It has been known for nearly 100 years that preeclampsia is a placental condition (Holland, 1909; Redman, 1991). Other workers have clarified that an important placental pathology is an insufficient uteroplacental circulation leading to placental hypoxia, oxidative stress and, in the most severe cases, infarction (described in the chapter by Pijnenborg).
The question of how the placental problem becomes a generalized maternal problem needs to be considered. One or several undefined placen-tal factors, which we have previously denoted ''factor X'' (Redman, 1992), must circulate to cause the maternal disorder. There are two aspects to consider. What is the relevant placental function, and how does this translate into systemic dysfunction? The stimulus should originate in the placenta, must be released during all pregnancies to account for the systemic inflammatory response encountered in normal pregnant women, and be atypically large when the placenta is oxidatively stressed. There are three interrelated possibilities: dissemination of growth factors, their soluble regulators or inflammatory cytokines released by syncytio-trophoblast or, second, placental oxidative stress or, last, placental debris.
The strongest candidate so far is the soluble receptor for vascular endothelial growth factor (VEGFR-1), also known as sFlt-1, which inhibits the actions of VEGF (Kendall et al., 1996). sFlt-1 is synthesized and released by endothelial cells and peripheral blood monocytes (Barleon et al., 2001). VEGF is an important survival factor for endothelium so systemic inhibition would be expected to cause generalized endothelial dysfunction. This has been confirmed in human and animal studies. Clinical trials of a neutralizing monoclonal antibody to VEGF for the treatment of metastatic colorectal or renal cancer have shown that hypertension and proteinuria are the commonest side effects (Kabbinavar et al., 2003; Yang et al., 2003). Likewise, the infusion of sFlt-1 into rats (Maynard et al., 2003) causes these signs to appear. In the latter study the associated glomerular lesions were the same as those seen specifically in preeclampsia (Pollak and Nettles, 1960). Serum-soluble flt-1 is increased in pre-eclampsia (Maynard et al., 2003). Because it is complexed to VEGF, its high levels in pre-eclampsia can explain the variable reports of changes of plasma VEGF in this condition. If total VEGF is measured it is increased, whereas if only free VEGF is assayed it is reduced. The origin of the circulating sFlt-1 is presumed to be the placenta, although this has not yet been directly demonstrated (Clark et al., 1998; Maynard et al., 2003). The most compelling evidence is its rapid decline in concentration after delivery (Maynard et al., 2003). If soluble Flt-1 were the main cause of pre-eclampsia this could explain the paradoxical protective effect of cigarette smoking on the occurrence of pre-eclampsia (Zabriskie, 1963). Non-pregnant cigarette smokers have lower levels of circulating sFlt-1 than controls who do not smoke (Belgore et al., 2000). The fact that fetuses with trisomy 13 are particularly likely to provoke pre-eclampsia in their mothers (Boyd etal., 1987) is consistent with the location of the gene for soluble flt-1 on chromosome 13 (Barr et al., 1991).
How does this link to the model that is presented here? The most direct attempt to chart the sources of soluble Flt-1 in the human pregnancy showed that it is predominantly produced by extravillous trophoblast in the decidua and by endothelial and stromal cells in the chorionic villi, but not by the villous trophoblast (Clark et al., 1998). Villous explants release sFlt-1 into the culture supernatant in significantly greater amounts when cultured under hypoxic conditions (Ahmed et al., 2000), which is consistent with the view that placental hypoxia is an important part of the pathogenesis. The fact that it is also released by endothelium and monocytes (Barleon et al., 2001) suggests an alternative possible source of this factor. In nonpregnant individuals, chronic medical conditions that are associated with mild systemic inflammatory responses yield conflicting findings with sFlt-1 measured as increased (Belgore et al., 2001) or decreased (Felmeden et al., 2003). It is likely that sF1t-1 is a relevant placental factor in the direct causation of the features of pre-eclampsia.
It is possible that syncytiotrophoblast could synthesize and release excessive amounts of pro-inflammatory cytokines. However, an analysis of production from chorionic villous explants failed to show increases in TNF-a, IL-6, IL-a and IL-10 (Benyo et al., 2001) when tissues from preeclamptic and normal pregnancies were compared. Thus, there is no convincing evidence that the pre-eclampsia placenta disseminates inflammatory cytokines into the maternal circulation.
Dissemination may also involve oxidative stress and the disseminators may be inflammatory leukocytes themselves exposed to oxidatively altered trophoblast in the intervillous space. Leukocytes in the uterine vein are significantly activated relative to those in the peripheral circulation in pre-eclampsia. Transient hypoxia in the intervillous space could account for at least some of the observed changes (Mellembakken et al., 2002).
Cellular, subcellular and molecular debris from the syncytial surface of the placenta is shed into the maternal circulation. We have proposed that its clearance comprises the systemic inflammatory stimulus in normal and pre-eclamptic pregnancies. Such debris is detected in the plasma of normal pregnant women but in significantly increased amounts in pre-clampsia and is probably the product of syncytial apoptosis and necrosis (Redman and Sargent, 2000).
The placental villi of the pre-eclamptic woman are characterized by focal syncytial necrosis, with loss and distortion of microvilli (Jones and Fox, 1980). However, necrosis is not a marked feature of normal placentas and is therefore unlikely to cause the release of the circulating syncytial debris found in normal pregnancies near term. The debris includes syncytiotrophoblast microparticles (Knight et al., 1998), which are the hallmark of apoptosis (Aupeix et al., 1997). Apoptosis of normal human syncytiotrophoblast results in characteristic features including loss of microvilli and blebbing of the surface membrane (Nelson, 1996). It has been proposed that apoptosis plays a central role in turnover of cytotrophoblast and renewal of the syncytial surface of chorionic villi (Huppertz et al., 1998). Apoptosis rates are significantly increased in the syncytiotrophoblast in pre-eclampsia (Ishihara et al., 2002). It is also known that in vitro hypoxia induces apop-tosis of cultured human cytotrophoblasts (Levy et al., 2000). Hence, if syncytiotrophoblast microparticles were derived from apoptotic processes, then the observation that more circulates in pre-eclampsia may be related to the degree of apoptosis in, and shedding from, the syncytio-trophoblast. The argument is strengthened by the increased concentrations, in pre-eclampsia, of other circulating markers of syncytial debris including cytokeratin (Schrocksnadel et al., 1993) and soluble fetal DNA (Lo et al., 1999). At the other end of the spectrum is the evidence for increased shedding of syncytial cells (Johansen et al., 1999), a process long known as trophoblast deportation.
Shedding of debris from the syncytial surface would be expected to increase in two situations. The first is with increased placental size. Pre-eclampsia is predominantly a disorder of the third trimester, when the placenta reaches its greatest size. The placenta grows larger with multiple pregnancies, which also increase the likelihood of pre-eclampsia. The second would be associated with placental oxidative stress, as with the most severe pre-eclampsia, typically of early onset and associated with intense fetal growth retardation. The placentas are usually abnormally small. Here, it must be presumed that there is an alteration in the quality of the inflammatory stimulus generated by the placenta, for example, by its content of peroxidized lipids (Cester et al., 1994).
The current evidence is that circulating placental debris is likely to be an important part of the systemic inflammatory stimulus associated with both normal and pre-eclamptic pregnancies. We have shown that they are directly damaging to endothelium (Smarason et al., 1993) which is stimulated to release pro-inflammatory substances (von Dadelszen et al., 1999). Our preliminary evidence is that they are directly pro-inflammatory (Sacks et al., unpublished observations; Branton etal., unpublished observations). It is possible that it is this circulating debris which is the danger signal of pregnancy to which the inflammatory system responds appropriately.
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