Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors☆
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.
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2022, American Journal of Obstetrics and GynecologyCitation 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
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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.