Placenta 35, Supplement A, Trophoblast Research, Vol. 28 (2014) S26eS31

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IFPA Award in Placentology Lecture: Preeclampsia, the decidual battleground and future maternal cardiovascular disease A.C. Staff a, b, c, *, C.W.G. Redman d a

Department of Obstetrics, Oslo University Hospital, Ullevål, Norway Department of Gynaecology, Oslo University Hospital, Ullevål, Norway c Faculty of Medicine, University of Oslo, Oslo, Norway d University of Oxford, Oxford, United Kingdom b

a r t i c l e i n f o

a b s t r a c t

Article history: Accepted 10 December 2013

The decidua basalis is one of the frontiers between placenta and mother. Its spiral arteries ensure that the placenta and fetus have adequate access to the maternal circulation, without compromising maternal health. Normally this requires a tightly regulated collaboration between tissues of genetically different individuals. But like all frontiers it can become a battlefield. The decidua is difficult to sample systematically. Some of the problems have been resolved by our vacuum suction method. We review the technique and how it has contributed to what we know of decidual tissue, especially when it becomes a battlefield in preeclampsia, with its increased oxidative stress and inflammation. Acute atherosis is a poorly studied decidual lesion of late pregnancy, which mainly affects the decidual tips of spiral arteries in preeclampsia. It is characterized by lipid-filled foam cells and resembles early atherosclerosis. Poorly remodelled spiral arteries seem to be especially susceptible. The underlying mechanisms are largely unknown, but are likely to be similar to those of atherosclerosis and primarily the consequence of vascular inflammation. Acute atherosis also occurs in other pregnancy complications, even in normal pregnancies. It appears not to be confined to maladapted spiral arteries nor be caused by hypertension. It is important that foam cells result from inflammatory stimulation of macrophages. Hence, we propose that decidual inflammation of multiple causes underlies acute atherosis, with or without preeclampsia. Women suffering from preeclampsia have an augmented risk of cardiovascular disease later in life and of premature death. Acute atherosis may more specifically identify those women at augmented risk for such later cardiovascular disorders, whether or not it is associated with preeclampsia. Ó 2014 Published by IFPA and Elsevier Ltd.

Keywords: Preeclampsia Cardiovascular disease Atherosclerosis Atherosis Hypertension Pregnancy Spiral artery

1. Introduction: Decidua basalis: a battleground that is poorly studied in late pregnancy and preeclampsia The third trimester decidua basalis is poorly studied. Few publications deal with this important fetalematernal interface late in pregnancy or in established preeclampsia, compared to the numbers describing specific spiral artery pathology early in pregnancy or in the myometrial portions of placental bed biopsies. The fetus has been named “Nature’s transplant”. In fact, it is the placenta that is the transplant, being the only part of the fetoplacental unit in direct contact with the maternal immune system. The decidua is the boundary between maternal and fetal tissues and one of two major fetaleimmune interfaces in pregnancy, the * Corresponding author. Dept of Obstetrics, Oslo University Hospital, Ullevål, Post Box 4950 Nydalen, N-0424 Oslo, Norway. E-mail addresses: [email protected], [email protected], staff.bakken@ online.no (A.C. Staff). 0143-4004/$ e see front matter Ó 2014 Published by IFPA and Elsevier Ltd. http://dx.doi.org/10.1016/j.placenta.2013.12.003

intervillous space being the second [1]. At both these immunological interfaces, fetal cells meet maternal cells. In the first half of pregnancy, the decidua has been extensively studied to define the vital spiral artery remodelling process, which may begin as early as 2 weeks post fertilization [2] and continues until about 8e18 weeks of pregnancy, which optimizes uteroplacental flow (reviewed in Ref. [3]). The remodelling results from a complex interaction between maternal decidual immune cells in the uterine wall and invasive trophoblasts, which express only HLA-C among the major transplantation antigens. During remodelling, the arterial media is replaced by fibrinoid and the arterial diameter increases 5-10-fold. In many cases of preeclampsia, the spiral arteries are incompletely remodelled [4]. Trophoblast invasion is often defective in preeclampsia, particularly in early-onset preeclampsia, affecting the endovascular, but not the interstitial invasion pathway, and the remodelling of myometrial spiral artery segments is particularly affected [5]. However, defective remodelling is also seen in cases of fetal growth restriction without

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2. Sampling decidual tissue Adequate decidual tissue is necessary to study late pregnancy decidual lesions. The preferred technique depends on several factors, the most important being the research question and delivery mode. Whether the decidua basalis (underlying the placenta) or parietalis or both is to be studied, is also important. Historically, the most complete sample could be obtained during hysterectomy with the placenta in situ, at deliveries in Catholic hospitals, not allowing tubal sterilization [12]. This would be considered to be unethical in most countries today. Placenta bed biopsies (Fig. 1), containing decidua basalis, have traditionally been obtained by punch or knife biopsies, most often during caesarean delivery, but also transvaginally after ultrasound localization of the placenta prior to abortion or delivery. These biopsies also contain myometrial tissue, and are preferable when studying remodelling of the spiral arteries, as the myometrial segments are where the remodelling process often fails [5]. Placental surface biopsies (Fig. 1) can easily be taken from delivered placentas, and will include a moderate sample of the decidua basalis. The decidual vacuum suction method (Fig. 1) that was developed by us yields adequate volumes of decidual tissue [13e16]. It is performed at cesarean section, preferably on nonlaboured tissue (avoiding variations in uteroplacental ischaemia and reperfusion). The placenta is localized by intrauterine placenta palpation during the caesarean section, after delivery of the baby. The uterine wall underlying the removed placenta is subjected to vacuum suction after the placenta has been gently delivered. We showed that the method is superior to traditional biopsies from the placental bed and maternal surface of placenta, in terms of the numbers of decidual spiral arteries and volume of decidual tissue obtained [15]. Advantages of decidual suction compared to placenta bed biopsy include: 1) a larger amount of tissue, which facilitates

PBB

DSM

hypertension, and in pregnancy induced hypertension (without proteinuria) and even rarely in normal pregnancy [3]. The resulting abnormal uteroplacental flow is associated with placental oxidative and endoplasmic reticulum stress, probably from ischaemiareperfusion injury [6]. This stimulates the release of placental factors that mediate the features of preeclampsia [3]. It is not known in detail why some pregnancies with inadequate spiral artery remodelling develop preeclampsia, and others not. The concept of the placental-fetal ‘allograft’ is obsolete [7]. Pregnancy progresses successfully because of immune modulation that allows invasive semi-allogeneic trophoblasts and the maternal immune system to collaborate and achieve success [8]. Although there is no evidence for classical immune rejection, there is potential for dysregulation which may turn the decidua, not so much into a battlefield, as into a scene of guerrilla warfare. This is exemplified during placentation where the risk of preeclampsia depends, at least in part, on the interactions between fetal (paternal) HLA-C expressed on invasive trophoblast and the highly polymorphic KIR (Killer immunoglobulin-like receptors) expressed by maternal uterine natural killer (NK) cells. The combination of maternal uNK cell genotype KIR-AA and fetal extravillous trophoblast HLA-C2 genotype has the highest risk of preeclampsia [9]. T cells and the adaptive immune system are also involved in that HLA-C incompatibility between mother and fetus is associated with increased T cell activation and generation of regulatory T cells [10]. We have recently proposed that local decidual maternalefetal immune cell interactions may continue to be important in the second half of the pregnancy and contribute to the development of acute atherosis. The distribution of maternal immune cells in the decidua basalis changes between early and late pregnancy [11], and their function in late pregnancy is understudied.

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Umbilical cord

BPS Myometrium Decidua basalis

Placenta

Fig. 1. Three methods for sampling late pregnancy decidua basalis tissue. The figure shows three decidual basalis tissue sampling methods in relation to the myometrium and decidua basalis of the uterine wall and in relation to the delivered placenta; PBB: placental bed biopsy, BPS: basal plate section; DSM: decidual suction method at cesarean delivery, as developed by the first author [14], and later evaluated in relation to the other two sampling methods [15].

both morphological and molecular studies; 2) sampling from the whole placental bed, which is less biased than collecting isolated biopsies; 3) speed and simplicity, without short- or long-term complications when performed by experienced operators [15]. This vacuum suction technique has proved to be applicable to studies of late pregnancy decidual lesions, such as acute atherosis, as well as to immunological studies of late pregnancy decidual immune cells, sorted by flow cytometry. The tissue does not include the myometrium, making it less suitable to study spiral artery remodelling in the myometrial segments, but more appropriate to study decidual segment pathology. It also lacks orientation within the decidual tissue, in contrast to placental bed biopsies, in which orientation is conserved in relation to the myometrium. Placenta bed biopsy, however, has its own limitations [15], including: 1) a lower tissue yield; 2) sampling error, increasing the possibility of unrepresentative findings; 3) potential clinical complications such as uterine wall perforation and bleeding, necessitating surgical repair. Extensive placenta bed biopsies may damage the uterine wall in the short- and long-term and need to be limited in women who have the specific requirement to conserve fertility. 3. Acute atherosis, an inflammatory decidual lesion of late pregnancy We find acute atherosis affecting 20e40% of cases of preeclampsia [16], but it does not affect the systemic maternal arteries [16]. It was first described in 1945 [17] and named in 1950 [18]. The hallmark of acute atherosis is CD68-positive subendothelial lipidfilled foam cells [19], derived from macrophages and possibly smooth muscle cells ([20], reviewed in Ref. [21]), associated with an inflammatory mononuclear cell infiltrate [22]. It resembles early stages of atherosclerosis, as in our samples (Fig. 2), and is strikingly similar to coronary artery atherosclerosis. Table 1 summarizes some of the similarities between atherosclerosis and acute atherosis features, as presented by us previously [21,23]. Acute atherosis and defective spiral artery remodelling during the first half of pregnancy may be related in that the lesions usually are restricted to downstream of the affected spiral arteries, namely at their tips where they feed into the intervillous space. Acute atherosis occurs more rarely in the myometrial segments of the

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Fig. 2. Acute atherosis of uterine spiral arteries and coronary artery atherosclerosis. The sections (aec) show acute atherosis in the spiral arteries during third trimester pregnancy, resembling the early stages of atherosclerosis development. Reprinted with permission from the journal [16]. aec: Parallel sections of decidual tissue spiral artery in a preeclamptic patient, collected with our vacuum section technique, stained with haematoxylin and eosin (a, b), showing decidual acute atherosis with subendothelial foam cells (FC) in the intima. The vessel lumen is occluded with a central thrombus. (c) Same artery with CD68 immunostaining, demonstrating lipid-laden foam cells in the vessel wall lining the subendothelial area. Non-laboured decidua basalis tissue collected with our vacuum suction method at caesarean delivery during third trimester [16]. The section d shows the presence of more “advanced” stages of the atherosclerotic process in the classical coronary artery atherosclerosis. This is a cross-section from a coronary artery from a patient who died of a myocardial infarction. It contains an occlusive thrombus superimposed on a lipid-rich atherosclerotic plaque that has ruptured [56].

spiral arteries [22,24], but is not a hypertensive lesion, as it occurs in normotensive cases [16]. We argue that acute atherosis represents an inflammatory lesion [21], similar to the view today that atherosclerosis is an inflammatory lesion of the arterial wall, not a hyperlipidemic or hypertensive disease per se [25]. Acute atherosis may also affect pregnancies complicated by fetal growth restriction (without maternal hypertension) and certain autoimmune diseases (including systemic lupus erythematosus and antiphospholipid syndrome), although there is currently limited information to estimate the incidence with these presentations [3]. We have also demonstrated CD68 þ subendothelial foam cells in 14% of uncomplicated pregnancies with presumed normal artery remodelling [16]. Given the limited data from small and heterogeneous studies, it is believed that acute atherosis is a feature of late pregnancy. The link to clinical phenotypes is uncertain, although Stevens et al. (2012) suggest an association with more severe preeclampsia [26]. Acute atherosis lesions narrow the spiral artery lumen, which would be expected to exacerbate dysfunctional uteroplacental flow, and predisposes to thrombosis and placental infarction [7]. Its time course is not defined, nor is it known why it affects some, but not all women with preeclampsia, nor the extent to which it develops in other pregnancies. 4. Preeclampsia: a state of excessive systemic and local decidual inflammation and oxidative stress As reviewed elsewhere [27], preeclampsia is a state of systemic maternal inflammation, exceeding that of normal pregnancies. Several studies support this concept (reviewed in Ref. [4]), showing excessive oxidative and inflammatory stress in the maternal circulation in preeclampsia as compared to uncomplicated pregnancies [28,29]. The current concept is that this is secondary to placental oxidative stress associated with failed spiral artery remodelling, probably caused by placental ischaemia-reperfusion injury with excess release of placental factors that cause the features of preeclampsia [6]. However, even in normal pregnancy the

placenta imposes increasing inflammatory stress on the maternal circulation. In preeclampsia, this inflammatory burden is excessive [30], either owing to excessive placental-associated factors and/or excessive maternal sensitivity to the normal amount of these factors. For both types, systemic inflammation may result from a variety of circulating factors such as pro- and antiangiogenic proteins, trophoblast-derived micro- and nanovesicles and other proinflammatory products [31], as well as activating autoantibodies against the AT1-receptor. Maternal susceptibility to preeclampsia from genetic variance may also be important [32], as genetic factors influence all the proposed pathophysiological mechanisms of preeclampsia [33]. The hyperlipidaemia of normal pregnancy worsens in preeclampsia, with a pro-atherogenic lipid profile [3], aggravating the pregnancy inflammatory burden. Important for understanding the pathophysiology of preeclampsia is that inflammation and oxidative stress are not separated entities, but occur together and represent two sides of the same coin. Oxidative stress is a powerful proinflammatory stimulus, and inflammatory stress creates oxidative stress [34,35]. The transcription factors NF-kappaB and HIF-1alpha orchestrate the inflammatory and hypoxia responses respectively and also activate each other. This close crosstalk is essential for understanding the vascular inflammation of preeclampsia. The augmented systemic inflammatory response of preeclampsia maps also to the placenta [36,37] and decidua [38e41]. Our studies confirm the oxidative stress of the decidua in preeclampsia, with augmented 8-isoprostane concentrations [14] and phospholipase A2 activity [42]. We have also shown that chloroform/methanol extracts of homogenized decidua basalis contain more lipids and lipid peroxides than equivalent preparations from uncomplicated pregnancies [13]. It is well known that the renin angiotensin system (RAS), essential for human blood pressure control, may be dysregulated in preeclampsia [43]. However its contribution to the pathophysiology is unclear. Important for our concept of decidual inflammation in acute atherosis and preeclampsia is that angiotensin II (AngII) is a potent pro-inflammatory cytokine and, together with

A.C. Staff, C.W.G. Redman / Placenta 35, Supplement A, Trophoblast Research, Vol. 28 (2014) S26eS31 Table 1 Acute atherosis (of pregnancy) and atherosclerosis (of non-pregnancy): similarities and dissimilarities (suggested by us in Refs. [21,23]). Features

Acute atherosis (as known from preeclampsia studies)

Atherosclerosis

Associated with dyslipidemia and oxidative stress Presence of CD68þ foam cells, derived from activated macrophages (as well as smooth muscle cells [20,55]) Develops over long time course

Yes

Yes

Yes

Yes

No (only during short time of pregnancy)

Affects larger arteries as well as small (not known to occur in veins) More often localized in arteries with altered flow and shear stress

No

Yes (fatty streaks may appear early in life, but advanced stage atherosclerosis likely to develop over decades) Yes

Plaque formation and rupture as terminal lesion event An inflammatory lesion. Hyperlipidaemia and hypertension not prerequisites for the lesion, but facilitating factors? Innate and adaptive immunity involved

Yes (downstream of unremodeled myometrial segments of spiral arteries) No (duration of lesion is too short)

Yes (after arterial branching)

Proposed by us [23]

Generally accepted [25]

Proposed by us [23]

Yes, although the mechanisms are not fully understood [25]

Yes

the angiotensin II type 1 receptor (AT1), is implicated in the progression of atherosclerosis through several mechanisms [44]. A key feature of many cases of preeclampsia is the presence of circulating agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA), also shown by us previously [43,45]. If these autoantibodies are as proinflammatory as angiotensin II itself, they could be expected to be a major contributor to the vascular inflammation of preeclampsia. We have also shown that the local RAS is upregulated in decidual, but not placental tissue, and that the AT1 receptor in decidual tissue is upregulated in preeclampsia [43]. If there is decidual oxidative stress in any pregnancy, inflammatory activation would be the corollary, as stated above. Acute atherosis is located particularly in the decidua where there is evidence for excessive inflammation, which raises the question of whether this could contribute to its development. 5. Decidual acute atherosis: new hypotheses 5.1. Is excessive decidual inflammation the final common pathway to acute atherosis? We have suggested that acute atherosis results from different pathways (separately or in combination), that are immunological, inflammatory, genetic and haemodynamic (the last secondary to impaired spiral arterial remodelling and perturbed laminar blood

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flow), leading to a common end-point, namely inflammatory stimulation of periarterial foam cell formation [21,23]. The inflammatory and immune cell populations of the decidua basalis, during the third trimester, are therefore a central issue, as has been recently reviewed [11]. The populations evolve as pregnancy progresses. In both decidua basalis and parietalis the numbers of macrophages and NK cells decline, T-cells do not change substantially, whereas those of NKT cells increase in the decidua basalis [46]. The continuing discovery of an increasing number of subsets of the classical inflammatory and immune cells means that decidual immune cells need to be phenotyped at a much greater resolution than has hitherto been available. The peri-arterial lymphocytic infiltrate of acute atherosis is a clear indicator of an inflammatory response in that location. However, the most recent characterization, more than 10 years ago, is confined to showing a relative increase in NK cells and CD8þ (cytotoxic) T cells, more prominent in cases with than without fetal growth restriction [47]. An unusual type of atherosis is found in transplanted allografts, for example of kidney or heart [25], prompting suggestions that alloreactivity between maternal decidual immune cells and fetal extravillous trophoblasts (EVT) may predispose to acute atherosis. Most attention has been given to such interactions occurring in the first half of pregnancy during trophoblast invasion of the placental bed and spiral artery remodelling. However, extravillous trophoblast and immune cells persist in the decidua throughout the second half of pregnancy and the possibility that inappropriate alloreactivity may develop or persist needs to be considered. For example, at term, the higher the number of HLA-C maternalefetal mismatches, the greater is the number of activated decidual T cells, associated with induction of functional T regulatory cells that are not present when there are no mismatches [10]. In short, there is maternal immune recognition of foreign fetal HLA-C on extravillous trophoblast, which has been appropriately modulated. The antiinflammatory Th2 milieu of normal pregnancy is altered to the more proinflammatory Th1 response in preeclampsia. Also, in general, proinflammatory Th17 cells are more prominent in decidual tissue than in the circulation [48]. Reinvestigation of these issues is now much easier given the availability of banked decidual tissue collected by vacuum suction technique. We propose that this and other pathways converge to cause excessive decidual inflammation as the final common step for acute atherosis. Excessive inflammation per se, even without hyperlipidaemia, inhibits reverse cholesterol transport, promoting lipid retention and foam cell development [23]. This mechanism, thought to be essential for the development of atherosclerosis, is likely to be relevant for acute atherosis in any inflamed decidual tissue, whatever the clinical context. We propose that a dysfunctional maternalefetal immune interaction may be an important driver for this excessive decidual inflammation, although the molecular mechanisms are unclear. This hypothesis, if correct, can explain some aspects of acute atherosis; for example, why acute atherosis is not restricted to maladapted (unremodelled) spiral arteries of pregnancies with preeclampsia or fetal growth restriction; or why some women with augmented systemic inflammation (obesity, type II diabetes, essential hypertension) or even women with totally normal pregnancies can be affected. 5.2. Is acute atherosis a late event in the development of preeclampsia? We have suggested a new multi-step pathway to clinical preeclampsia [23] expanding on a previous 3-step model [30]. We suggest that acute atherosis usually develops after the phase of

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spiral artery remodelling has been competed. We hypothesize that acute atherosis, irrespective of how it develops in the spiral artery wall, whether coexisting with non-remodelled spiral arteries or not, contributes to abnormal uteroplacental flow [21], with ensuing placental stress, mediating clinical preeclampsia. 5.3. Does acute atherosis target women with excessive risk for atherosclerotic cardiovascular disease?

cardiovascular follow-up of women with or without a diagnosis of decidual acute atherosis. Conflict of interest statement The authors declare that they do not have any conflict of interest. Acknowledgements

Cardiovascular disease (CVD), including coronary heart disease, stroke, and other atherosclerotic conditions, is the leading cause of death for men and women in developed countries and most emerging economies [49]. Several studies have shown that women with preeclampsia, or a growth restricted fetus or diabetes in pregnancy have increased risk for later CVD, as do their offspring [50,51]. The association strengthens with more severe preeclampsia [52], including early-onset preeclampsia (reviewed in Ref. [53]). The link between preeclampsia and CVD may have two general causes. The first is that preeclampsia and atherosclerosis share risk factors for systemic inflammation and endothelial dysfunction, which are unmasked by the “stress” of pregnancy. Such factors include obesity, dyslipidemia, diabetes mellitus, other insulin resistance, hypertension, endothelial dysfunction and a family history [3]. The second possibility, which does not exclude the first, is that pregnancy, and especially preeclampsia, may induce permanent arterial changes, mediating risk for future CVD. It is possible that the pro-atherogenic stress of pregnancy, which is excessive in many women with preeclampsia, could activate arterial wall inflammation that fails to resolve after delivery [54]. Whatever the mechanisms, only subsets of women with pregnancy complications, such as preeclampsia, have augmented risk for severe or premature CVD, and we presently lack the tools to identify them. We hence propose that postpartum detection of acute atherosis could identify a subset of women with high liability of severe atherosclerotic cardiovascular disease later in life [21]. We envisage that normotensive acute atherosis could also antedate atherosclerosis in young women, in whom hypertension is a less prominent risk factor and metabolic dysfunction (insulin resistance and dyslipidemia) are more significant epidemiological risks. We suggest that vessel wall inflammation is likely to be the common mechanism for both types of arterial disease, in pregnancy and in older, non-pregnant women. 6. Summary and future studies to test our hypotheses Studies of the third trimester decidua are facilitated by our vacuum suction sampling method. In preeclampsia, the excessive oxidative and inflammatory stress is not confined to the placenta, but shared by the decidual tissue. Local decidual factors may also contribute to augmented decidual inflammation, such as immune interaction between maternal decidual NK cells or T cells and foreign fetal HLA-C. We propose that acute atherosis of the decidual spiral arteries is an inflammatory lesion akin to atherosclerosis, not unique to preeclamptic pregnancies, and may be a partial consequence of fetalematernal immune conflict in the decidual battlezone. We have summarized new hypotheses of several pathways to acute atherosis, and of how acute atherosis may be a late stage in the development of preeclampsia. As acute atherosis will worsen intervillous perfusion, it may contribute to clinical preeclampsia deterioration. Acute atherosis may signal increased maternal risk to atherosclerotic cardiovascular disease. Access to high-quality term decidual tissue will facilitate future studies of the molecular mechanisms of acute atherosis, combined with long term,

The work of present and previous research group members in Oslo (Norway) and Oxford (UK) are to be acknowledgement for their important contribution to the research work of the authors, as is vital contribution and inspiration from other collaborators, in special Ian Sargent (Oxford, UK) and Ralf Dechend (Berlin, Germany). Previous PhD student Nina K Harsem performed the important validation work of the vacuum suction method, and PhD student Patji Alnæs-Katjavivi is contributing to further development of acute atherosis evaluations of decidual tissue collected by the vacuum suction methods, generously assisted by Professors Fiona Lyall (Glasgow, Scotland) and Borghild Roald (Oslo University Hospital, Norway). References [1] Sargent IL, Borzychowski AM, Redman CW. NK cells and human pregnancye an inflammatory view. Trends Immunol 2006 Sep;27(9):399e404. [2] Hamilton WJ, Boyd JD. Development of the human placenta in the first three months of gestation. J Anat 1960 Jul;94:297e328. [3] Staff AC, Dechend R, Pijnenborg R. Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia-novel aspects for atherosclerosis and future cardiovascular health. Hypertension 2010 Dec;56(6):1026e34. [4] Redman CW, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory responseea review. Placenta 2003 Apr;24(Suppl. A):S21e 7. [5] Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006 Sep;27(9e10):939e58. [6] Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 2009 Jun;30(6):473e82. [7] Robertson SA. Immune regulation of conception and embryo implantation-all about quality control? J Reprod Immunol 2010 May;85(1):51e7. [8] Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 2010 Jun;63(6):425e33. [9] Trowsdale J, Moffett A. NK receptor interactions with MHC class I molecules in pregnancy. Semin Immunol 2008 Dec;20(6):317e20. [10] Tilburgs T, Scherjon SA, van der Mast BJ, Haasnoot GW, Versteeg V, Roelen DL, et al. Fetal-maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells. J Reprod Immunol 2009 Nov;82(2):148e57. [11] Erlebacher A. Immunology of the maternal-fetal interface. Annu Rev Immunol 2013;31:387e411. [12] Brosens I. How the role of the spiral arteries in the pathogenesis of preeclampsia was discovered. Hypertens Pregnancy 1996;15:143e6. [13] Staff AC, Ranheim T, Khoury J, Henriksen T. Increased contents of phospholipids, cholesterol, and lipid peroxides in decidua basalis in women with preeclampsia. Am J Obstet Gynecol 1999 Mar;180(3 Pt 1):587e92. [14] Staff AC, Halvorsen B, Ranheim T, Henriksen T. Elevated level of free 8-isoprostaglandin F2alpha in the decidua basalis of women with preeclampsia. Am J Obstet Gynecol 1999 Nov;181(5 Pt 1):1211e5. [15] Harsem NK, Staff AC, He L, Roald B. The decidual suction method: a new way of collecting decidual tissue for functional and morphological studies. Acta Obstet Gynecol Scand 2004 Aug;83(8):724e30. [16] Harsem NK, Roald B, Braekke K, Staff AC. Acute atherosis in decidual tissue: not associated with systemic oxidative stress in preeclampsia. Placenta 2007 Aug;28(8e9):958e64. [17] Hertig AT. Vascular pathology in hypertensive albuminuric toxemias of pregnancy. Clinics 1945;4:602e14. [18] Zeek PM, Assali NS. Vascular changes in the decidua associated with eclamptogenic toxemia of pregnancy. Am J Clin Pathol 1950 Dec;20(12): 1099e109. [19] Hanssens M, Pijnenborg R, Keirse MJ, Vercruysse L, Verbist L, Van Assche FA. Renin-like immunoreactivity in uterus and placenta from normotensive and hypertensive pregnancies. Eur J Obstet Gynecol Reprod Biol 1998 Dec;81(2): 177e84. [20] Katabuchi H, Yih S, Ohba T, Matsui K, Takahashi K, Takeya M, et al. Characterization of macrophages in the decidual atherotic spiral artery with special

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