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Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia

Open AccessPublished:September 20, 2020DOI:https://doi.org/10.1016/j.ajog.2020.09.026
      Physiological transformation with remodeling of the uteroplacental spiral arteries is key to a successful placentation and normal placental function. It is an intricate process that involves, but is not restricted to, complex interactions between maternal decidual immune cells and invasive trophoblasts in the uterine wall. In normal pregnancy, the smooth muscle cells of the arterial tunica media of uteroplacental spiral arteries are replaced by invading trophoblasts and fibrinoid, and the arterial diameter increases 5- to 10-fold. Poor remodeling of the uteroplacental spiral arteries is linked to early-onset preeclampsia and several other major obstetrical syndromes, including fetal growth restriction, placental abruption, and spontaneous preterm premature rupture of membranes. Extravillous endoglandular and endovenous trophoblast invasions have recently been put forth as potential contributors to these syndromes as well. The well-acknowledged disturbed extravillous invasion of maternal spiral arteries in preeclampsia is summarized, as are briefly novel concepts of disturbed extravillous endoglandular and endovenous trophoblast invasions.
      Acute atherosis is a foam cell lesion of the uteroplacental spiral arteries associated with poor remodeling. It shares some morphologic features with early stages of atherosclerosis, but several molecular differences between these lesions have also recently been revealed. Acute atherosis is most prevalent at the maternal-fetal interface, at the tip of the spiral arteries. The localization of acute atherosis downstream of poorly remodeled arteries suggests that alterations in blood flow may trigger inflammation and foam cell development. Acute atherosis within the decidua basalis is not, however, confined to unremodeled areas of spiral arteries or to hypertensive disorders of pregnancy and may even be present in some clinically uneventful pregnancies. Given that foam cells of atherosclerotic lesions are known to arise from smooth muscle cells or macrophages activated by multiple types of inflammatory stimulation, we have proposed that multiple forms of decidual vascular inflammation may cause acute atherosis, with or without poor remodeling and/or preeclampsia. Furthermore, we propose that acute atherosis may develop at different gestational ages, depending on the type and degree of the inflammatory insult.
      This review summarizes the current knowledge of spiral artery remodeling defects and acute atherosis in preeclampsia. Some controversies will be presented, including endovascular and interstitial trophoblast invasion depths, the concept of 2-stage trophoblast invasion, and whether the replacement of maternal spiral artery endothelium by fetal endovascular trophoblasts is permanent. We will discuss the role of acute atherosis in the pathophysiology of preeclampsia and short- and long-term health correlates. Finally, we suggest future opportunities for research on this intriguing uteroplacental interface between the mother and fetus.

      Key words

      Click Video under article title in Contents at ajog.org

      Uterine spiral arteries

      The blood to the uterus is supplied by the uterine arteries, arising from the internal iliac arteries and joined by blood supply from the ovarian arteries. The uterine arteries deliver blood to the arcuate branches within the myometrium and thereafter to the radial arteries, which continue on as spiral arteries.
      • Boyd J.D.
      • Hamilton W.J.
      The human placenta.
      The basal arteries branch from the distal ends of the radial arteries, supplying the basal portion of the endometrium. In contrast, the spiral arteries extend beyond the basal endometrial layer, supplying the outer functional layer. The outer layer of the endometrium undergoes hormone-dependent structural changes during the menstrual cycle. In pregnancy, this layer of the endometrium is transformed into a “decidua,” destined to “fall off” (from the Latin word “decidere”) at the end of pregnancy. The spiral arteries, approximately 50 to 100 μm in diameter in the nonpregnant state, penetrate the inner part of the myometrium and the endometrium and are nonbranching end arteries with a corkscrew shape.
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      Physiological transformation of spiral arteries

      Approximately 30 to 60 uterine spiral arteries are estimated to supply the intervillous space of the placenta and maintain uteroplacental perfusion during pregnancy,
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      but other studies suggest higher numbers.
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      Normal and abnormal transformation of the spiral arteries during pregnancy.
      ,
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • Romero R.
      The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
      As pregnancy progresses, uteroplacental blood flow increases from 45 mL/min to 750 mL/min at term, a dramatic increase in blood flow that is necessary for maintaining adequate placental function
      • Burton G.J.
      • Woods A.W.
      • Jauniaux E.
      • Kingdom J.C.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      and for meeting the high demands of the growing fetus. These hemodynamic changes are facilitated by massive physiological transformation of the spiral arteries,
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      • Robertson W.B.
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      The physiological response of the vessels of the placental bed to normal pregnancy.
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      also known as spiral artery remodeling.
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      The uterine spiral arteries in human pregnancy: facts and controversies.
      Expansive remodeling causes loss of smooth muscle cells and their rich autonomic innervation, which in turn leads to functional changes in arterial wall reactivity, enhanced vasodilation, and a major decrease in uterine vascular resistance.
      • Burton G.J.
      • Woods A.W.
      • Jauniaux E.
      • Kingdom J.C.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      The physiological remodeling of the spiral arteries into highly dilated thin-walled vessels is vital to human pregnancy development.
      At the start of pregnancy, spiral artery remodeling by endovascular trophoblasts has yet to begin.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      Before the establishment of the uteroplacental circulation during the first trimester of pregnancy, uterine glands provide histiotrophic nutrition for the fetus.
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      • Skepper J.N.
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      Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy.
      Before 9 weeks’ gestation, endovascular (extravillous) trophoblast plugs limit maternal blood entry into the intervillous chambers. Plugging helps to maintain a state of physiological hypoxia early in the placentation process, favoring cytotrophoblast proliferation rather than differentiation and invasiveness.
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      • Zhou Y.
      • Genbacev O.
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      Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface.
      After the disintegration of these plugs around 9 weeks’ gestation, the uteroplacental spiral arteries start to supply maternal blood to the intervillous space.
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      Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution.
      The physiological spiral artery remodeling process has been divided into 5 stages by Pijnenborg et al
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      (Figure 1). Stage 1 (decidua-associated early vascular remodeling) consists of endothelial vacuolization and swelling of individual muscle cells.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      Craven et al
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      Decidual spiral artery remodelling begins before cellular interaction with cytotrophoblasts.
      highlight that initial vascular remodeling occurs in the absence of trophoblast invasion, whereas others point out that complete pregnancy-associated spiral artery remodeling cannot occur without trophoblasts.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      ,
      • King A.
      • Loke Y.W.
      Placental vascular remodelling.
      In stage 2, interstitial trophoblasts invade stromal and perivascular tissue and induce further disorganization of the vascular smooth muscle and weakening of the elastic lamina of the arteries. In stage 3, endovascular extravillous trophoblasts enter from the spiral artery lumen into the vessel wall. Stage 4 (labeled by Pijnenborg as the physiological change) involves the incorporation of trophoblasts into the vessel wall, where a fibrinoid layer replaces the original vascular smooth muscle and elastic lamina.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      This loss of smooth muscle cells converts the arteries into flaccid conduits.
      • Burton G.J.
      • Charnock-Jones D.S.
      • Jauniaux E.
      Regulation of vascular growth and function in human placenta.
      ,
      • Harris L.K.
      IFPA Gabor Than Award lecture: transformation of the spiral arteries in human pregnancy: key events in the remodelling timeline.
      Stage 5 involves maternal vascular repair with reendothelialization and subintimal thickening.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      Figure thumbnail gr1
      Figure 1The different steps in uterine artery remodeling
      The earliest step in vascular remodeling (stage 1) consists of endothelial vacuolation and some swelling in individual muscle cells. Invasion of stromal and perivascular tissues by interstitial trophoblast is associated with further disorganization of the vascular smooth muscle layer (stage 2). Afterward, endovascular trophoblast appears (stage 3). Trophoblast becomes embedded intramurally within a fibrinoid layer, which replaces the original vascular smooth muscle (stage 4). Finally, reendothelialization occurs, which may be accompanied by the appearance of subintimal cushions containing α-actin immunopositive myointimal cells (stage 5). Reproduced, with permission from the journal Placenta, from Pijnenborg et al.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      .
      Staff. Failure of physiological transformation and spiral artery atherosclerosis in preeclampsia. Am J Obstet Gynecol 2022.
      As reviewed previously,
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      the local uterine lining’s (decidual) immune system is vital to spiral artery remodeling and thereby to successful placentation. There is increasing evidence for a role of both decidual natural killer (NK) cells and T cells (including regulatory T cells [Tregs]) in facilitating uteroplacental spiral artery remodeling.
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      Placental extravillous trophoblasts (EVTs) invading the uterine spiral arteries are special in that they express only human leukocyte antigen (HLA)-C among the classical polymorphic class I HLAs, as reviewed by us.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      HLA-C expressed on EVTs is a key molecule that can elicit immune responses by both decidual NK cells and T cells. It is therefore essential for a successful pregnancy that maternal-fetal immune tolerance toward HLA-C is well established. Appropriate remodeling requires successful interaction between these fetal HLA-C proteins, and killer cell immunoglobulinlike receptor (KIR) proteins, expressed on the maternal decidual NK cells.
      • Robson A.
      • Harris L.K.
      • Innes B.A.
      • et al.
      Uterine natural killer cells initiate spiral artery remodeling in human pregnancy.
      KIR genetics have been shown to impact baby weight percentiles and preeclampsia rates worldwide.
      • Nakimuli A.
      • Chazara O.
      • Hiby S.E.
      • et al.
      A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia.
      ,
      • Hiby S.E.
      • Apps R.
      • Chazara O.
      • et al.
      Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.
      T cells and the adaptive immune system are also involved, as HLA-C incompatibility between the mother and fetus is associated with increased T-cell activation and generation of Tregs.
      • Tilburgs T.
      • Scherjon S.A.
      • van der Mast B.J.
      • et al.
      Fetal-maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells.
      Decidual Tregs are essential to promoting maternal-fetal immune tolerance, a mechanism central to ensuring robust placentation and spiral artery remodeling.
      • Robertson S.A.
      • Care A.S.
      • Moldenhauer L.M.
      Regulatory T cells in embryo implantation and the immune response to pregnancy.
      Tregs contribute to implantation and placental development by several mechanisms. These include preventing destructive effector T-cell responses to fetal antigens, regulating other decidual immune cells and thus promoting an anti-inflammatory environment, and by regulating maternal vascular changes through interaction with decidual NK cells.
      • Robertson S.A.
      • Care A.S.
      • Moldenhauer L.M.
      Regulatory T cells in embryo implantation and the immune response to pregnancy.
      We previously reported that induction of Tregs ameliorated intrauterine growth restriction in a transgenic rat model of preeclampsia.
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      • Ibrahim T.
      • Haase N.
      • et al.
      Regulatory T cells ameliorate intrauterine growth retardation in a transgenic rat model for preeclampsia.
      Recently, in a mouse model, it was shown that Treg deprivation caused reduced maternal vascular adaptation in pregnancy.
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      • Morton J.S.
      • Hjartarson E.P.
      • Robertson S.A.
      • Davidge S.T.
      Reduction in regulatory T cells in early pregnancy causes uterine artery dysfunction in mice.
      Insufficient numbers or impaired function of Tregs is linked to human reproductive disorders, such as preeclampsia and recurrent implantation failure or miscarriage.
      • Robertson S.A.
      • Care A.S.
      • Moldenhauer L.M.
      Regulatory T cells in embryo implantation and the immune response to pregnancy.
      Studies in mice have also indicated that pregnancy imprints Tregs with protective memory to fetal antigens and that these memory Tregs persist and rapidly accumulate during a subsequent pregnancy.
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      • Ertelt J.M.
      • Xin L.
      • Way S.S.
      Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.
      Another important finding is that human decidual NK cells also possess some features of adaptive immunity. The decidual NK cells develop trained “memory” after a first pregnancy and differ from decidual NK cells from a first pregnancy in that they express higher levels of some receptors that interact with EVTs and growth factors that are important for spiral artery remodeling, potentially promoting more efficient placentation in subsequent pregnancies.
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      • Isaacson B.
      • et al.
      Trained memory of human uterine NK cells enhances their function in subsequent pregnancies.
      Immune cells with pregnancy-imprinted memory could be part of the reason why there is an additional risk of preeclampsia in first pregnancies.
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      Perhaps the effects of these immune cells with pregnancy memory decline over time, which may explain why the protective benefit of a previous pregnancy conceived with the same partner is lost after a long interpregnancy interval.
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      The interval between pregnancies and the risk of preeclampsia.
      However, more research is needed to investigate these hypotheses.

      Dysfunctional spiral artery remodeling in preeclampsia

      A major contribution to the understanding of how failed spiral artery transformation contributes to the development of preeclampsia was made by Robertson and Brosens. In 1967, they reported that preeclampsia is associated with poor placentation, observed as shallow remodeling of the uteroplacental spiral arteries.
      • Robertson W.B.
      • Brosens I.
      • Dixon H.G.
      The pathological response of the vessels of the placental bed to hypertensive pregnancy.
      Some scientific controversies remain regarding the dysfunctional nature of spiral artery remodeling in preeclampsia.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      One controversy has been Pijnenborg’s “2-wave” hypothesis of trophoblast invasion,
      • Pijnenborg R.
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      • Robertson W.B.
      • Brosens I.
      Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.
      based on hysterectomy specimens. This hypothesis has been refuted by Lyall,
      • Lyall F.
      The human placental bed revisited.
      who concluded based on placental bed findings that continuous endovascular migration from decidual to myometrial arteries occurs, rather than 2 distinct trophoblast invasion waves. Furthermore, a common misunderstanding is that both the interstitial and endovascular depths of trophoblast invasion are altered in preeclampsia. Interstitial trophoblast invasion occurs before endovascular invasion
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      ; however, in preeclampsia, the interstitial trophoblast invasion depth remains normal, whereas the endovascular trophoblast invasion is more shallow than in normotensive pregnancies, as shown in detailed placental bed studies by Lyall et al.
      • Lyall F.
      • Robson S.C.
      • Bulmer J.N.
      Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome.
      Whether the superficial decidua basalis spiral arteries in preeclampsia are also severely affected by poor trophoblast invasion and failure of physiological transformation, as reported by Labarrere et al,
      • Labarrere C.A.
      • DiCarlo H.L.
      • Bammerlin E.
      • et al.
      Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
      is also debatable. This is not found in other decidua basalis studies.
      • Lyall F.
      • Robson S.C.
      • Bulmer J.N.
      Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome.
      ,
      • Meekins J.W.
      • Pijnenborg R.
      • Hanssens M.
      • McFadyen I.R.
      • van Asshe A.
      A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
      • Redman C.
      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      • Brosens I.A.
      • Robertson W.B.
      • Dixon H.G.
      The role of the spiral arteries in the pathogenesis of preeclampsia.
      Differences among studies may however result from differences in patient selection, tissue collection techniques (including localization of biopsies from the placental bed and efficiency in spiral artery collection), assessment of smaller nutritional basal arteries vs wider uteroplacental spiral arteries, and immunohistochemical markers.
      As Pijnenborg et al
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      point out, a misconception is that endovascular trophoblast invasion results in permanent replacement of maternal spiral artery endothelial cells by invading fetal trophoblasts. This concept was derived from findings by Zhou et al,
      • Zhou Y.
      • Fisher S.J.
      • Janatpour M.
      • et al.
      Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion?.
      ,
      • Zhou Y.
      • Damsky C.H.
      • Fisher S.J.
      Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?.
      showing that endovascular trophoblasts normally transform their adhesion receptor phenotype and begin to express endothelial markers, whereas those in preeclampsia fail to do so. As argued by Pijnenborg et al,
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      maternal spiral artery endothelial cell replacement by trophoblasts is only temporary (Figure 1, stage 4), as these endovascular trophoblasts are then embedded intramurally and the spiral arteries are reendothelialized by maternal endothelial cells. In line with this, third-trimester immunohistochemical findings show that all spiral artery endothelial cells are cytokeratin negative and therefore unlikely trophoblast derived.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      We
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
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      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      and others
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      • DiCarlo H.L.
      • Bammerlin E.
      • et al.
      Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
      ,
      • Labarrere C.A.
      • Faulk W.P.
      Antigenic identification of cells in spiral artery trophoblastic invasion: validation of histologic studies by triple-antibody immunocytochemistry.
      ,
      • Lyall F.
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      • Cousins F.
      • Theriault A.
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      Human trophoblast invasion and spiral artery transformation.
      have confirmed this finding and further reported that these cells are positive for the endothelial cell markers CD31 and von Willebrand factor.
      The failure of deep endovascular invasion and spiral artery remodeling, as observed in early-onset preeclampsia, was previously assumed to lead to placental underperfusion
      • Roberts J.M.
      • Redman C.W.
      Pre-eclampsia: more Than pregnancy-induced hypertension.
      and thereby chronic hypoxia.
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      • Sargent I.L.
      Preeclampsia: an excessive maternal inflammatory response to pregnancy.
      A 2009 model by Burton et al
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      • Woods A.W.
      • Jauniaux E.
      • Kingdom J.C.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      argued that flow volume is minimally affected by unsuccessful spiral artery remodeling but that the uteroplacental perfusion has a more pulsatile and higher pressure flow quality than normally remodeled arteries, partly because of the remaining contractile smooth muscle cells. This abnormal flow generates ischemia-reperfusion injury and placental oxidative stress rather than chronic hypoxia per se.
      • Burton G.J.
      • Woods A.W.
      • Jauniaux E.
      • Kingdom J.C.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      Furthermore, placental endoplasmic reticulum (ER) stress is increased, and the unfolded protein response is activated by this abnormal flow.
      • Burton G.J.
      • Yung H.W.
      • Cindrova-Davies T.
      • Charnock-Jones D.S.
      Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia.
      The dysfunctional placental perfusion results in adverse placental function and release of inflammatory placental factors.
      • Redman C.W.
      • Sacks G.P.
      • Sargent I.L.
      Preeclampsia: an excessive maternal inflammatory response to pregnancy.
      These factors mediate an excessive maternal inflammatory response,
      • Redman C.W.
      • Sacks G.P.
      • Sargent I.L.
      Preeclampsia: an excessive maternal inflammatory response to pregnancy.
      involving endothelial dysfunction and generalized vascular inflammation, resulting in the observed clinical maternal features of preeclampsia.
      • Redman C.W.
      • Sargent I.L.
      • Staff A.C.
      IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.
      These inflammatory factors are not fully defined but include syncytiotrophoblast microvesicles and angiogenic factors, contributing to an antiangiogenic imbalance in the maternal circulation (eg, elevated soluble fms-like tyrosine kinase 1 and low placental growth factor [PlGF]),
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      ,
      • Redman C.W.
      • Staff A.C.
      Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.
      as observed in early-onset preeclampsia and fetal growth restriction (FGR), both of which are placental syndromes characterized by inadequately remodeled spiral arteries.
      • Brosens I.
      • Puttemans P.
      • Benagiano G.
      Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes.
      Of note, poor placentation and risk of preeclampsia involve much more than inadequate trophoblast-associated spiral artery remodeling.
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      ,
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      Periconceptional endometrial function, early decidual vascular remodeling (before trophoblast invasion), and vascular plugging by trophoblasts all play a role.
      • Red-Horse K.
      • Zhou Y.
      • Genbacev O.
      • et al.
      Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface.
      Obesity and other risk factors for preeclampsia affecting the inflammatory state of the endometrium likely confer risk partly through their effects on periconceptional endometrial function
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      and spiral artery remodeling.
      • Avagliano L.
      • Bulfamante G.P.
      • Morabito A.
      • Marconi A.M.
      Abnormal spiral artery remodelling in the decidual segment during pregnancy: from histology to clinical correlation.
      Such risk factors may cause defective maturation of endometrial and decidual NK cells during the secretory phase and early pregnancy,
      • Rabaglino M.B.
      • Post Uiterweer E.D.
      • Jeyabalan A.
      • Hogge W.A.
      • Conrad K.P.
      Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia.
      also contributing to poor placentation.

      Extravillous trophoblast invasion failure: affecting more than the remodeling of uteroplacental spiral arteries?

      The acknowledged disturbed extravillous invasion of maternal spiral arteries in preeclampsia is summarized above. Recent studies have however also demonstrated extravillous glandular and extravillous endovenous invasions, occurring early on during placentation.
      • Moser G.
      • Windsperger K.
      • Pollheimer J.
      • de Sousa Lopes S.C.
      • Huppertz B.
      Human trophoblast invasion: new and unexpected routes and functions.
      • Moser G.
      • Weiss G.
      • Sundl M.
      • et al.
      Extravillous trophoblasts invade more than uterine arteries: evidence for the invasion of uterine veins.
      • Windsperger K.
      • Dekan S.
      • Pils S.
      • et al.
      Extravillous trophoblast invasion of venous as well as lymphatic vessels is altered in idiopathic, recurrent, spontaneous abortions.
      It is possible that adverse regulation of these processes contributes to several obstetrical syndromes, including preeclampsia and FGR.

      The 2-stage model of preeclampsia: more than remodeling problems

      We have proposed that incomplete spiral artery remodeling along with other factors contributing to poor placentation is 1 of several pathways increasing the risk of preeclampsia.
      • Redman C.W.
      • Sargent I.L.
      • Staff A.C.
      IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.
      ,
      • Redman C.W.
      • Staff A.C.
      Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.
      Poor placentation increases the risk of early severe placental dysfunction and “early-onset” preeclampsia, with concomitant FGR. “Late-onset” preeclampsia, without evidence of poor spiral artery remodeling and FGR, may be caused by overcrowding of the terminal villi in large placentas and also by senescent placentas.
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      ,
      • Redman C.W.
      • Sargent I.L.
      • Staff A.C.
      IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.
      ,
      • Redman C.W.
      • Staff A.C.
      Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.
      These pathways are however not mutually exclusive and may interact in causing placental dysfunction with cellular syncytiotrophoblast stress, resulting in the maternal syndromic signs of preeclampsia caused by generalized vascular inflammation. Hence, we propose that the pathways to early- and late-onset preeclampsia may differ in the time course and underlying causes but that the maternal signs of hypertension and other organ dysfunction (eg, proteinuria) are the same. This integrative concept takes into account that all pathways trigger placental (syncytiotrophoblast) stress and similar maternal responses but that FGR is more prevalent in early-onset preeclampsia as this preeclampsia form results mainly from early placental dysfunction with severe adverse effects on fetal growth.
      • Redman C.W.
      • Sargent I.L.
      • Staff A.C.
      IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.
      ,
      • Redman C.W.
      • Staff A.C.
      Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.
      Our revised 2-stage model of preeclampsia accommodates most known risk factors, including chronic prepregnancy disease, primiparity, and other pregnancy-related risk factors (including multiples).
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      First, maternal obesity, for instance, is a well-known risk factor for both preeclampsia and gestational hypertension,
      • Egeland G.M.
      • Klungsøyr K.
      • Øyen N.
      • Tell G.S.
      • Næss Ø.
      • Skjærven R.
      Preconception cardiovascular risk factor differences between gestational hypertension and preeclampsia: cohort Norway study.
      a finding that fits well with our concept of these hypertensive disorders representing a spectrum of disease, rather than distinct entities.
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      Second, maternal obesity causes chronic inflammation, which may contribute to reduced periconceptional endometrial function and dysfunctional spiral artery remodeling, in turn resulting in increased early-onset preeclampsia risk. Third, maternal obesity is also associated with large placentas and fetal macrosomia,
      • Strøm-Roum E.M.
      • Tanbo T.G.
      • Eskild A.
      The associations of maternal body mass index with birthweight and placental weight. Does maternal diabetes matter? A population study of 106 191 pregnancies.
      thereby potentially contributing to placental overcrowding and late-onset preeclampsia or gestational hypertension risk. In line with this, maternal obesity is a risk factor for poor spiral artery remodeling across several placental syndromes.
      • Avagliano L.
      • Bulfamante G.P.
      • Morabito A.
      • Marconi A.M.
      Abnormal spiral artery remodelling in the decidual segment during pregnancy: from histology to clinical correlation.
      Incomplete spiral artery remodeling and resulting placental dysfunction are however not unique to preeclampsia but are associated with a spectrum of severe obstetrical outcomes.
      • Redman C.W.
      Current topic: pre-eclampsia and the placenta.
      These include (recurrent) pregnancy loss, FGR, preterm premature rupture of membranes, intrauterine fetal demise, and placental abruption.
      • Avagliano L.
      • Bulfamante G.P.
      • Morabito A.
      • Marconi A.M.
      Abnormal spiral artery remodelling in the decidual segment during pregnancy: from histology to clinical correlation.
      Similar to how dysfunctional spiral artery remodeling may not be a prerequisite for all forms of preeclampsia, it is well documented that FGR and other placental syndromes may occur in the absence of spiral artery remodeling dysfunction.

      Acute atherosis: what, where, and when?

      Hertig
      • Hertig A.T.
      Vascular pathology in the hypertensive albuminuric toxemias of pregnancy.
      described in 1945 spiral artery wall lesions characterized by foam cells and fibrinoid necrosis of the tunica media. This finding was later termed acute atherosis by Zeek and Assali
      • Zeek P.M.
      • Assali N.S.
      Vascular changes in the decidua associated with eclamptogenic toxemia of pregnancy.
      in 1950. Fibrinoid necrosis and perivascular infiltrate, the features often used to define acute atherosis in addition to foam cells, have themselves been poorly and heterogeneously defined,
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      making comparisons of studies challenging. Acute atherosis usually occurs downstream in inadequately remodeled spiral arteries, namely, at their tips, in the decidua basalis. More rarely, acute atherosis is found in the myometrial segments, which is the compartment where the potential spiral artery remodeling problems are seen (eg, inadequate physiological remodeling and less deep endovascular trophoblast invasion).
      • Meekins J.W.
      • Pijnenborg R.
      • Hanssens M.
      • van Assche A.
      • McFadyen I.R.
      Immunohistochemical detection of lipoprotein(a) in the wall of placental bed spiral arteries in normal and severe preeclamptic pregnancies.
      ,
      • Robertson W.B.
      • Brosens I.
      • Dixon G.
      Uteroplacental vascular pathology.
      Acute atherosis lesions are usually focal,
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      ,
      • Meekins J.W.
      • Pijnenborg R.
      • Hanssens M.
      • McFadyen I.R.
      • van Asshe A.
      A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.
      ,
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      not necessarily affecting all spiral arteries, the entire circumference of a single artery, or its entire length. Apart from the placental bed, acute atherosis may be found in the decidua parietalis,
      • Zeek P.M.
      • Assali N.S.
      Vascular changes in the decidua associated with eclamptogenic toxemia of pregnancy.
      ,
      • Robertson W.B.
      • Brosens I.
      • Dixon G.
      Uteroplacental vascular pathology.
      ,
      • Alnaes-Katjavivi P.
      • Roald B.
      • Staff A.C.
      Uteroplacental acute atherosis in preeclamptic pregnancies: rates and clinical outcomes differ by tissue collection methods.
      where there is no physiological transformation of the spiral arteries. These lesions are however not found outside the uterus. Figure 2 (reproduced with permission from Fosheim
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
      • Redman C.
      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      ) shows examples of decidual acute atherosis in serial tissue section staining.
      Figure thumbnail gr2
      Figure 2Decidua basalis identification of spiral arteries and acute atherosis
      Slides are stained with (from left to right) hematoxylin and eosin (H & E), desmin and PAS, CK7 and PAS, CD68 and PAS, and MSB. Representative images of (A) a spiral artery from a normotensive control with complete physiological transformation, characterized by the presence of CK7-positive trophoblasts and intramural fibrinoid (bright purple on PAS staining, white arrowhead) in the vessel wall, and complete absence of intramural smooth muscle cells (no desmin stain). B, Spiral artery from a patient with preeclampsia with partial physiological transformation (both intramural fibrinoid and trophoblasts [CK7 positive] and areas with traces of mural smooth muscle cells [desmin positive]). C, Spiral artery with acute atherosis from the same sample as in (B), lacking bright purple fibrinoid and CK7-positive trophoblasts in the vessel wall. Traces of intramural smooth muscle cells (desmin positive) are seen. Fibrinoid necrosis is visible as a gray-pink material in the vessel wall (asterisk), which stains red on MSB staining (asterisk). Erythrocytes in the lumen of the AA artery stain red-brown color on MSB staining. Intramural CD68-positive foam cells are present (black arrowhead). D, Spiral artery from a patient with preeclampsia with almost complete physiological transformation (lack of desmin-positive smooth muscle cells, presence of CK7-positive trophoblasts), yet acute atherosis lesion present (asterisk; fibrinoid necrosis, black arrowhead; foam cells, white arrowhead; purple physiological fibrinoid). Reproduced, with permission from the journal Placenta, from Fosheim et al.
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
      • Redman C.
      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      CD68, cluster of differentiation 68; CK7, cytokeratin 7; H & E, hematoxylin and eosin; MSB, martius scarlet blue; PAS, periodic acid-Schiff staining.
      Staff. Failure of physiological transformation and spiral artery atherosclerosis in preeclampsia. Am J Obstet Gynecol 2022.
      The time course of acute atherosis development is not definitively known, as longitudinal biopsies for histologic studies are infeasible. Decidual acute atherosis has been observed as early as the first trimester of pregnancy in women with chronic autoimmune diseases characterized by excessive inflammation (eg, systemic lupus erythematosus [SLE] with antiphospholipid syndrome).
      • Nayar R.
      • Lage J.M.
      Placental changes in a first trimester missed abortion in maternal systemic lupus erythematosus with antiphospholipid syndrome; a case report and review of the literature.
      Delivery of the placenta is followed by gradual shedding of the remaining decidual tissue (where the lesion is most prevalent) over a few weeks, and the lesion likely regresses soon after delivery,
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      as confirmed by small autopsy studies.
      • Zeek P.M.
      • Assali N.S.
      Vascular changes in the decidua associated with eclamptogenic toxemia of pregnancy.
      The rate of acute atherosis is elevated in preeclampsia compared with that in normotensive pregnancies but not all preeclampsia pregnancies are affected.
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      ,
      • Kim Y.M.
      • Chaemsaithong P.
      • Romero R.
      • et al.
      The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion.
      • Stevens D.U.
      • Al-Nasiry S.
      • Bulten J.
      • Spaanderman M.E.
      Decidual vasculopathy and adverse perinatal outcome in preeclamptic pregnancy.
      • Harsem N.K.
      • Roald B.
      • Braekke K.
      • Staff A.C.
      Acute atherosis in decidual tissue: not associated with systemic oxidative stress in preeclampsia.
      Acute atherosis also affects some pregnancies complicated by FGR or diabetes mellitus (without maternal hypertension),
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      ,
      • Khong T.Y.
      Acute atherosis in pregnancies complicated by hypertension, small-for-gestational-age infants, and diabetes mellitus.
      SLE and antiphospholipid syndrome,
      • Staff A.C.
      • Dechend R.
      • Pijnenborg R.
      Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia-novel aspects for atherosclerosis and future cardiovascular health.
      and even sometimes normotensive uncomplicated pregnancies.
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      ,
      • Meekins J.W.
      • Pijnenborg R.
      • Hanssens M.
      • van Assche A.
      • McFadyen I.R.
      Immunohistochemical detection of lipoprotein(a) in the wall of placental bed spiral arteries in normal and severe preeclamptic pregnancies.
      ,
      • Harsem N.K.
      • Roald B.
      • Braekke K.
      • Staff A.C.
      Acute atherosis in decidual tissue: not associated with systemic oxidative stress in preeclampsia.
      ,
      • Katabuchi H.
      • Yih S.
      • Ohba T.
      • et al.
      Characterization of macrophages in the decidual atherotic spiral artery with special reference to the cytology of foam cells.
      Our decidua basalis studies suggest that the foam cell lesions are much rarer in normotensive uncomplicated pregnancies than in preeclamptic pregnancies and that the lesions, when present, are smaller and affect fewer arteries.
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      The reported rates of acute atherosis vary from 10% to 52% in preeclampsia and from 0.4% to 11% in normotensive pregnancies.
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      ,
      • Kim Y.M.
      • Chaemsaithong P.
      • Romero R.
      • et al.
      The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion.
      • Stevens D.U.
      • Al-Nasiry S.
      • Bulten J.
      • Spaanderman M.E.
      Decidual vasculopathy and adverse perinatal outcome in preeclamptic pregnancy.
      • Harsem N.K.
      • Roald B.
      • Braekke K.
      • Staff A.C.
      Acute atherosis in decidual tissue: not associated with systemic oxidative stress in preeclampsia.
      This huge variation likely reflects differences in the populations investigated and the heterogeneous sampling techniques and diagnostic criteria.
      • Alnaes-Katjavivi P.
      • Roald B.
      • Staff A.C.
      Uteroplacental acute atherosis in preeclamptic pregnancies: rates and clinical outcomes differ by tissue collection methods.
      Acute atherosis assessment is not part of routine clinical practice because of the need for careful tissue sampling and the time-consuming morphologic and immunohistochemical investigations after delivery. Hitherto, there is no available noninvasive imaging strategy to reliably identify uteroplacental acute atherosis.
      Various tissue sampling techniques have been used to investigate acute atherosis, including rare whole uterus specimens with placenta in situ (from postpartum hysterectomies),
      • Brosens I.
      How the role of the spiral arteries in the pathogenesis of preeclampsia was discovered.
      placental bed biopsies (including decidual and myometrial tissues),
      • Lyall F.
      • Robson S.C.
      • Bulmer J.N.
      Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome.
      ,
      • Harsem N.K.
      • Staff A.C.
      • He L.
      • Roald B.
      The decidual suction method: a new way of collecting decidual tissue for functional and morphological studies.
      vacuum curettage of the placental bed (published by us in 1999),
      • Harsem N.K.
      • Staff A.C.
      • He L.
      • Roald B.
      The decidual suction method: a new way of collecting decidual tissue for functional and morphological studies.
      • Staff A.C.
      • Halvorsen B.
      • Ranheim T.
      • Henriksen T.
      Elevated level of free 8-iso-prostaglandin F2alpha in the decidua basalis of women with preeclampsia.
      • Staff A.C.
      • Ranheim T.
      • Khoury J.
      • Henriksen T.
      Increased contents of phospholipids, cholesterol, and lipid peroxides in decidua basalis in women with preeclampsia.
      biopsies from the basal plate of the delivered placenta, and placental membranes (providing decidua parietalis, not the decidua basalis of the placental bed).
      • Kim Y.M.
      • Chaemsaithong P.
      • Romero R.
      • et al.
      The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion.
      ,
      • Harsem N.K.
      • Staff A.C.
      • He L.
      • Roald B.
      The decidual suction method: a new way of collecting decidual tissue for functional and morphological studies.
      As summarized in a state-of-the-art paper on optimizing sample collection for placental research,
      • Burton G.J.
      • Sebire N.J.
      • Myatt L.
      • et al.
      Optimising sample collection for placental research.
      our technique of decidual vacuum suction of the placental bed during cesarean delivery
      • Harsem N.K.
      • Staff A.C.
      • He L.
      • Roald B.
      The decidual suction method: a new way of collecting decidual tissue for functional and morphological studies.
      • Staff A.C.
      • Halvorsen B.
      • Ranheim T.
      • Henriksen T.
      Elevated level of free 8-iso-prostaglandin F2alpha in the decidua basalis of women with preeclampsia.
      • Staff A.C.
      • Ranheim T.
      • Khoury J.
      • Henriksen T.
      Increased contents of phospholipids, cholesterol, and lipid peroxides in decidua basalis in women with preeclampsia.
      represents the superior sampling method if one wishes to study the decidua basalis alone.
      • Burton G.J.
      • Sebire N.J.
      • Myatt L.
      • et al.
      Optimising sample collection for placental research.
      Studies examining conventional placental tissue samples have found a higher frequency of acute atherosis in the fetal membranes, relative to tissue samples from the maternal surface of the placenta.
      • Kim Y.M.
      • Chaemsaithong P.
      • Romero R.
      • et al.
      The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion.
      ,
      • Stevens D.U.
      • Al-Nasiry S.
      • Bulten J.
      • Spaanderman M.E.
      Decidual vasculopathy in preeclampsia: lesion characteristics relate to disease severity and perinatal outcome.
      However, the rate of acute atherosis is lower in fetal membranes when directly compared with vacuum-suctioned decidual tissue from the placental bed.
      • Alnaes-Katjavivi P.
      • Roald B.
      • Staff A.C.
      Uteroplacental acute atherosis in preeclamptic pregnancies: rates and clinical outcomes differ by tissue collection methods.
      This is not surprising, as most acute atherosis lesions are present in the decidua basalis.
      • Meekins J.W.
      • Pijnenborg R.
      • Hanssens M.
      • van Assche A.
      • McFadyen I.R.
      Immunohistochemical detection of lipoprotein(a) in the wall of placental bed spiral arteries in normal and severe preeclamptic pregnancies.
      ,
      • Robertson W.B.
      • Brosens I.
      • Dixon G.
      Uteroplacental vascular pathology.
      Advantages of the decidual vacuum suction methodology compared with that of traditional biopsies from the placental bed and maternal surface of the placenta include the following: (1) tissue yield is larger; (2) decidual tissue is collected from the whole placental bed in an unbiased way; and (3) it is easy and rapid and does not lead to short- or long-term complications when performed by experienced clinicians.
      • Harsem N.K.
      • Staff A.C.
      • He L.
      • Roald B.
      The decidual suction method: a new way of collecting decidual tissue for functional and morphological studies.
      One drawback is that the tissue lacks orientation, in contrast to placental bed biopsies. An issue that affects acute atherosis evaluation irrespective of the sampling method is that the diagnostic criteria have not always been clear from all studies. Our recently published, simple, and reproducible set of criteria have proven useful when comparing the rates of acute atherosis across pregnancy outcome groups and among different tissue sources.
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      ,
      • Alnaes-Katjavivi P.
      • Roald B.
      • Staff A.C.
      Uteroplacental acute atherosis in preeclamptic pregnancies: rates and clinical outcomes differ by tissue collection methods.
      Based on the ubiquity of perivascular infiltrate and fibrinoid, our simplified definition is based on identifying at least 2 adjacent foam cells in the spiral artery wall that are also CD68 positive.
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      ,
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
      • Redman C.
      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      ,
      • Johnsen G.M.
      • Størvold G.L.
      • Alnaes-Katjavivi P.H.
      • et al.
      Lymphocyte characterization of decidua basalis spiral arteries with acute atherosis in preeclamptic and normotensive pregnancies.
      Other researchers, also acknowledging that all 3 classically required components of acute atherosis are not always present, have used the terminology decidual vasculopathy for these spiral artery pathologies.
      • Stevens D.U.
      • Al-Nasiry S.
      • Bulten J.
      • Spaanderman M.E.
      Decidual vasculopathy and adverse perinatal outcome in preeclamptic pregnancy.

      Acute atherosis in preeclampsia: why?

      The causes and consequences of acute atherosis in preeclampsia and other obstetrical syndromes mediated by placental dysfunction are not completely understood. Although more rare and less extensive, the lesion’s presence in clinically uncomplicated pregnancies
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      has also been an enigma. To shed light on the associations linking acute atherosis and placental dysfunction, breaking down the characteristics of the lesion may be useful.
      The immunohistochemical hallmark of acute atherosis is CD68-positive subendothelial lipid-filled foam cells. CD68 is part of the scavenger receptor family and can bind and internalize oxidized low-density lipoprotein (LDL). Foam cells themselves are products of inflammatory stress, typically of the intima, and are characteristic of early stages of atherosclerosis.
      • Tabas I.
      • García-Cardeña G.
      • Owens G.K.
      Recent insights into the cellular biology of atherosclerosis.
      In atherosclerosis, foam cells have been shown to derive from both macrophages and smooth muscle cells.
      • Allahverdian S.
      • Chehroudi A.C.
      • McManus B.M.
      • Abraham T.
      • Francis G.A.
      Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis.
      Foam cells are not, however, specific to atherosclerosis but may form in several inflammatory states (as reviewed in Staff et al
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      ). Like foam cells, myointimal cell proliferation and fibrinoid necrosis, the 2 other defining features of acute atherosis, are also markers of arterial injury.
      We have proposed that acute atherosis may be the histologic manifestation of several decidual inflammatory mechanisms leading to arterial damage.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      These underlying mechanisms may vary in timing and intensity during a pregnancy, explaining the association of preeclampsia and a plethora of pregnancy complications with the lesion.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      This is in line with our 2-stage model of the complex preeclampsia syndrome, including heterogeneous pathways and risk factors for both early- and late-onset preeclampsia (summarized above in “Extravillous trophoblast invasion failure: affecting more than the remodeling of uteroplacental spiral arteries?”).
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      ,
      • Redman C.W.
      • Sargent I.L.
      • Staff A.C.
      IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.
      ,
      • Redman C.W.
      • Staff A.C.
      Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.
      In our model, acute atherosis may not only be a consequence of placental dysfunction and the result of its underlying mechanisms but also be a risk factor for placental dysfunction, as illustrated in our 2014 model shown in Figure 3 (reproduced with permission from the American Journal of Obstetrics & Gynecology).
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      Figure thumbnail gr3
      Figure 3A multistage 2014 preeclampsia placenta model
      The model recognizes preplacentation factors leading to poor placentation and suggests uteroplacental acute atherosis as part of a multistep pathway of preeclampsia. In this model, acute atherosis may be both a consequence of any form of placental dysfunction and the results of its underlying mechanisms, including remodeling problems. Furthermore, the model also proposes that acute atherosis may represent a risk factor for placental dysfunction and preeclampsia. This is in line with acute atherosis developing very early in women with excessive vascular inflammation, such as in systemic lupus erythematosus, who also have a high risk for developing early-onset preeclampsia. Reproduced (own figure), with permission from the Journal of Reproductive Immunology, from Staff et al.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      Staff. Failure of physiological transformation and spiral artery atherosclerosis in preeclampsia. Am J Obstet Gynecol 2022.
      The mechanisms mediating placental dysfunction may also cause acute atherosis; we propose several, potentially synergistic, pathways to acute atherosis involving inflammatory, immunogenetic, and hemodynamic risks,
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      ,
      • Staff A.C.
      • Dechend R.
      • Pijnenborg R.
      Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia-novel aspects for atherosclerosis and future cardiovascular health.
      ,
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      as shown in Figure 4. Firstly, decidual inflammation may be a sufficient cause of acute atherosis. We have put forward that uteroplacental acute atherosis could develop at any stage of pregnancy in the setting of sufficient decidual inflammation,
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      including in normotensive pregnancies. This is in line with findings that some women develop acute atherosis very early in pregnancy, in situations of excessive prepregnancy and early pregnancy vascular inflammation, such as in SLE.
      • Nayar R.
      • Lage J.M.
      Placental changes in a first trimester missed abortion in maternal systemic lupus erythematosus with antiphospholipid syndrome; a case report and review of the literature.
      This is not surprising, as it has become widely recognized that immunity and inflammation play a key role in the pathogenesis of arterial diseases affecting all wall layers of the arteries, at all levels of the arterial tree, including smaller vessels,
      • Libby P.
      • Hansson G.K.
      Inflammation and immunity in diseases of the arterial tree: players and layers.
      where the spiral arteries belong to the latter group.
      Figure thumbnail gr4
      Figure 4Multiple pathways to the decidua parietalis acute atherosis formation
      We propose several, potentially synergistic, pathways to acute atherosis, involving inflammatory, immunogenetic, and hemodynamic risks.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      ,
      • Staff A.C.
      • Dechend R.
      • Pijnenborg R.
      Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia-novel aspects for atherosclerosis and future cardiovascular health.
      ,
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      Staff. Failure of physiological transformation and spiral artery atherosclerosis in preeclampsia. Am J Obstet Gynecol 2022.
      Secondly, immunologic mechanisms are likely important for acute atherosis development. The localization of acute atherosis is intriguing and may provide a clue to its origins. The lesion is found mainly in the tips of the spiral arteries, in the decidual end and is not found in other maternal arteries outside the uterine wall. We propose that the decidual spiral artery tips are particularly prone to arterial damage because of their colocalization with cells from a genetically distinct fetus, including invading extravillous trophoblasts. Dysregulated local maternal tolerization to these allogeneic trophoblasts is likely 1 aspect of poor placentation
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      ,
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      ,
      • Redman C.W.
      Immunological aspects of pre-eclampsia.
      and may also play a role in the development of acute atherosis.
      Finally, altered hemodynamics may lead to acute atherosis. The localization of acute atherosis, usually downstream of unremodeled spiral arteries in the myometrial part of the spiral arteries, is also consistent with hemodynamic risk factors playing a role in its pathogenesis. Altered laminar blood flow caused by incomplete remodeling likely promotes endothelial shear stress, thus stimulating foam cell generation. This is similar to the formation of atherosclerotic lesions, tending to localize beyond arterial branching points in areas of altered blood flow patterns.
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      We have suggested that the pathways outlined above, alone or in combination, may lead to a common endpoint, namely, inflammatory stimulation of foam cell formation, and thereby acute atherosis lesions.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      Once present, the acute atherosis lesions may themselves contribute to further placental dysfunction. Acute atherosis narrows the spiral artery lumina, exacerbating dysfunctional uteroplacental flow.
      • Burton G.J.
      • Woods A.W.
      • Jauniaux E.
      • Kingdom J.C.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      ,
      • Staff A.C.
      • Dechend R.
      • Pijnenborg R.
      Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia-novel aspects for atherosclerosis and future cardiovascular health.
      The greater the number of spiral arteries affected in a pregnancy, the more likely it is to lead to exacerbation of placental dysfunction, with oxidative and ER cellular stress responses,
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      ,
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      as seen in preeclampsia. The acute atherosis lesions are also associated with an increased rate of local arterial thrombosis
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      ,
      • Alnaes-Katjavivi P.
      • Lyall F.
      • Roald B.
      • Redman C.W.
      • Staff A.C.
      Acute atherosis in vacuum suction biopsies of decidua basalis: an evidence based research definition.
      ,
      • Maqueo M.
      • Chavezazuela J.
      • Dosaldelavega M.
      Placental pathology in eclampsia and preeclampsia.
      ,
      • De Wolf F.
      • Robertson W.B.
      • Brosens I.
      The ultrastructure of acute atherosis in hypertensive pregnancy.
      and thereby increased risk of downstream placental ischemia and infarctions.
      • Robertson W.B.
      • Brosens I.
      • Dixon H.G.
      The pathological response of the vessels of the placental bed to hypertensive pregnancy.
      Clinically, acute atherosis lesions in preeclampsia have been associated with more severe disease forms, including preterm delivery and FGR,
      • Alnaes-Katjavivi P.
      • Roald B.
      • Staff A.C.
      Uteroplacental acute atherosis in preeclamptic pregnancies: rates and clinical outcomes differ by tissue collection methods.
      ,
      • Khong T.Y.
      Acute atherosis in pregnancies complicated by hypertension, small-for-gestational-age infants, and diabetes mellitus.
      ,
      • Stevens D.U.
      • Al-Nasiry S.
      • Bulten J.
      • Spaanderman M.E.
      Decidual vasculopathy in preeclampsia: lesion characteristics relate to disease severity and perinatal outcome.
      both well known to further increase the risk of premature cardiovascular disease after preeclampsia.
      • Staff A.C.
      • Redman C.W.
      • Williams D.
      • et al.
      Pregnancy and long-term maternal cardiovascular health: progress through harmonization of research cohorts and biobanks.
      This suggests a link between this short-term manifestation of uteroplacental arterial damage and chronic damage to the systemic maternal cardiovasculature.

      Acute atherosis: molecular pathways

      Acute atherosis was named after its morphologic resemblance of early atherosclerosis stages, but the lesions have several differing features and likely partly differing etiologies. We have previously argued that acute atherosis and atherosclerosis share inflammatory mechanisms for foam cell generation but that acute atherosis likely has additional, pregnancy-specific underlying mechanisms.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      As argued by us,
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      ,
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      although macrophage-derived foam cells represent a shared feature of acute atherosis and atherosclerotic lesions of larger arteries, the lesions differ with respect to time course (long vs short development), the size of the artery affected (acute atherosis only affects the small spiral arteries, in contrast to atherosclerosis affecting much larger arteries), and artery wall composition. Atherosclerotic lesions are more complex and develop plaques that may rupture.
      The histologic similarities between acute atherosis and graft vascular disease have also been highlighted for several decades,
      • Robertson W.B.
      • Brosens I.
      • Dixon H.G.
      The pathological response of the vessels of the placental bed to hypertensive pregnancy.
      ,
      • Labarrere C.A.
      Acute atherosis. A histopathological hallmark of immune aggression?.
      although subendothelial foam cell lesions are less prominent in the latter. Fibrinoid necrosis and intimal hyperplasia are however a shared feature, and both types of lesions involve perivascular lymphocyte infiltration, complement,
      • Hering L.
      • Herse F.
      • Verlohren S.
      • et al.
      Trophoblasts reduce the vascular smooth muscle cell proatherogenic response.
      and immunoglobulin deposits. Strikingly, the arterial lesions of graft vascular disease and acute atherosis both occur at the boundaries between tissues from genetically distinct individuals, as reviewed by us.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      Both allograft rejection and preeclampsia correlate with the presence of circulating angiotensin II type 1 receptor agonistic autoantibody (AT1-AA),
      • Herse F.
      • Dechend R.
      • Harsem N.K.
      • et al.
      Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia.
      but our study did not find increased rates of this autoantibody in preeclampsia with acute atherosis compared with that of preeclampsia without acute atherosis.
      • Rieber-Mohn A.B.
      • Sugulle M.
      • Wallukat G.
      • et al.
      Auto-antibodies against the angiotensin II type I receptor in women with uteroplacental acute atherosis and preeclampsia at delivery and several years postpartum.
      However, in line with the hypothesis that acute atherosis shares certain molecular pathways with graft vessel disease and acute atherosis, we,
      • Hering L.
      • Herse F.
      • Verlohren S.
      • et al.
      Trophoblasts reduce the vascular smooth muscle cell proatherogenic response.
      like others previously,
      • Labarrere C.
      • Alonso J.
      • Manni J.
      • Domenichini E.
      • Althabe O.
      Immunohistochemical findings in acute atherosis associated with intrauterine growth retardation.
      have found presence of complement around uteroplacental decidual spiral arteries afflicted with acute atherosis.
      • Labarrere C.A.
      Acute atherosis. A histopathological hallmark of immune aggression?.
      When comparing decidual “tissue” features of preeclampsia and normotensive pregnancies, we previously demonstrated excessive tissue inflammation in preeclampsia, with increased content of lipids (total cholesterol, phospholipids, and triglycerides)
      • Staff A.C.
      • Ranheim T.
      • Khoury J.
      • Henriksen T.
      Increased contents of phospholipids, cholesterol, and lipid peroxides in decidua basalis in women with preeclampsia.
      and increased levels of 8-isoprostane,
      • Staff A.C.
      • Halvorsen B.
      • Ranheim T.
      • Henriksen T.
      Elevated level of free 8-iso-prostaglandin F2alpha in the decidua basalis of women with preeclampsia.
      a marker of oxidative stress, and increased phospholipase A2 activity decidual tissue,
      • Staff A.C.
      • Ranheim T.
      • Halvorsen B.
      Augmented PLA2 activity in pre-eclamptic decidual tissue—a key player in the pathophysiology of ‘acute atherosis’ in pre-eclampsia?.
      the latter liberating 8-isoprostane from tissue phospholipids. We also showed in vitro that 8-isoprostane affects trophoblast function, including matrix metalloproteinase, NF-kappa B, and LOX-1 activities.
      • Staff A.C.
      • Ranheim T.
      • Henriksen T.
      • Halvorsen B.
      8-iso-prostaglandin f(2alpha) reduces trophoblast invasion and matrix metalloproteinase activity.
      ,
      • Halvorsen B.
      • Staff A.C.
      • Henriksen T.
      • Sawamura T.
      • Ranheim T.
      8-iso-prostaglandin F(2alpha) increases expression of LOX-1 in JAR cells.
      Our renin-angiotensin system studies also demonstrated its local up-regulation in the decidua compared with that in placental tissues and a 5-fold up-regulation of decidual expression of the angiotensin II type 1 receptor in preeclampsia compared with that of normotensive pregnancies.
      • Herse F.
      • Dechend R.
      • Harsem N.K.
      • et al.
      Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia.
      As for comparing “cellular” features of acute atherosis and early atherosclerosis, we have in our decidual studies found evidence of both differences and similarities. Most arterial injuries begin with endothelial dysfunction and activation,
      • Liao J.K.
      Linking endothelial dysfunction with endothelial cell activation.
      but in our recent study, immunohistochemical evidence of endothelial activation was lacking in most decidua basalis spiral arteries with acute atherosis, with the absence of intercellular adhesion molecule 1 (ICAM-1) expression.
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
      • Redman C.
      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      Labarrere et al
      • Labarrere C.A.
      • DiCarlo H.L.
      • Bammerlin E.
      • et al.
      Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
      found evidence of ICAM-1 expression in decidua basalis spiral arteries with acute atherosis, but the authors studied mainly nonremodeled arteries, in contrast to our work.
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
      • Redman C.
      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      We did however find other evidence of endothelial abnormalities in acute atherosis lesions, characterized by weak CD31 staining, possibly secondary to cellular stress. Our findings
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
      • Redman C.
      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      and the findings of others
      • Katabuchi H.
      • Yih S.
      • Ohba T.
      • et al.
      Characterization of macrophages in the decidual atherotic spiral artery with special reference to the cytology of foam cells.
      ,
      • Pijnenborg R.
      • Anthony J.
      • Davey D.A.
      • et al.
      Placental bed spiral arteries in the hypertensive disorders of pregnancy.
      of fibrinoid necrosis in acute atherosis of the arterial wall (colored red by Martius scarlet blue [MSB] staining and gray-pink by periodic acid-Schiff [PAS] staining)
      • Fosheim I.K.
      • Alnaes-Katjavivi P.
      • Redman C.
      • Roald B.
      • Staff A.C.
      • Størvold G.L.
      Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation.
      are consistent with an altered local endothelial phenotype, likely leaking factors from the maternal circulation into the vessel wall, depositing fibrin or fibrinlike (fibrinoid) material. Our recent immunohistochemical investigations confirmed that perivascular infiltrates were not consistently present or large around all acute atherosis lesions and that adaptive CD4 helper T cells may be involved, whereas the presence of Tregs (FOXP3+) was almost absent,
      • Johnsen G.M.
      • Størvold G.L.
      • Alnaes-Katjavivi P.H.
      • et al.
      Lymphocyte characterization of decidua basalis spiral arteries with acute atherosis in preeclamptic and normotensive pregnancies.
      again demonstrating similarities and discrepancies relative to early atherosclerosis lesions.
      • Kyaw T.
      • Toh B.H.
      • Bobik A.
      Foxp3+CD4+ regulatory T-cell subtypes and atherosclerosis.
      The recent findings of a more prevalent proinflammatory macrophage phenotype in the decidua basalis with acute atherosis and an intravascular monocyte source for macrophages in acute atherosis
      • Gill N.
      • Leng Y.
      • Romero R.
      • et al.
      The immunophenotype of decidual macrophages in acute atherosis.
      support our hypothesis that both tissue-based and circulation-based cellular pathways lead to decidual acute atherosis.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      Similarities among the circulating biomarkers also exist between acute atherosis and atherosclerosis. Another of our recent papers suggests that older women with decidual acute atherosis (both preeclamptic and normotensive pregnancies) have a lipidemic profile resembling that of patients with atherosclerosis, including elevated levels of apolipoprotein B and LDL.
      • Moe K.
      • Alnaes-Katjavivi P.
      • Størvold G.L.
      • et al.
      Classical cardiovascular risk markers in pregnancy and associations to uteroplacental acute atherosis.
      Furthermore, we recently showed that the presence of decidual acute atherosis or other evidences of placental dysfunction (eg, low levels of PlGF) was associated with dysregulated patterns of circulating cardiovascular disease–related multiplex biomarkers at delivery,
      • Lekva T.
      • Sugulle M.
      • Moe K.
      • Redman C.
      • Dechend R.
      • Staff A.C.
      Multiplex analysis of circulating maternal cardiovascular biomarkers comparing preeclampsia subtypes.
      supporting our model of potentially shared mechanisms.

      Acute atherosis and long-term maternal health

      Pregnancy is seen as a stress test for future maternal health, and preeclampsia is associated with 2- to 8-fold increased risk of cardiovascular death.
      • Staff A.C.
      • Redman C.W.
      • Williams D.
      • et al.
      Pregnancy and long-term maternal cardiovascular health: progress through harmonization of research cohorts and biobanks.
      We have suggested that the subset of women who develop acute atherosis lesions in pregnancy may have increased risk of atherosclerotic disease later in life.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      ,
      • Staff A.C.
      • Dechend R.
      • Pijnenborg R.
      Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia-novel aspects for atherosclerosis and future cardiovascular health.
      Acute atherosis may represent an accelerated atherosclerotic process, driven by the dramatic physiological changes that occur in pregnancy. We have proposed that diagnosing acute atherosis thereby could aid in better targeting preeclamptic women at higher risk of long-term cardiovascular disease,
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      and our findings of dyslipidemia in the follow-up of older pregnant women with acute atherosis support this notion.
      • Moe K.
      • Alnaes-Katjavivi P.
      • Størvold G.L.
      • et al.
      Classical cardiovascular risk markers in pregnancy and associations to uteroplacental acute atherosis.
      This concept has also been followed up by Veerbeek et al
      • Veerbeek J.H.
      • Brouwers L.
      • Koster M.P.
      • et al.
      Spiral artery remodeling and maternal cardiovascular risk: the spiral artery remodeling (SPAR) study.
      and Stevens et al,
      • Stevens D.U.
      • Al-Nasiry S.
      • Fajta M.M.
      • et al.
      Cardiovascular and thrombogenic risk of decidual vasculopathy in preeclampsia.
      the latter study demonstrating an adverse cardiovascular risk profile at 7 months after delivery in women with a history of preeclampsia and decidual vasculopathy. However, both short- and long-term studies of acute atherosis are potentially hampered with the challenges in obtaining enough tissue for optimal diagnosis of decidual acute atherosis.
      • Alnaes-Katjavivi P.
      • Roald B.
      • Staff A.C.
      Uteroplacental acute atherosis in preeclamptic pregnancies: rates and clinical outcomes differ by tissue collection methods.
      Early stages of atherosclerosis are reversible, and statins have been shown to confer antiatherogenic and anti-inflammatory effects in large clinical trials.
      • Sipahi I.
      • Tuzcu E.M.
      Candidate mechanisms for regression of coronary atherosclerosis with high-dose statins: insight from intravascular ultrasonography trials.
      We have therefore put forward that use of statins in established preeclampsia may ameliorate acute atherosis, thereby improving uteroplacental perfusion and pregnancy outcome.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      In support of this, small clinical studies of statins used in women with antiphospholipid syndrome presenting with preeclampsia or FGR have shown promising results with improved uteroplacental perfusion, although randomized trials are lacking.
      • Lefkou E.
      • Mamopoulos A.
      • Dagklis T.
      • Vosnakis C.
      • Rousso D.
      • Girardi G.
      Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy.
      Whether postpartum statins or other pharmacologic anti-inflammatory interventions (eg, metformin) following preeclampsia or acute atherosis would be useful to women in delaying atherosclerosis progression and improving long-term cardiovascular health is neither known nor tested.

      Remaining enigmas of acute atherosis

      We are still far from understanding all molecular, immunologic, genetic, and environmental mechanisms leading to the different clinical presentations of the placental syndromes, including preeclampsia and acute atherosis. Areas that merit more research are preimplantation heterogeneity, the decidua-related (trophoblast-independent) vascular remodeling processes, trophoblast invasion routes (arterial, venous, and glandular), decidual and immune cell interactions, and cytokine and growth factor production before and during trophoblast invasion. The cellular precursors of acute atherosis foam cells may include trophoblast cells
      • Halvorsen B.
      • Staff A.C.
      • Henriksen T.
      • Sawamura T.
      • Ranheim T.
      8-iso-prostaglandin F(2alpha) increases expression of LOX-1 in JAR cells.
      in addition to activated macrophages and smooth muscle cells
      • Allahverdian S.
      • Chehroudi A.C.
      • McManus B.M.
      • Abraham T.
      • Francis G.A.
      Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis.
      and should be further detailed. Emerging studies demonstrating accelerated placental aging in early-onset preeclampsia and autophagy
      • Saito S.
      • Nakashima A.
      A review of the mechanism for poor placentation in early-onset preeclampsia: the role of autophagy in trophoblast invasion and vascular remodeling.
      ,
      • Aoki A.
      • Nakashima A.
      • Kusabiraki T.
      • et al.
      Trophoblast-specific conditional Atg7 knockout mice develop gestational hypertension.
      are worth pursuing, also in the setting of other placental syndromes with remodeling defects. As argued previously,
      • Staff A.C.
      The two-stage placental model of preeclampsia: an update.
      preeclampsia represents a complex and multifaceted syndrome, as it involves several genomes; the maternal (oocyte and uterine), paternal, and fetal genomes. Dissecting its molecular pathology and interaction with environmental and modifiable risk factors is likely to uncover biologic understanding relevant to many human diseases, in addition to refining our conceptions and models of preeclampsia.
      Finally, whether acute atherosis in pregnancy truly correlates with excessive cardiovascular risk
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      ,
      • Staff A.C.
      • Dechend R.
      • Pijnenborg R.
      Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia-novel aspects for atherosclerosis and future cardiovascular health.
      ,
      • Veerbeek J.H.
      • Brouwers L.
      • Koster M.P.
      • et al.
      Spiral artery remodeling and maternal cardiovascular risk: the spiral artery remodeling (SPAR) study.
      ,
      • Stevens D.U.
      • Al-Nasiry S.
      • Fajta M.M.
      • et al.
      Cardiovascular and thrombogenic risk of decidual vasculopathy in preeclampsia.
      is still an intriguing topic for further investigation.

      Acknowledgments

      The authors would like to express gratitude to Profs Emeriti Chris Redman (Oxford, United Kingdom) and Robert Pijnenborg (Leuven, Belgium) for their excellent mentorship and inspiration and for our joint work in the field of preeclampsia and vascular remodeling. Our long-lasting collaboration with Prof Ralf Dechend (Berlin, Germany) has been invaluable to our interdisciplinary translational research work. For their extensive contributions in unveiling some of the mysteries of acute atherosis, the assistance of all participants of our research group, in particular Nina Kittelsen Harsem and Gro Leite Størvold, and other collaborators is greatly appreciated.

      Supplementary Video

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      Linked Article

      • Origins of the “great” obstetric and gynecologic syndromes
        American Journal of Obstetrics & GynecologyVol. 225Issue 3
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          A.T. Hertig1 (Harvard, MA) described narrowed arterioles in the placental bed in preeclampsia in 1945. In 1967, it was proposed that the narrowed uterine arterioles resulted from a “failure of physiological transformation” between 8 and 18 weeks’ gestation.2 Dr Staff and colleagues3 updated this long-standing hypothesis in their recent review.
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