maternal erythrocytes can be observed within therecursors of the placental intervillous space. Traditionally,herefore, it has been widely assumed that the maternal in-raplacental circulation is established soon after implantation,16

nd the precocious supply of nutrients this provides for haseen considered a key evolutionary advantage of the invasiveorm of implantation displayed by the great apes and humans.

However, the presence of maternal erythrocytes does notecessarily signify an effective circulation, and in the classicexts describing placental development doubt was expressed aso when connections between the maternal arteries and thentervillous space are first observed.17,18 Although this remains

somewhat controversial subject, recent studies employingiverse techniques, including hysteroscopy, perfusion of hys-erectomy specimens with the placenta in situ, and Dopplerltrasound studies of the early placenta in vivo, have presentedompelling evidence that the maternal intraplacental circula-ion is only fully established at 10 to 12 weeks of pregnan-y.19–23 Until then, the intervillous space is filled with a clearluid, most likely a maternal plasma filtrate supplemented by

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ecretions from the uterine glands. The human placenta

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344 J Soc Gynecol Investig Vol. 11, No. 6, September 2004 Burton and Jauniaux

annot therefore be considered truly hemochorial until the endf the first trimester. Fundamental to this new understanding ishe process of physiological conversion of the endometrialpiral arteries.

In the nonpregnant state, the spiral arteries are small-caliber,asoreactive vessels that arise from the radial arteries and feed

igure 2. Photomicrograph of a placenta-in-situ associated with a0-mm fetus (Boyd Collection) showing the definitive placenta (largerrow). P � placental tissue; D � decidua; M � myometrium. Notehe regression of villi over the nonembryonic pole to form thehorion laeve, and the irregularity of the decidua with the presence ofaternal vessels in a septum (small arrow). *Fixation artifact.

igure 3. Doppler mapping and spectral analysis of uteroplacental b
ypical venous-like nonpulsatile flow. B) Spiral artery blood flow at the le
nto the superficial capillary plexus within the endometrium.uring pregnancy they undergo conversion into distended,

laccid uteroplacental vessels, capable of accommodating thencrease in uterine arterial blood flow from just a few milliliterser minute in the nonpregnant state to approximately 700L/min at term.18,23 The architecture of their decidual andyometrial segments is disrupted during this process by the

oss of myocytes from the media and the internal elastic lamina,hich are progressively replaced by fibrinoid.26,27 The physi-logical change only occurs in the presence of extravillousrophoblast cells that arise from the tips of the cytotrophoblastell columns of anchoring villi.28 Where these columns abuthe endometrium, the cytotrophoblast cells spread laterally toorm a continuous layer several cells deep, termed the cytotro-hoblastic shell. Cells migrate from the deep surface of thishell, invading between the uterine glands as interstitial tro-hoblast, and down the lumens of the vessels as endovascularrophoblast.26,28,29 The process begins soon after the blastocystas implanted and gradually extends laterally, reaching theeriphery of the placenta around mid-gestation. Depth-wisehe changes normally extend as far as the inner third of theyometrium within the central region of the placental bed,

ut the extent of invasion is progressively shallower towardshe periphery.30 Therefore, even in normal pregnancies not allhe arteries are completely transformed.31

In the early stages the volume of endovascular trophoblastells migrating down the arterial lumens is sufficient to occluder “plug” the tips of the maternal vessels.22,32 Free flow ofaternal blood into the intervillous space is therefore not

ossible, although slow seepage of plasma through the networkf intercellular clefts may occur. At about the 10th week theselugs begin to dissipate, establishing free communications be-ween the spiral arteries and the placenta (Figure 3). Thereater trophoblast invasion that occurs in the central region ofhe placental bed30 means that the plugs are more extensive andomplete in this region, and so it might be predicted thatissipation of the plugs will occur first at the periphery of the

flows at 12 weeks’ gestation. A) Intervillous blood flow showing a
lood vel of the placental bed.

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lacenta. Our recent Doppler studies have confirmed that ishe case in the majority of normal pregnancies.3

INTRAPLACENTAL OXYGEN CONCENTRATIONSDURING EARLY PREGNANCY

he human fetoplacental unit is therefore exposed to majorluctuations in O2 concentration during pregnancy. The O2

ension in the oviduct and uterus of most mammalian speciest the time of implantation has been found to range between1 and 60 mmHg, which corresponds to approximately 1–9%

2.33–35 The partial pressure of oxygen (PO2) measured

ithin the human placenta in vivo is less than 20 mmHg at 7o 10 weeks gestation, and is therefore equivalent.36,37 Main-aining a low oxygen concentration during the embryoniceriod appears to favor blastulation and normal cell differen-iation, and may protect from the damaging effects of oxygenree radical species.38 Once this process is complete at 11 to 14eeks, the intraplacental oxygen tension rises to greater than0 mmHg as the maternal circulation becomes fully estab-ished.36,37 Despite this rise values remain low within the fetuss the diffusional characteristics of the placenta are limited athis stage of gestation.39,40 At 13 to 16 weeks, the PO2 in theetal blood is 24 mmHg, whereas during the second half ofregnancy that in the umbilical vein ranges between 35 and 55mHg. All of these values are relatively low compared to theO2 values found in the maternal circulation,41 suggesting thathere is a significant O2 gradient between the maternal andetal tissues throughout pregnancy.

PHYSIOLOGICAL OXIDATIVE STRESS INEARLY PLACENTAL TISSUES

he sharp increase in O2 tension experienced by the placentan vivo when the maternal circulation is fully established isssociated with a burst of oxidative stress within the placentalissues.37 This is particularly marked in the syncytiotrophoblast,here we detected immunohistochemically the presence ofitrotyrosine residues indicating the formation of peroxynitriteONOO2

�) from nitric oxide (NO.) and O2.� (Figure 1),

ydroxynonenal adducts (HNE) indicating oxidation of lipids,nd expression of heat shock protein (Hsp) 70.37 The latter isecognized as a sensitive marker of oxidative stress in otherystems.42 The expression of these markers can be induced initro by exposing villi to 21% O2, and is associated withncreased generation of ROS as detected by the fluorescentye dichlorofluorescein diacetate (DCFH-DA).43,44 The cel-ular source of the ROS is not known, but the fact webserved swelling of the mitochondrial intracristal space bothn vivo and in vitro suggests that mitochondria are a significantontributor. This is supported by the finding that addition of0 �m diazoxide, a mitochondrial ATP-dependent K� chan-el opener, partially reduces both the generation of ROS andhe expression of markers of oxidative stress.45 Generation ofOS occurs within minutes of exposure to 21% O2, but if villi

re maintained for longer periods then mitochondrial mem-rane potential is lost after 1 hour, and degeneration of the

46
yncytiotrophoblast occurs after 4 hours. The tissue rapidly o
ndergoes vacuolation, dilation of the mitochondrial intracri-tal space, loss of the microvillous covering, and blebbing ofhe apical membrane. However, the underlying cytotropho-last and stromal cells remain viable, reflecting the greateroncentrations of the principal antioxidant enzymes withinhese cell types.47,48 Indeed, the cytotrophoblast cells differen-iate and fuse to form a new syncytiotrophoblastic layer that isorphologically equivalent to the original.46 Degeneration

nd regeneration of the syncytiotrophoblast have subsequentlyeen reported for term villi maintained under 21% O2.

49,50

The physiological role of this burst of oxidative stress is onlyeginning to be elucidated, but a number of cell functionsithin the placenta are now recognized as being influenced by

he prevailing oxygen concentration. These include matrixemodeling,51 angiogenesis,52 cytotrophoblast proliferationnd migration,53–55 cytotrophoblast fusion,56,57 endocrine se-retion,58,59 and cytokine production.60 A further and moreramatic effect may be villous regression over the superficialole of the chorionic sac to form the smooth chorion orhorion laeve (Figures 2 and 4). We recently reported that theegree of oxidative stress is greatest in the peripheral regions ofarly placentas, correlating with the pattern of onset of theaternal blood flow.3 Although measurements of the O2 con-

entration within different regions of the early placenta are notvailable, it is not unreasonable to assume on the basis of theoppler evidence of maternal blood flow that the PO2 will be

reatest in the peripheral region. Examination of placentae-initu specimens has revealed that the villi over the superficialole are less extensive than their central counterparts at 8eeks gestational age.3 They are surrounded by maternal

rythrocytes but are themselves conspicuously avascular, con-istent with down-regulation of vascular endothelial growthactor (VEGF), a hypoxically regulated gene.52 They also havethin trophoblastic covering and a virtually acellular stromal

ore.Hence, onset of the maternal circulation may have a pro-

ound impact on villous function and integrity, and it is essen-ial for a successful pregnancy that it happens in a carefullyoordinated periphery-central manner.

DEFECTIVE PLACENTATION, OXIDATIVESTRESS, AND EARLY PREGNANCY FAILURE

n approximately two thirds of early pregnancy failures there isnatomical evidence of defective placentation, which is mainlyharacterized by a thinner and fragmented trophoblast shell andeduced cytotrophoblast invasion of the lumen at the tips ofhe spiral arteries.61 This is associated with both prematurenset of the maternal circulation and loss of the periphery-enter coordination in most cases of miscarriage, with bloodlow occurring throughout the placenta.3,62,63 These defectsre similar in euploid and most aneuploid miscarriages,64 buthey are more pronounced in triploid partial moles. In com-lete hydatidiform mole the extravillous trophoblast invasionnto the decidua and superficial myometrium is almost entirelybsent.65,66 A recent histological investigation of the products
f conception from miscarriage associated with primary an-

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iphospholipid (aPL) antibody syndrome has also confirmedefective decidual endovascular trophoblast invasion in theseases.67 The data show that by contrast to what has been foundn other organs, in aPL syndrome the frequency of placentalhrombosis is not increased compared to aneuploid early preg-ancy failure. In vitro, aPL antibodies induce VE-cadherinown-regulation and E-cadherin up-regulation at both therotein and mRNA levels.68 The abnormal trophoblast adhe-ion molecules expression found in aPL antibody syndrome,nd in particular the decrease in alpha-1 integrin expression, isimilar to that reported in preeclampsia.

As might be expected, the excessive entry of maternal bloodnto the intervillous space has a direct mechanical effect on theillous tissue, and an indirect oxidative stress effect, whichontributes to cellular dysfunction and/or damage. Levels ofxidative stress are considerably higher within the whole pla-enta than in normal cases3,4 (Figure 4). Indeed, the extent ofyncytiotrophoblast degeneration on central villi from cases ofissed miscarriage is almost identical to that seen within the

eripheral regions of normal pregnancies (healthy syncytiotro-hoblast represents 45.9 � 20.8% versus 46.4 � 19.6% of theillous surface, P � .964). Large areas of degenerate syncy-iotrophoblast may be seen sloughing from the villous surface,

igure 4. Diagrammatic representation of the proposed relationship bregnancies, late-onset preeclampsia, early-onset preeclampsia, and mggregates of cytotrophoblast cells derived from the cytotrophoblasticirculation (arrows) starts in the periphery, and causes local oxidative saeve. In miscarriage, trophoblast invasion is severely deficient, leadingremature and disorganized onset of blood flow, and overwhelmingreeclampsia. In early-onset cases, the onset of the maternal circulationarly oxidative stress may lead to impaired villous growth, while seconlacental hypoxia and intrauterine growth restriction. In late-onset caowards the end of gestation.

ccompanied by increased apoptosis and reduced proliferation i

mong the underlying cytotrophoblast cells.4,69 Despite this,ome of the cytotrophoblast cells differentiate and fuse to form

new syncytiotrophoblast layer that is immunoreactive foruman chorionic gonadotrophin. As a result, serum concen-rations are within the normal range, maintaining the preg-ancy as a missed miscarriage.64 With time, however, the fetalapillaries within the villi regress, presumably due to down-egulation of VEGF in response to the increased oxygen ten-ion prevailing, and the villous cores become virtuallycellular.4,70 Villous atrophy follows, so that the placenta be-omes only a thin shell, and finally the pregnancy is lost.

Overall, the placental histology closely reflects that seenithin the peripheral regions of the normal placenta, suggest-

ng that regression of the villi over the nonembryonic pole ofhe chorionic sac to form the chorion leave and that seen inissed miscarriage are manifestations of the same process in-

uced by an elevated O2 concentration. The former might beonsidered physiological and the latter pathological, althought is arguable that miscarriage may be a physiological mecha-ism for the removal of genetically abnormal conceptuses.aternal screening of the migrating extravillous trophoblast

ells and limitation of invasion may be the fundamental pro-ess, with abnormal onset of the maternal blood flow provid-

en the degree of oxidative stress and placental development in normalrriage. In normal pregnancies trophoblast invasion is extensive andl effectively plug the tips of the spiral arteries. Onset of the maternal(depicted by shading), villous regression and formation of the chorionthin cytotrophoblastic shell, incomplete plugging of the spiral arteries,ative stress throughout the placenta. The situation is intermediate inbe abnormal due to poor development of the cytotrophoblastic shell.

atherotic changes (depicted by shading) in the spiral arteries will causehe situation is less severe, and placental oxidative stress only develops

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There are, of course, other causes of oxidative stress thatay also contribute to pregnancy failure. For example, among

iabetic women, poor glycemic control is associated with anncreased risk of spontaneous miscarriage.71 There is also in-reasing evidence showing an association between miscarriagend an anomaly of one of the enzymes involved in the me-abolism of ROS.72,73 In addition, our recent data on the rolef uterine glands in early fetal nutrition and the transport ofitamin E suggest that insufficient decidualization could haven impact on placentation.25,74 These glands remain activentil at least the 10th week of pregnancy, and their secretionsre delivered freely into the placental intervillous space. Anndometrial thickness of 8 mm or more is considered to beavorable for embryo implantation.75 Both adequate endome-rial thickness and vascularization are needed for implantation,nd women with a good endometrial thickness on ultrasoundut a poor intra-endometrial blood flow tend to have a pooreproductive outcome.76 Furthermore, uterine perfusion ap-ears to regulate endometrial receptivity, and a high uterineesistance to blood flow is associated with recurrent miscar-iages.77 Decreased expression of SOD and increased levels ofipid peroxidation have also been reported in the decidua ofomen undergoing early pregnancy loss,78 although whether

hese changes are a primary cause or a secondary event is notlear as they are only observed in those cases with associatedaginal bleeding.The causes of early pregnancy failure may therefore be

ivided into three main anatomic categories: disorders affect-ng primarily the villous development such as in aneuploidynd/or lethal fetal anomalies, disorders affecting mainly theytotrophoblast invasion such as in the aPL antibody syn-rome, and disorders of the uteroplacental interface such as inuteal phase deficiency or chronic inflammatory reaction.ome factors, particularly toxins contained within active orassive cigarette smoke, radiation, or viral infection, can haven impact at all three levels, whereas some fetoplacental anom-lies, such as paternally inherited triploidy, can have an impactn both villous development and cytotrophoblast invasiveness.hatever the initial factor, a major defect of the placentation

rocess will lead to an incomplete development of the pla-ento-decidual interface and subsequent premature and wide-pread onset of the intervillous circulation. This will result inevere oxidative damage to the villous trophoblast, whichnevitably leads to a complete placental development arrest.

PLACENTAL OXIDATIVE STRESS IN LATERPREGNANCY AND IN PREECLAMPSIA

easurements of the O2 concentration within the intervillouspace indicate that there is a gradual decline from approxi-ately 60 mmHg at 16 weeks to about 40 mmHg at term.79

espite this decline, and a supposed switch to a less oxidativenvironment, we have found evidence of oxidative stress intherwise normal placentas delivered at term by cesarean sec-ion.80 The cause of this stress is not certain, but extrapolatingur findings from the first trimester suggests that hypoxia alone
s not a sufficient cause. The O2 concentration at term is still a
wice that during the first trimester, when the trophoblasthows no evidence of oxidative stress. Equally, if villi fromerm placentas are maintained in vitro under constant condi-ions of low O2 (12–16 mmHg), they display no increase inxidative stress.80 However, reintroducing O2 after a period ofypoxia causes rapid production of ROS, and evidence ofissue oxidative stress in terms of the formation of nitrotryosineesidues and lipid peroxidation. We have therefore proposedhat the constancy of the O2 concentration may be a moremportant factor in the generation of placental oxidative stresshan the absolute value.81

Oxygen concentrations may fluctuate within the intervillouspace during the second and trimesters through three principalechanisms: intrinsic contraction of the spiral arteries, external

ompression of the arteries, and redistribution of maternallood flow. First, angiographic studies on the macaque, whichisplays a similar maternal vascular anatomy to the human,emonstrated that during normal pregnancy flow from spiralrteries into the intervillous space is often intermittent.18,82 Ashese studies were performed during periods of uterine relax-tion, the investigators concluded that the effect was due toasoconstriction within the unconverted segments of individ-al arteries rather than external compression. This was sup-orted by the observation that an injection of L-epinephrinento the maternal circulation caused a dramatic reduction inhe number of arteries that discharged into the intervillouspace. Second, towards term the strength of the uterine con-ractions increases, and leads to transient compression of theyometrial arteries, either blocking or severely impairing in-

low into the intervillous space.18,83,84 Third, major alterationsn uterine perfusion can occur as part of the general redistri-ution of blood flow in response to factors such as maternalxercise and changes in posture.85 Since the placenta and fetusontinually extract oxygen from the maternal blood within thentervillous space it is expected that transient hypoxia willesult during the periods of relative stasis. Some degree ofypoxia-reoxygenation type injury is therefore likely be aeature of the normal human pregnancy, especially towardserm when the fetal and placental extraction of oxygen are atheir highest.81 This would certainly seem to be the caseuring vaginal delivery when the contractions are at theirtrongest, and there is evidence both of increased xanthinexidase activity within the placenta86 and depletion of mater-al serum vitamin C.87

There is now compelling evidence that placental oxidativetress plays a pivotal role in the pathogenesis of preeclampsia,lthough the precise mechanism remains elusive.1,2,88 Quali-atively, the situation within the placenta in preeclampsia ap-ears to be an extension of that seen towards the end of normalestation, as there is evidence of increased nitrotyrosine for-ation, increased lipid peroxidation, increased trophoblast ap-ptosis, decreased activity of the principal antioxidantnzymes, and reduced tissue concentrations of nonenzymaticntioxidant molecules such as vitamin E.89–94 Again the causeor the oxidative stress is not known, although it is widely
ssumed to be secondary to placental hypoxia consequent to

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he deficient trophoblast invasion that typifies the majority ofases.30,31 The defect involves both the number of vessels thatre converted, and the extent of the transformation withinndividual arteries. The cause for the incomplete conversion isot known, but it appears that only the endovascular compo-ent of trophoblast invasion is impaired. Interstitial invasionxtends as far as normal, and so there may be a primary defectf the endovascular cytotrophoblast or an abnormality in theterine endometrium that these cells are attempting to in-ade.27 It has also been reported that macrophages, which areound in excess in the placental bed of preeclamptic women,re also able to limit the extravillous trophoblastic invasion,95

lthough their influence on the endovascular population is notlear.

The end result is a failure to convert the distal portions ofhe spiral arteries into large-caliber flaccid conduits. We sug-est that by itself this is likely to have relatively little impact onhe volume of intervillous blood flow and O2 concentrations ashese sections of the arteries are not flow-limiting.96,97 Thenconverted segment of the spiral artery where it arises fromhe radial artery will always be of smaller caliber, and so servehat function. By contrast, dilatation of the vessel distal to thisection will have a major impact on the rate and the pressureith which the maternal blood enters the intervillous space,

educing both. In doing so it will benefit materno-fetal ex-hange by ensuring an appropriate passage time through thelacenta and prevent collapse of the fetal villous capillaries.here is also no conclusive evidence that the placenta isypoxic in preeclampsia, particularly in late-onset cases, or thathe placental changes seen in preeclampsia are typical of hyp-xia.81,98 An alternative explanation may lie in the fact that dueo incomplete conversion the majority of spiral arteries withinhe placental bed retain considerable smooth muscle withinheir walls.99 A greater degree of vasoreactivity will thereforeersist, exacerbating the intermittent perfusion seen in normalregnancies. Modeling these effects in vitro has shown thatypoxia-reoxygenation is a much more potent stimulus for theeneration of placental oxidative stress than hypoxialone,80,100 and so likely to be the causative insult underhysiological conditions.

THE SPECTRUM OF PLACENTALOXIDATIVE STRESS

reeclampsia is not an all or nothing phenomenon and therere major differences in the clinical manifestations and out-omes between the early-onset and late-onset forms of theyndrome. In particular, early-onset preeclampsia is almostniversally associated with intrauterine growth restriction,hereas this is rarely the case with late onset. Whether the two

orms represent different disorders or different maternal sus-eptibilities to the products of the stressed placenta is notnown.We propose the two forms represent a spectrum of oxidative

tress induced by differing degrees of impairment of tropho-last invasion. Recent longitudinal studies of placental growth
y ultrasound have revealed that in cases of early-onset pre- p
clampsia associated with intrauterine growth restriction, pla-ental volume is reduced from as early as 12 weeks ofestation.101 This suggests the placental pathology is initiated athe time of onset of the maternal circulation. Because endo-ascular trophoblast invasion is associated with both pluggingf the spiral arteries during the first trimester and their physi-logical conversion, it is likely that onset of the maternalirculation will be perturbed in the most serious cases ofreeclampsia. We speculate that this will lead to high levels ofxidative stress, although insufficient to cause pregnancy lossFigure 4). Nonetheless, there may be increased apoptosis andecreased proliferation, as we have seen in the missed miscar-iage specimens,4 leading to a reduced villous development aterm.102 The altered hemodynamics of maternal blood entrynto the intervillous space, with entry being at too great a rates result of the failure of the distal segments of the spiral arterieso dilate, may also cause the blood-lakes and increased throm-osis that typify these cases.103,104 In addition, early-onsetreeclampsia is commonly associated with acute atherotichanges in the spiral arteries in later pregnancy, which restrictheir caliber still further.31,105 Whether these are primary ef-ects or secondary insults is not known. However, we speculatehat the distal segments of the arteries in which these changesccur will themselves be involved in any hypoxia-reoxygen-tion resulting from increased vasoconstriction of the uncon-erted segments. We consider it most likely, therefore, thathese are secondary changes, and that as they develop there wille an increasing impairment of placental perfusion. Placentalypoxia will ensue, and this, along with reduced placentalunction as result of increased oxidative stress, will contributeo the fetal growth restriction observed. Similar atherotichanges have also been reported in cases of intrauterine growthestriction without hypertension, and so they are not in them-elves causative of preeclampsia.106 Whether the placentasrom these cases display equivalent oxidative stress to that seenn preeclampsia is not known.

By contrast, in cases of late-onset preeclampsia, placentalolume is slightly larger than normal at 12 weeks, and growsapidly until 22 weeks.101 The placental insult is clearly lessevere as villous growth is normal,102,107 and the maternalascular changes are less extensive.31 We propose that theseases represent an exaggeration of the situation that normallyevelops towards term, and that there is insufficient time fortherotic changes in the spiral arteries to become manifestFigure 4). As a result, birth weight is normal, and there will beonsiderable overlap in the values of clinical parameters be-ween these cases and normal pregnancies.

CONCLUSIONaken together, these findings emphasize the critical impor-

ance of the maternal circulation to the well-being of thelacenta. Although confirmatory physiologic data are notvailable, the human placenta is probably unique in undergo-ng a transition in oxygenation at the end of the first trimester.n other species, that part of the placenta involved in hemotro-
hic exchange appears to develop under a more constant O2

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oncentration. For example, the labyrinth of the mouse isascularized by a maternal circulation almost from its origin.he difference is that in the mouse labyrinth developmentommences about half-way through gestation, by which timembryogenesis is almost complete, whereas in humans devel-pment of the placenta occurs much earlier. Maternal meta-olic disorders, for example, diabetes, which are associatedith an increased production of ROS, are also known to be

ssociated with a higher incidence of fetal structural defects.108

urthermore, the teratogenicity of drugs such as thalidomideas recently been shown to involve ROS-mediated oxidativeamage,109 indicating that the human fetus can be irreversiblyamaged by oxidative stress. These findings suggest fetal de-elopment is highly sensitive to perturbation by ROS, andence maintaining a low O2 environment inside the humanterus during early pregnancy may confer protection.By contrast, a profuse and steady maternal blood flow to the

lacenta is clearly required to support fetal growth during theecond and third trimesters. What we observe, however, is thathe transition in the maternal placental circulation at 10 to 12eeks is a potentially dangerous one. It must be carefullyrchestrated in a periphery-center fashion to prevent over-helming oxidative stress to the placenta, which may contrib-te to pregnancy failure. Plugging/unplugging of the spiralrteries appears to be related to successful invasion of thextravillous trophoblast cells, a process that is also linked toonversion of the spiral arteries. Hence, we speculate that inormal pregnancies trophoblast invasion is complete, unplug-ing of the vessels is orderly, and the arteries are fully con-erted. If trophoblast invasion is less complete, the vessels mayetain some of their vasoreactivity, leading to a greater degreef intermittent perfusion of the intervillous space and placentalxidative stress and predisposing the mother to preeclampsia. Ifrophoblast invasion is particularly shallow, then unplugging ofhe vessels may be premature and disorganized, resulting inverwhelming placental oxidative stress and pregnancy failure
Figure 5). Miscarriage and preeclampsia may therefore be part
f a continuum of placental oxidative stress, which althougheing heavily influenced by the depth of trophoblast invasion,ay also integrate other factors such as polymorphisms in

nzymes either generating or scavenging ROS, metabolic dis-rders, drug intake, dietary micronutrients, and maternal sus-eptibility to the products of placental oxidative stress.

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Placental oxidative stress: From miscarriage to preeclampsia

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