Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors

https://doi.org/10.1016/j.jri.2013.09.001Get rights and content

Abstract

Acute atherosis (Aa) affects uteroplacental spiral arteries in 20–40% of cases of preeclampsia. Its hallmark is lipid-filled, CD68-positive foam cells. It usually develops in the decidua (the pregnancy endometrium) at the distal ends of arteries that are often unremodelled in their proximal segments. Aa resembles the early stages of atherosclerosis, which becomes symptomatic in the middle-aged and elderly, in contrast to the young age of pregnant women with Aa. Although the mechanisms of Aa are largely unknown, they are likely to resemble those of early atherosclerosis, which is an inflammatory lesion of the arterial wall. However, Aa is likely to have added pregnancy-specific features. Because it also occurs in normotensive pregnancies, complicated by foetal growth restriction, diabetes mellitus or autoimmune disease or even without any complications, we suggest that Aa is the final manifestation of several inflammatory processes. We revisit an old proposition that immunological incompatibility between mother and foetus may sometimes induce Aa. We propose that excessive inflammatory activation, of other aetiologies, primarily in the decidua basalis, may explain the different ways in which Aa occurs. We speculate that the subset of women who develop these lesions may be at an increased risk of atherosclerotic arterial disease later in life. We hypothesise that use of anti-atherogenic statins during established preeclampsia may ameliorate Aa, improve uteroplacental perfusion and enhance pregnancy outcome.

Introduction

Preeclampsia, affecting 3–5% of pregnancies, appears to have heterogeneous origins (Ness and Roberts, 1996, Redman et al., 1999). It is associated with long-term risks of maternal cardiovascular disease (reviewed in Staff et al., 2010). The placenta is necessary and sufficient to cause preeclampsia. Several candidate placenta-derived ‘preeclampsia’ factors are proposed (reviewed in Staff et al., 2010, Staff et al., 2013a). About 30–60 spiral arteries maintain uteroplacental perfusion (reviewed in Staff et al., 2010). Abnormal spiral artery remodelling at 8–18 weeks’ gestation (poor placentation) is deemed to cause preeclampsia in the conventional two-stage model of “placental” preeclampsia (Redman, 1992). Normal remodelling depends on a complex interplay between extravillous trophoblast (EVT) and decidual cells, including NK cells, macrophages and spiral artery smooth muscle and endothelial cells to establish normal perfusion of the growing placenta. Restricted remodelling (shallow placentation) causes abnormal uteroplacental perfusion and placental dysfunction with excessive release of placental factors into the maternal circulation. Downstream, an exaggerated maternal systemic inflammatory response ensues that includes endothelial dysfunction, maternal hypertension, proteinuria and other features. In “maternal preeclampsia”, women with normal placentation (including normal remodelling of the spiral arteries) and normal placental function are believed to develop preeclampsia owing to an abnormal constitutional systemic inflammatory response from pre-existing obesity, diabetes mellitus, or chronic hypertension (Staff et al., 2013b). Moreover, mixed presentations of maternal and placental disease are to be expected.

Defective artery remodelling is not specific to preeclampsia, occurring, more rarely, in foetal growth restriction (FGR), pregnancy-induced hypertension (without proteinuria), and even in normal pregnancy (Staff et al., 2010).

Section snippets

Placentation, immune factors and excessive inflammation

Although primiparity predisposes to preeclampsia, primipaternity may be more important, as summarised elsewhere in this issue. It is thought that inadequate maternal tolerisation to alloantigens, expressed by foetal trophoblasts, leads to poor placentation and its sequelae of dysfunctional uteroplacental perfusion, placental oxidative stress and release of pro-inflammatory factors. A first pregnancy tolerises a mother to a second pregnancy by the same partner (Rowe et al., 2012). However,

Acute atherosis

First described in 1945 (Hertig, 1945) and named in 1950 (Zeek and Assali, 1950), acute atherosis (Aa) is a spiral artery lesion, characterised by subendothelial lipid-filled foam cells, fibrinoid necrosis and leucocyte infiltration (Hanssens et al., 1998). It resembles early atherosclerosis, which typically affects coronary and other larger arteries in older non-pregnant women and in men. The foam cells include CD68-positive macrophages.

Aa most often occurs downstream of inadequately

Atherosclerosis is an inflammatory disorder

The innate immune system not only triggers rapid responses to infection, but responds to endogenous “danger molecules” (Matzinger, 2002). Atherosclerosis is a chronic inflammatory lesion of large and medium sized arteries, characterised by lipid deposition and oxidative stress. The trigger seems to be chronic, focal endothelial activation from the shear stress of turbulent blood flow (Tsou et al., 2008) or infection, for example, Chlamydia pneumonia (Tufano et al., 2012), or other undefined

Is decidual inflammation the final common step to Aa?

Given our arguments above, we suggest four mechanisms for the development of Aa, with excessive decidual inflammation as the final common pathway: (1) shear flow stress caused by abnormal blood flow in inadequately remodelled spiral arteries; (2) decidual inflammation, including maternal alloreactivity to feto-paternal HLA-C or minor histocompatibility antigens; (3) background (systemic) maternal inflammatory stress secondary to changes induced by pregnancy and preeclampsia; and (4) maternal

Testing the hypothesis, clinical consequences and conclusion

We have devised a new multistage model of preeclampsia that incorporates the possible late added effects of Aa, the possibility that it may develop without impaired placentation and that poor placentation may result either from impaired maternal tolerisation or from pre-existing vascular inflammation (Fig. 1).

To test our hypotheses, we are analysing decidual tissue from our Oslo pregnancy biobank from different pregnancy phenotypes (preeclamptic, normotensive, diabetic, etc.) for the presence

Conflict of interest statement

None declared.

References (71)

  • C.A. Labarrere

    Acute atherosis. A histopathological hallmark of immune aggression?

    Placenta

    (1988)
  • A. Majdalawieh et al.

    LPS-induced suppression of macrophage cholesterol efflux is mediated by adipocyte enhancer-binding protein 1

    Int. J. Biochem. Cell Biol.

    (2009)
  • J.W. Meekins et al.

    Immunohistochemical detection of lipoprotein(a) in the wall of placental bed spiral arteries in normal and severe preeclamptic pregnancies

    Placenta

    (1994)
  • R.B. Ness et al.

    Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications

    Am. J. Obstet. Gynecol.

    (1996)
  • C.W. Redman

    Immunological aspects of pre-eclampsia

    Baillieres Clin. Obstet. Gynaecol.

    (1992)
  • C.W. Redman et al.

    Preeclampsia: an excessive maternal inflammatory response to pregnancy

    Am. J. Obstet. Gynecol.

    (1999)
  • W.B. Robertson et al.

    Uteroplacental vascular pathology

    Eur. J. Obstet. Gynecol. Reprod. Biol.

    (1975)
  • P.Y. Robillard et al.

    Association of pregnancy-induced-hypertension, pre-eclampsia, and eclampsia with duration of sexual cohabitation before conception

    Lancet

    (1996)
  • V.A. Rodie et al.

    Pre-eclampsia and cardiovascular disease: metabolic syndrome of pregnancy?

    Atherosclerosis

    (2004)
  • I.L. Sargent et al.

    NK cells and human pregnancy – an inflammatory view

    Trends Immunol.

    (2006)
  • D. Schonkeren et al.

    Differential distribution and phenotype of decidual macrophages in preeclamptic versus control pregnancies

    Am. J. Pathol.

    (2011)
  • A.C. Staff et al.

    Elevated level of free 8-iso-prostaglandin F2alpha in the decidua basalis of women with preeclampsia

    Am. J. Obstet. Gynecol.

    (1999)
  • A.C. Staff et al.

    Increased contents of phospholipids, cholesterol, and lipid peroxides in decidua basalis in women with preeclampsia

    Am. J. Obstet. Gynecol.

    (1999)
  • A.C. Staff et al.

    Review: Preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses

    Placenta

    (2013)
  • D.U. Stevens et al.

    Decidual vasculopathy and adverse perinatal outcome in preeclamptic pregnancy

    Placenta

    (2012)
  • T. Tilburgs 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)
  • T. Tilburgs et al.

    Elsevier Trophoblast Research Award Lecture: unique properties of decidual T cells and their role in immune regulation during human pregnancy

    Placenta

    (2010)
  • S. Travaglione et al.

    Epithelial cells and expression of the phagocytic marker CD68: scavenging of apoptotic bodies following Rho activation

    Toxicol. In Vitro

    (2002)
  • J. Trowsdale et al.

    NK receptor interactions with MHC class I molecules in pregnancy

    Semin. Immunol.

    (2008)
  • M.G. Tuuli et al.

    Review: Oxygen and trophoblast biology – a source of controversy

    Placenta

    (2011)
  • P.J. Williams et al.

    Decidual leucocyte populations in early to late gestation normal human pregnancy

    J. Reprod. Immunol.

    (2009)
  • I. Brosens et al.

    On the pathogenesis of placental infarcts in pre-eclampsia

    J. Obstet. Gynaecol. Br. Commonw.

    (1972)
  • J.J. Chiu et al.

    Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives

    Physiol. Rev.

    (2011)
  • E. Galkina et al.

    Immune and inflammatory mechanisms of atherosclerosis (*)

    Annu. Rev. Immunol.

    (2009)
  • A.M. Germain et al.

    Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events?

    Hypertension

    (2007)
  • Cited by (122)

    • The etiology of preeclampsia

      2022, American Journal of Obstetrics and Gynecology
    • Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia

      2022, American Journal of Obstetrics and Gynecology
      Citation Excerpt :

      Early stages of atherosclerosis are reversible, and statins have been shown to confer antiatherogenic and anti-inflammatory effects in large clinical trials.98 We have therefore put forward that use of statins in established preeclampsia may ameliorate acute atherosis, thereby improving uteroplacental perfusion and pregnancy outcome.18 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.99

    View all citing articles on Scopus

    This paper is based on a presentation held at the 8th International Workshop on Immunology/Immunological Tolerance and Immunology of Preeclampsia, November 2012, Réunion Island.

    View full text