Placenta
Volume 30, Supplement , Pages 38-42, March 2009

Placental Stress and Pre-eclampsia: A Revised View

Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK

Accepted 26 November 2008. published online 12 January 2009.

Article Outline

Abstract 

In pre-eclampsia, poor placentation causes both oxidative and endoplasmic reticulum stress of the placenta. It is believed placental hypoxia stimulates excessive production of soluble fms-like tyrosine kinase 1 (sFlt-1), which binds and deactivates circulating vascular endothelial growth factor (VEGF). When maternal endothelium is deprived of VEGF it becomes dysfunctional hence leading to the clinical syndrome of the mother.

In this paper the previous claim that poor placentation may predispose more to placental oxidative stress than hypoxia is reiterated. We show why pre-eclampsia is not only an endothelial disease, but also a disorder of systemic inflammation. We question that hypoxia is the only or indeed the main stimulus to release of sFlt-1; and emphasise the role of inflammatory mechanisms. Hypoxia cannot be assumed simply because hypoxia-inducible transcription factors (HIF) are upregulated. Concurrent assessments of nuclear factor-kappaB (NF-κB), a transcription factor for inflammatory responses are desirable to obtain a more complete picture. We point out that the pre-eclampsia placenta is the source of bioactive circulating factors other than sFlt-1 in concentrations that are much higher than in normal pregnancy. These may also contribute to the final inflammatory syndrome. We propose a modified version of the two-stage model for pre-eclampsia.

Keywords: Pre-eclampsia, Oxidative stress, Hypoxia, Systemic inflammatory response, sFlt-1, Endoglin, HIF-1, NF-kappaB

 

This is a brief overview intended to show how inflammatory processes participate in the pathogenesis of pre-eclampsia in a broader way than has been previously appreciated. It starts with the two-stage model of pre-eclampsia (see Ref. [56]) and the localised placental stress of pre-eclampsia, including the endoplasmic reticulum stress that has been elegantly presented by Burton et al. [57], and considers how this becomes the generalised or systemic stress of the clinical disease. We review the relationship between endothelial and inflammatory stress, the wider consequences of the inflammatory response that are seen in pre-eclampsia and conclude that pre-eclampsia is not just an endothelial disease. We then discuss the evidence that syncytiotrophoblast factors other than sFlt-1 may be involved in generating pre-eclampsia and the possibility that inflammatory stimuli may be the cause of its release from the placenta instead of, or in addition to, hypoxia. The other syncytiotrophoblast factors that are released in greater amounts from the pre-eclampsia placenta are considered. These are bioactive, and in some cases, pro-inflammatory and are likely to contribute to the maternal disorder. Because of limitations of space it is not possible to provide detailed and full references. Instead the reader is often referred to authoritative reviews where the basic sources for the concepts outlined here can be found and which give access to many more relevant references.

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1. Placental stress 

It is known that the pre-eclampsia placenta is affected by oxidative stress (reviewed in Ref. [1]) and nitrosative stress [2]. There are differing views as to how this arises. The first is that it is secondary to reduced uteroplacental arterial flow, which is smaller than it should be owing to inadequate remodelling of the spiral arteries during placentation (see Kaufmann et al [3], for example). The second is that it is not the volume flow that is abnormal but its intermittency, through narrow arteries that retain their smooth muscle, which creates the conditions of ischaemia reperfusion [1]. The implication of the former view is that the placenta is chronically hypoxic. In the latter case, intermittent high velocity flow leads to variable oxygenation in the intervillous space, which would be predicted to create oxidative stress and reactive oxygen species.

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2. Systemic stress in pre-eclampsia 

The end-stage of the placental disorder of pre-eclampsia is a maternal syndrome defined in terms of its cardiovascular and renal features (new hypertension and proteinuria that resolve after delivery). The proteinuria is associated with a specific endothelial renal lesion (glomerular endotheliosis), [4] and there is wide-ranging evidence that the hypertension is secondary to diffuse endothelial dysfunction [5]. Hence, it is now considered that pre-eclampsia is an endothelial disease. This is true but the concept is incomplete.

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3. The systemic inflammatory response 

The endothelium is a component of the inflammatory system. Endothelial cells are key players in systemic inflammatory responses as well as mediating local inflammation by upregulating adhesion molecules that tether and then anchor marginated leukocytes. Atherosclerosis is a focal inflammatory large vessel disease; whereas microvascular endothelium promotes diffuse systemic inflammation [6]. If pre-eclampsia is an endothelial disorder then the corollary is that it is also an inflammatory disorder. The latter is a more generalised concept that includes the former. The inflammatory response is generated by the systemic inflammatory network which involves, apart from the inflammatory immune cells (monocytes, polymorphonuclear leukocytes, and natural killer cells), the clotting and complement systems, the endothelium and, in addition, metabolic and other changes. The last are not normally considered to be part of endothelial dysfunction. Communication between the various components of the inflammatory network is facilitated by a large range of secreted proteins such as cytokines and other factors that have a confusing nomenclature.

The term cytokine originally referred to those proteins that are produced by, and act on, immune and haemopoietic cells. But they can also be secreted by non-immune cells. Some cytokines are chemokines, for example, interleukin-8 (IL-8). Adipokines include all proteins that are secreted from, and are synthesized by, adipocytes but exclude products of other cell types (such as macrophages) in adipose tissue [7]. Adipokines include cytokines such as interleukin-6 (IL-6), classical adipokines (leptin, resistin, adiponectin) and even acute phase proteins such as plasminogen activator inhibitor-1 (PAI-1) and angiotensinogen. Angiogenic factors include cytokines, for example, VEGF, which is also a growth and survival factor for endothelium. The three adipokines listed also have actions on the immune cells (cytokine activity) and, in addition, angiogenic activity, as reviewed by Ribatti et al [8]. Other biologically active proteins or peptides can have cytokine-like activity, such as angiotensin II (Ang II); which is directly pro-inflammatory [9]. Insulin on the other hand is anti-inflammatory (as reviewed by Dandona et al [10]). Despite these cytokine-like actions, neither Ang II nor insulin are considered to be cytokines.

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4. Normal pregnancy is associated with a systemic inflammatory response 

Normal pregnancy evokes a systemic inflammatory response [11]. This manifests in several ways, summarised Redman and Sargent [12], including activation of monocytes and granulocytes, and of the endothelium. It is associated with evidence of increasing systemic oxidative stress as pregnancy advances in terms of several circulating markers particularly oxidized lipids as, for example, reported by Belo et al [13].

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5. Pre-eclampsia is not just an endothelial disorder 

All the inflammatory changes of normal pregnancy are exaggerated in pre-eclampsia (Table 1). This of course involves the endothelium but also other components of the inflammatory network, including inflammatory leukocytes. There is no question that the features of the disease that are clinically most prominent derive from dysfunctional endothelium. But the stress response is wider: there are associated changes such as the acute phase response and metabolic responses triggered by systemic inflammation.

Table 1. The systemic inflammatory network is stimulated in pre-eclampsia relative to normal pregnancy.
Inflammatory componentReference
Leukocytosisa[14]
Increased leukocyte activationa[15]
Complement activationa, b[16]
Activation of the clotting systema[17]
Activation of plateletsa[18]
Markers of endothelial activationa[19]

Increased circulating pro-inflammatory cytokines
Plasma tumour necrosis factor-αa[20]
Plasma interleukin-6a, c[21]
Plasma interleukin-8a, c[22]

There are usually multiple references to justify each change.

aSignificant change(s) relative to normal pregnant women.

bNot all authors agree.

cAlmost all authors agree.

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6. Acute phase response 

The acute phase response, which also may be a chronic response, is a variable reaction to inflammation, local or systemic. It comprises changes in circulating plasma protein concentrations and other phenomena such as fever or leukocytosis and metabolic adaptations, which are summarised by Gabay and Kushner [23]. Proteins linked to the acute phase response, acute phase proteins, are synthesized in the liver. They are classed as positive, if they increase with systemic inflammation, of which C reactive protein is the best known, or as negative, if they decrease. In pre-eclampsia, many acute phase proteins change. These comprise increases in CRP, angiotensinogen, fibrinogen, various other clotting proteins including plasminogen, complement components including C3, alpha-1-antitrypsin, caeruloplasmin, soluble phospholipase A2, sialic acid and alpha-1-acid glycoprotein (reviewed by Redman and Sargent, [24]). Albumin, an example of a negative acute phase reactant, is reduced.

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7. Other metabolic responses 

Systemic inflammation has other effects on metabolism, specifically involving central adipose tissue. Experimental administration of endotoxin, tumour necrosis factor-α (TNF-α) or other pro-inflammatory factors cause insulin resistance and hyperlipidaemia (see review by Harris et al [25]). TNF-α mediates these changes: it induces insulin resistance, inhibits lipogenesis and stimulates lipolysis [26]. Lipolysis releases free fatty acids (FFA), of which circulating levels are increased in pre-eclampsia [27].

Obesity, which is a risk factor for pre-eclampsia, is characterized by a systemic inflammatory response in non-pregnant individuals. Adipose tissue is not simply an energy store but a rich source of pro-inflammatory cytokines and other metabolic mediators (adipokines). Visceral, rather than subcutaneous, fat is more important in this context. Adipocytes secrete TNF-α, IL-6 and PAI-1, and are the principal source of leptin. Leptin is secreted during acute inflammation and has an important action on immune cells, all of which express the leptin receptor. Leptin thereby causes or enhances pro-inflammatory responses (Reviewed by Matarese et al [28]) and could be classed as cytokine as well as an adipokine. An inflammatory response is amplified in obese individuals because of the pro-inflammatory input from adipose tissue [29].

In summary, the evidence for involvement of the entire systemic inflammatory network in pre-eclampsia justifies the conclusion that the disorder is more than endothelial dysfunction.

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8. The role of placenta factors 

In the context of the hypothesis of systemic inflammation, it would be predicted that it is caused by one or more pro-inflammatory factors released from the syncytial surface of the placenta into the maternal circulation.

Syncytiotrophoblast secretes many bioactive factors (Table 2) which are significantly altered in pre-eclampsia. Of most interest is the soluble receptor for vascular endothelial growth factor, sVEGFR-1 which is also called sFlt-1. When present in excess, as in pre-eclampsia, it binds to, and inactivates, VEGF, a key survival factor for endothelium [34], and thereby induces systemic endothelial dysfunction.

Table 2. Circulating placental factors that are altered in pre-eclampsia.
Dissemination of the placental problem
FactorReference
Corticotrophin releasing hormone (CRH)[30]
Activin-A[31]
Inhibin A[31]
Leptin[32]
Endoglin[33]
sFlt-1[34]
Placental growth factor[35]
Trophoblast microparticles[36]

Hypoxia stimulates release of sFlt-1 from the placenta [37]. Hence there is a view that the pathogenesis is more or less clarified. Poor placentation leads to poor uteroplacental perfusion and hypoxia, which stimulates sFlt-1 production which causes the maternal syndrome. One purpose of this overview is to challenge this assumption.

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9. Hypoxic or inflammatory stimulation of sFlt-1 and sEndoglin release? 

Although hypoxia is one trigger for release of sFlt-1 from the pre-eclampsia placenta [37], inflammatory mechanisms may contribute or even predominate. For example, TNFα provokes sFlt-1 release from cultured placental explants in a dose–response manner [38]. There is no question that hypoxia is an important stimulus. Our purpose is to highlight that pro-inflammatory stimulation has a similar effect without hypoxia and to propose that what has previously been ascribed to hypoxia, on the basis of upregulation of HIF-1α protein may, in fact, be owing to placental inflammatory stress.

In other tissues and contexts there is evidence that HIF-1α itself can be stimulated and stabilised by inflammatory stimuli under normoxic conditions [39], [40], [41], [42], [43]. This is an example of a more general phenomenon namely of overlap between inflammatory and hypoxia responses. Blouin et al, 2004 [39], for example, show that lipopolysaccharide (LPS), a classical pro-inflammatory stimulus, activates expression of a typical set of hypoxia gene products (VEGF, Glucose Transporter-1 (GLUT-1), PAI-1, inducible nitric oxide synthase (iNOS)) in a rat macrophage cell line, when cultured under normoxic conditions. They also demonstrate, in primary rat macrophages or in the macrophage cell line, that LPS stimulates HIF-1α protein expression, again in normoxia. The stimulation is both dose and time dependent. The time course of HIF-1α protein expression is faster with hypoxia than normoxic inflammatory stimulation [39]. In this model, LPS works by increasing HIF-1α gene transcription, which accounts for the slower response, whereas hypoxia acts by stabilising HIF-1α gene expression. LPS acts through the classical protein kinase C (PKC) and the phosphoinositol 3-kinase (PI3K) pathway, (demonstrated by specific inhibitors) which have little effect on the induction of HIF-1α by hypoxia [39]. In summary, a similar set of stress response genes can be induced quickly by stabilising HIF-1α protein expression by hypoxia or, more slowly, under normoxic conditions by pro-inflammatory stimuli. The latter involves a different mechanism, namely, inducing transcription of the HIF-1α gene via pathways involving PKC and PI3K. The authors summarize more than 10 other studies that give primary evidence of inflammatory induction of hypoxia genes under normoxic conditions [39].

There are other inflammatory stimuli including thrombin, growth factors, vasoactive peptides and cytokines such as TNF-alpha that can activate HIF-1α [40]; reactive oxygen species (ROS) have a similar effect. The wider picture involves interaction between HIF-1α and NF-κB, a major transcription factor for the inflammatory response [40], [41]. The HIF-1α promoter contains an active NF-κB binding site upstream of the transcription start site [42]. This has been shown to bind several NF-κB subunits directly. Moreover, depletion of NF-κB reduces unstimulated levels of HIF-1α mRNA, suggesting that its presence sustains a basal level of production [42], as has been confirmed in another study [43]. Hence it seems that the HIF-1α is misnamed. Its responses are not limited to hypoxia but are also responses to inflammatory stimuli, in particular those mediated by NF-κB. These conclusions have not yet been fully explored in relation to hypoxic and inflammatory responses of trophoblast. However, a recent report shows that AngII, a pro-inflammatory stimulus, increases the expression of HIF-1α at both mRNA and protein levels in cultured placental explants [44], which is consistent with these concepts.

Soluble endoglin is another anti-angiogenic factor, derived from syncytiotrophoblast whose circulating levels are increased in pre-eclampsia [33]. It is upregulated by hypoxia [45], although there is inconsistency in the reports, see Ref. [46] for an example. Relevant to our argument, is that its release from endothelial cells or placental explants is also stimulated by inflammatory cytokines (interferon-γ, TNF-α) under normoxic conditions [47].

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10. Pro-inflammatory products of syncytiotrophoblast 

There are several other bioactive circulating factors derived from syncytiotrophoblast that could affect maternal systemic inflammation or angiogenesis or both (see Table 2). Many are pro-inflammatory including corticotrophin releasing hormone (CRH), [48], activin-A [49], leptin [28], placental growth factor (PlGF) [50] and trophoblast-derived microparticles [51]. CRH, for example, has both peripheral and central actions. Its peripheral actions are mediated by two receptors (CRH-R1, CRH-R2), of which both are expressed on endothelium. CRH-R2 stimulates endothelial release of endothelin [52], known to be involved in the genesis of pre-eclamptic hypertension [53] and a pro-inflammatory factor in its own right [54]. Activin-A together with pro-inflammatory cytokines TNF-α, interleukin-1β and IL-6, are released after LPS challenge in mice as an immediate downstream effect of activation of Toll-like receptor-4 [49]. Administration of the endogenous inhibitor of activin-A, follistatin, blocks the increases in the inflammatory cytokines [49] indicating the importance of activin-A in mediating the inflammatory responses to LPS. As stated earlier, leptin is an activator of monocytes and macrophages [28]. In addition it alters T cell function, with polarization towards Type 1 activation [28], which is a feature of pre-eclampsia [55]. Except for PlGF, circulating levels of the listed factors are all increased in pre-eclampsia. It is not known if they contribute to the systemic inflammatory activation of normal pregnancy but the issue merits investigation.

In terms of endothelial dysfunction there is an important secondary involvement of neutrophils, which are activated (see above). There is evidence that they interact with the endothelium in pre-eclampsia [55], where they may cause endothelial damage. If this mechanism is involved in pre-eclampsia, it is most likely to be secondary, if only because it is of maternal not placental origin. The anti-endothelial or other proteins released by syncytiotrophoblast (sFlt-1, sEndoglin) are more likely to be the primary causes of the endothelial dysfunction.

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11. Conclusion 

The primary placental problem that generates the pre-eclampsia syndrome is likely to be oxidative stress rather than hypoxia, as proposed by Hung and Burton [1]. Oxidative stress is an inflammatory stimulus mediated by reactive oxygen species; hence we speculate that this provokes the release of sFlt-1 and possibly soluble endoglin via NF-κB as much as or more than hypoxia. We argue that pre-eclampsia is not only an endothelial disease. but the consequence of a wider systemic inflammatory response. There are several pro-inflammatory factors other than sFlt-1 and sEndoglin released in excess by the syncytiotrophoblast in pre-eclampsia; we speculate whether they also contribute to the maternal systemic inflammatory stress. An updated version of the two-stage model is shown in Fig. 1. If these concepts can stimulate new thinking and new research, then this paper will have served its purpose.

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12. Conflict of interest 

The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.

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PII: S0143-4004(08)00395-0

doi:10.1016/j.placenta.2008.11.021

Placenta
Volume 30, Supplement , Pages 38-42, March 2009

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