The possible role of AhR in the protective effects of cigarette smoke on preeclampsia

Although smoking during pregnancy may lead to many adverse effects, such as fetal growth restriction, placental abruption, stillbirth, and preterm labor, smoking is the only environmental exposure known to consistently reduce the risk of preeclampsia and gestational hypertension. The exact mechanisms through which cigarette smoke reduces the risk of preeclampsia are not yet understood. Aryl hydrocarbon receptor (AhR), as the most abundant expression protein in the placenta, was widely studied in the human reproduction. We propose that cigarette smoke decreases the risk of developing preeclampsia via direct activation of AhR system in placenta. In this review we will address, and provide evidence for, our specific hypotheses that: cigarette significantly enhance trophoblast invasion and decrease placental oxidative damage through activation of AhR. This mechanism of suppression must be further investigated as they may provide valuable clues to novel therapeutic design in the realm of preeclampsia research.     

Fetal cells and cell-free fetal DNA in maternal blood: new insights into pre-eclampsia

The examination of fetal cells, specifically erythroblasts, and cell-free fetal DNA from the blood of pregnant women is currently the subject of intense research with the aim of developing new risk-free methods for prenatal diagnosis. An unexpected finding made during these studies was that the traffic of fetal erythroblasts into the maternal peripheral circulation was enhanced in pre-eclampsia. Independent prospective studies examining samples collected in the second trimester indicated that this perturbation in fetal cell trafficking occurs early in pregnancy, well before the onset of pre-eclampsia symptoms. The quantitative analysis of cell-free fetal and maternal DNA levels indicated that these concentrations were elevated in a co-ordinate manner in manifest pre-eclampsia, and that these elevations corresponded to disease severity. On the other hand, analysis of prospectively collected samples indicated that only cell-free fetal but not maternal DNA levels were elevated before onset of symptoms in pregnancies which subsequently developed pre-eclampsia. These data support hypotheses suggesting that pre-eclampsia is a multi-step disorder, initiated by a placental lesion that occurs early in pregnancy and which subsequently leads to a systemic maternal inflammatory response and associated endothelial cell damage.     

Carbon monoxide inhibits hypoxia/reoxygenation-induced apoptosis and secondary necrosis in syncytiotrophoblast

Pre-eclampsia, a hypertensive disorder of pregnancy, affects 5 to 7% of pregnancies. Oxidative stress-induced placental injury and subsequent release of placental debris into the maternal circulation are key pathogenic events in the progression of pre-eclampsia. Women who smoke cigarettes throughout pregnancy are 33% less likely to develop this disorder than nonsmoking women. We postulated that elevated carbon monoxide concentrations in serum of smoking women inhibits apoptosis and debris shedding of trophoblast cells exposed to ischemia-reperfusion injury because carbon monoxide has cytoprotective effects on endothelial and smooth muscle cells in culture. This may be responsible for the reduced risk of pre-eclampsia in smoking women. To assess the cytoprotective properties of carbon monoxide within placental tissue, carbon monoxide treatments were administered to in vitro hypoxia/reoxygenation-insulted villous explants cultured from term human placenta. Induction of apoptosis was assessed using molecular and morphological approaches. Placental villous explants treated with carbon monoxide demonstrated 60% less hypoxia/reoxygenation-induced apoptosis in the differentiated syncytiotrophoblast layer compared with untreated explants undergoing a similar insult. In addition, retention of intact syncytial membranes was observed in carbon monoxide-treated explants. These observations indicate that carbon monoxide has potent antiapoptotic properties within human placenta and may hold therapeutic potential in the treatment of pre-eclampsia.     

Maternal human leukocyte antigen-G polymorphism is not associated with pre-eclampsia in a Chinese Han population

Pre-eclampsia is a multisystem disorder of pregnancy and remains the leading cause of both maternal and fetal morbidity and mortality in many countries. Despite extensive studies, the underlying mechanisms still remain unknown. Besides its restricted expression in the tissues of placenta and its function in regulating immune suppression and in ensuring successful invasion of placental tissues into maternal deciduas, it has been postulated that HLA-G may play a role in modulation of immune tolerance at the fetal-maternal interface. Aberrant HLA-G expression may result in pregnancy disorders that are associated with poor invasion of extravillous cytotrophoblast into maternal spiral arteries, such as pre-eclampsia. Studies have shown that pre-eclampsia is largely under genetic control, but genetic mechanisms underlying the disorder have yet to be determined. In the current study, we focus on the potential role of HLA-G polymorphism in the pathogenesis of pre-eclampsia. Samples were obtained from Chinese Han primiparous women with pre-eclampsia and irrelative normal women, and case-matched placentas were genotyped for the HLA-G polymorphism in the exons 2, 3, and 4, and the 14-base-pair (bp) insertion/deletion polymorphism in the 3'-untranslated region of exon 8 was analyzed separately. The frequency of HLA-G polymorphism in these samples was not significantly different from those of normal controls, indicating that maternal HLA-G polymorphism is not associated with the risk for pre-eclampsia in this Chinese Han population. However, the maternal 14-bp insertion/deletion polymorphism is ethnically different.     

Placental-related diseases of pregnancy: Involvement of oxidative stress and implications in human evolution

Miscarriage and pre-eclampsia are the most common disorders of human pregnancy. Both are placental-related and exceptional in other mammalian species. Ultrasound imaging has enabled events during early pregnancy to be visualized in vivo for the first time. As a result, a new understanding of the early materno-fetal relationship has emerged and, with it, new insight into the pathogenesis of these disorders. Unifying the two is the concept of placental oxidative stress, with associated necrosis and apoptosis of the trophoblastic epithelium of the placental villous tree. In normal pregnancies, the earliest stages of development take place in a low oxygen (O2) environment. This physiological hypoxia of the early gestational sac protects the developing fetus against the deleterious and teratogenic effects of O2 free radicals (OFRs). In miscarriage, development of the placento-decidual interface is severely impaired leading to early and widespread onset of maternal blood flow and major oxidative degeneration. This mechanism is common to all miscarriages, with the time at which it occurs in the first trimester depending on the aetiology. In contrast, in pre-eclampsia the trophoblastic invasion is sufficient to allow early pregnancy phases of placentation but too shallow for complete transformation of the arterial utero-placental circulation, predisposing to a repetitive ischaemia-reperfusion (I/R) phenomenon. We suggest that pre-eclampsia is a three-stage disorder with the primary pathology being an excessive or atypical maternal immune response. This would impair the placentation process leading to chronic oxidative stress in the placenta and finally to diffuse maternal endothelial cell dysfunction.     

Placental pathophysiology in preeclampsia

The two central pathophysiological themes of preeclampsia are: (1) placental trophoblast dysfunction; and (2) endothelial dysfunction within the maternal systemic vasculature. No single factor has been identified as the cause of preeclampsia, however, substantial evidence suggests that the increased oxidative stress, production of vasoconstrictor agents, altered placental cytokine generation, and the formation of other toxic compounds produced by the placenta promote several forms of endothelial dysfunction in preeclampsia. The effects of such placental factors on maternal vascular cells (e.g. endothelial cells, neutrophils and platelets), combined with pre-existing maternal risk factors (vascular, renal, and metabolic diseases), with immune abnormalities and genetic factors pose substantial risks for developing this disorder during pregnancy. While placental dysfunction may not be the sole cause of preeclampsia, placental dysfunction may trigger, or significantly contribute to the vascular complications associated with preeclampsia.     

Intrauterine hypoxia and sudden infant death syndrome

Sudden infant death syndrome (SIDS) or crib or cot death are synonyms for the sudden, unexpected and unexplained death of an infant. The incidence of SIDS has been estimated to be from 1-2% to 3%. Protracted intrauterine hypoxia or recurrent hypoxic insults during fetal life undoubtedly influence the development of the central nervous structures as a tissue most susceptible to hypoxia, although well developed mechanisms of defense against hypoxia exist during the fetal life. The mechanisms underlying SIDS include neurologically compromised infants who are deprived of compensatory mechanisms during sleep, sustaining a hypoxic insult with alterations in neurotransmitter receptors within the regions involved in chemoreception and cardiovascular control. Changes in the brain result from perinatal prolonged hypoxia (persistent reticular pathways in the pons and medulla, astroglia in the brainstem, gliosis of brain nerve nuclei, defects in neurotransmitter receptors, neuronal apoptosis, microthrombosis, and hypoxic ischemic lesion). Hypoxic perinatal risk factors for SIDS included passive and active exposure to cigarette smoking in pregnancy, abuse of drugs, alcohol, coffee and medication in pregnancy, intrauterine growth retardation, perinatal hypoxia with or without resuscitation, preeclampsia, anemia in pregnancy, prematurity, multiparity, multiple pregnancy, pregnant women aged < 20 years and > 35 years, cardiocirculatory, pulmonary and endocrine diseases in pregnancy, and short time interval between two pregnancies. As cigarette smoking has been demonstrated to lead to fetoplacental insufficiency, which result in fetal hypoxia, it is concluded that hypoxia is a precondition for the occurrence of SIDS. Prenatal exposure to cigarette smoke decreases maternal red blood cell count, and concentrations of tyrosine and selenium, reduces fetal and neonatal cerebral blood flow, and increases maternal MCV, leukocytosis, especially neutrophils, monocytes and lymphocytes, maternal and fetal heart rate, systolic and diastolic blood pressure, resistance index in umbilical artery, fetal hemoglobin, cytokine, serotonine, dopamine, catecholamine, hypoxanthine, endorphin and interleukin-6. Pregnancy at a risk of hypoxia, especially in heavy smokers, is a major risk factor for SIDS, and such pregnancy requires close and intensive antenatal monitoring.     

The role of lipoprotein (a) in pregnancies complicated by pre-eclampsia

Endothelial cell dysfunction is a key feature of the pathogenesis of pre-eclampsia. The cause of the endothelial cell injury is probably multifactorial, but poor placenta perfusion plays a major role. In pre-eclampsia, characteristic pathological lesions in the placenta are fibrin deposits, acute atherosis and thrombosis. The similarity between the lesions of pre-eclampsia and atherosclerosis has led to speculations of a common pathophysiological pathway. An abnormal lipid profile is known to be strongly associated with atherosclerotic cardiovascular disease and has a direct effect on endothelial function. Abnormal lipid metabolism seems important in the pathogenesis of pre-eclampsia too. An elevated plasma lipoprotein (a) concentration is a known risk factor for atherosclerotic cardiovascular disease. In this paper, we discuss three hypotheses about the mechanisms by which lipoprotein (a) may be associated with pre-eclampsia: 1. Lp(a), as an acute-phase reactant, transporting cholesterol to sites of endothelial damage for reparation, temporarily increases during pregnancy and increases more during a pregnancy complicated by mild to moderate pre-eclampsia as compared to an uncomplicated pregnancy, in response to a greater extend of endothelial injury in pre-eclampsia. After delivery, pre-eclampsia subsides and Lp(a) concentrations return to baseline levels. 2. In cases of severe pre-eclampsia, there is even more extensive endothelial damage and consequently a higher consumption of Lp(a) in reparation of this vascular damage. These women will have lower concentrations of Lp(a). 3. High baseline concentrations of Lp(a), which are genetically determined, may induce or contribute to the development of pre-eclampsia by promoting endothelial dysfunction. In this line of reasoning one would expect to find higher concentrations of Lp(a) in women at risk for developing pre-eclampsia in a future pregnancy or with a history of pre-eclampsia. As discussed above, these women are also at increased risk for future cardiovascular disease as compared to women with a history of normal pregnancy. The pathophysiologic changes associated with cardiovascular disease may also be responsible for the increased incidence of pre-eclampsia in these women.     

Placental ischaemia is a consequence rather than a cause of pre-eclampsia

The aetiology or pre-eclampsia remains unknown, but it is widely accepted that the disorder is placental in origin. Failed trophoblast invasion of the maternal spiral arteries is accepted to be a central pathogenetic mechanism. However, the concept of failed trophoblast invasion is based on an assumption rather than direct scientific observation and there are other likely explanations for this phenomenon. The criteria for disease causation, such as the Bradford-Hill criteria are central to the ascertainment of causal relationships in modern medicine and these criteria are used here to assess the relationship between the placenta and pre-eclampsia. There is a strong association between pre-eclampsia and small (rather than large) placentas and an appropriate dose-response relationship does not exist. Failed trophoblast invasion of the spiral arteries is not specific to pre-eclampsia and occurs in other pregnancy complications and in up to 40% of biopsies from normal pregnancies and the relationship between placental ischaemia and pre-eclampsia is very inconsistent. A placental cause for pre-eclampsia is not consistent with the pathogenesis of other pregnancy complications like gestational diabetes mellitus. If pre-eclampsia was a disease of trophoblast origin, the risk of the disease should be determined by trophoblast rather than maternal factors. However, evidence from assisted reproduction shows that the risk of a woman developing pre-eclampsia is almost entirely dependent on maternal factors and independent of the embryo from which the placenta develops. There is currently no plausible proven mechanism by which the placenta causes pre-eclampsia. The syndrome typically gets worse, and can arise de-novo after the placenta has been removed, calling into question the role of the placenta in its causation. Uterine artery ligation in humans, unlike in animal experiments, is not associated with an increased incidence of pre-eclampsia, calling into question the role of poor utero-placental perfusion in the cause of the disease in humans. The signals that initiate maternal adaptive responses during pregnancy come from or through the placenta into the maternal milieu but as is the case with gestational diabetes mellitus, are not necessarily the cause of maternal disease. Pre-eclampsia causes renal, hepatic, myocardial, cerebral and adrenal ischaemia--that is ischaemia in all highly vascular organs. Placental ischaemia, like ischaemia in all other organs, is a consequence rather than a causal factor in the development of the syndrome and this has profound consequences for research strategies.     

Antiphospholipid antibodies internalised by human syncytiotrophoblast cause aberrant cell death and the release of necrotic trophoblast debris

Antiphospholipid antibodies (aPL) are the strongest maternal risk factor for pre-eclampsia, a hypertensive disease of human pregnancy. Pre-eclampsia is triggered by a toxic factor released from the placenta that activates the maternal endothelium. Antiphospholipid antibodies cause the release of necrotic trophoblast debris from the placental syncytiotrophoblast and this debris can activate endothelial cells. In this study, we investigated how aPL affects syncytiotrophoblast death and production of necrotic trophoblast debris by examining the interaction between aPL and human first trimester placental explants. Human polyclonal and murine monoclonal aPL, but not control antibodies, were rapidly internalised by the syncytiotrophoblast. Inhibitors of endocytosis or the low-density lipoprotein receptor (LDLR) family, but not toll-like receptors, decreased the internalisation of aPL and prevented the release of necrotic trophoblast debris from the syncytiotrophoblast. Once internalised, aPL increased inner mitochondrial membrane leak and Cytochrome c release while depressing oxidative flux through Complex IV of the electron transport system in syncytiotrophoblast mitochondria. These data suggest that the human syncytiotrophoblast internalises aPL by antigen-dependent endocytosis involving LDLR family members. Once internalised by the syncytiotrophoblast, aPL affects the death-regulating mitochondria, causing extrusion of necrotic trophoblast debris which can activate maternal endothelial cells thereby contributing to the pathogenesis of pre-eclampsia.     

Pre-eclampsia: a mistake of trophoblastic cells for tumour cells?

Pre-eclampsia is a severe form of hypertension induced by pregnancy. In pre-eclampsia, there is deficient trophoblast invasion of the spiral arteries terminating in the placental bed. Perhaps some abnormality occurs in the immunosuppressive process as the maternal immune system encounters paternal antigens expressed by immunosuppressive decidual cells. This immunosuppressive abnormality might cause the deficient trophoblast invasion. Abnormal placentation might then lead to maternal endothelial cell damage by an ongoing process. There might be a recurring sequence of 4 steps: (1) The placenta releases trophoblastic cells with potentially cytotoxic characteristics. These circulating trophoblastic cells have an abnormal pattern of expression of integrins and perhaps other glycoproteins or proteins. (2) The circulating trophoblastic cells loosely bind to maternal endothelial cells, targeting them for anti-tumourigenesis. (3) The maternal immune system reacts against targeted maternal endothelial cells through anti-tumourigenic mechanisms. (4) Widespread maternal endothelial damage causes the characteristic kidney lesion called glomerula endotheliosis.     

Serum levels of macrophage colony stimulating, vascular endothelial, and placenta growth factor in relation to later clinical onset of pre-eclampsia and a small-for-gestational age birth

PROBLEM: The multisystem disorder of pre-eclampsia (PE) becomes manifest in late gestation, but the pathology originates in early pregnancy by the deleterious action of placental substances to the maternal endothelial system. These factors were searched for in the attempt to identify, as early as possible, the pregnancies with an increased risk of developing pre-eclampsia. The literature is equivocal regarding the usefulness of various markers including vascular endothelial growth factor (VEGF) and macrophage colony-stimulating factor (M-CSF). Results are often confounded by a varying fraction of pregnancies affected by foetal growth restriction (FGR) amongst the case and control groups. METHOD OF STUDY: In a nested case-control study we compared the serum levels of M-CSF, VEGF, and placenta growth factor (PLGF) in 23 pregnancies with subsequent mild PE without FGR and nine FGR pregnancies without PE with 40 matched controls at 17, 25, and 33 weeks of gestation cross-sectionally and longitudinally. RESULTS: VEGF levels were reduced in FGR but not in subsequently pre-eclamptic pregnancies at 17, 25, and 33 weeks. In contrast, PLGF was reduced in the PE but not in the FGR group. M-CSF did not differ between the three groups. CONCLUSION: Depending on which growth factor is found to be reduced, an early distinction can be made in terms of an increased risk for PE or FGR. Inconsistencies in the literature may reflect differences in PE disease severity between studies and the presence of a varying fraction of cases with FGR.     

The genetics of pre‐eclampsia: a feto‐placental or maternal problem?

Pre-eclampsia is a potentially life-threatening disease of women during pregnancy leading to hypertension and proteinuria. It affects 1 in 15 pregnancies but, despite intense research efforts, the cause of the disease remains mysterious. Because pre-eclampsia only occurs during pregnancy and its symptoms resolve after delivery, factors from the placenta are thought to be involved. The role of the placenta could be production of 'abnormal' factors that initiate widespread inflammation and vaso-constriction. Alternatively, because the placenta normally contributes to maternal cardiovascular adaptations of pregnancy, it may be that normal placental functions fail in pre-eclampsia or that susceptibilities in the mother to hypertensive, vascular and/or renal disease prevent the appropriate normal responses to them. The potential contributions of both maternal and fetal genes to the onset of the disease have complicated the genetic analysis of the disease in humans. Recent studies have identified strains of transgenic and mutant mice that develop the hallmark features of pre-eclampsia-like disease - gestational hypertension, proteinuria and kidney lesions (glomerulosclerosis). Comparison of three different mouse models suggests that pre-eclampsia can be initiated by at least three independent mechanisms: pre-existing borderline maternal hypertension that is exacerbated by pregnancy (BPH/5 strain of mice), elevated levels of the vasoconstrictor angiotensin II in the maternal circulation by placental over-production of renin (renin/angiotensinogen transgenic mice), and placental pathology (p57Kip2 mutant mice). These findings imply that the pathogenesis of pre-eclampsia cannot be explained by a single mechanism. Therefore, segregation of the human disease into different subtypes may be a key first step in identifying genetic risk factors.     

细胞命运决定因子numb在先兆子痫胎盘组织中的表达及作用

目的探讨先兆子痫胎盘组织中细胞命运决定因子numbs表达情况及意义。方法获取正常妊娠胎盘组织以及先兆子痫胎盘组织,分别运用实时荧光定量PCR法、免疫印迹法、免疫组织化学法检测numbmRNA、蛋白分布及其表达水平。结果numb在以上两种胎盘组织中均有表达,且主要集中在细胞膜上表达。numb在先兆子痫组（实验组）的表达水平明显高于正常胎盘组（对照组）（P〈0．05）。结论numb参与的滋养细胞凋亡失调可能是先兆子痫的发病机制之一。     

SIRT1: A Novel Protective Molecule in Pre-eclampsia

Pre-eclampsia is a severe pregnant complication, mainly characterized by insufficient trophoblast invasion, impaired uterine spiral artery remodeling, placental hypoxia and ischemia, and endothelial dysfunction. However, the potential mechanisms of pre-eclampsia remain unclear. SIRT1 is a NAD+-dependent deacetylase, involving in multiple biological processes, including energy metabolism, oxidative stress, inflammatory response, and cellular autophagy. Several studies showed that SIRT1 might play a vital role in the pathogenesis of pre-eclampsia. In this review, we aim to integrate the latest research on SIRT1 and pre-eclampsia to explore the comprehensive mechanisms of SIRT1 in pre-eclampsia. More specifically, SIRT1 might affect placental development and trophoblast invasion through autophagy and senescence in pre-eclampsia, and SIRT1 protects vascular endothelial cells from oxidative stress, inflammatory response, autophagy, and senescence. Furthermore, SIRT1 deficiency mice showed typical pre-eclampsia-like performances, which can be reversed via direct SIRT1 supplement or SIRT1 agonist treatment. Additionally, resveratrol, a SIRT1 agonist, attenuates vascular endothelial injury and placental dysfunction, and exerts protective effect on decreasing blood pressure. In this review, we provide new insights into the development of pre-eclampsia, which can establish a theoretical basis for prevention and treatment for pre-eclampsia. Besides, we also propose questions that still need to be further addressed in order to elucidate the comprehensive molecular mechanisms of pre-eclampsia in the future.     

Calreticulin in human pregnancy and pre-eclampsia

Pre-eclampsia is a disorder of human pregnancy that involves pregnancy-induced maternal hypertension and proteinuria. Evidence indicates that pre-eclampsia involves widespread activation of maternal endothelial cells. Calreticulin is a ubiquitously expressed, multi-functional protein that has been shown to have both pro- and anti-inflammatory effects on cultured endothelial cells in vitro and in whole animals. In order to clarify the role of this protein in normal human pregnancy and in pre-eclampsia, this study has measured expression of calreticulin in maternal blood and in placenta in patients with pre-eclampsia and in control pregnancies. There was a significant increase (approximately 5-fold) in calreticulin in plasma in term pregnant women compared with women who were not pregnant. There was no difference, however, in calreticulin in plasma from women who were sampled at first trimester, second trimester and at term. In addition, there was a significant increase (approximately 50%) in calreticulin in plasma from pre-eclamptic women compared to controls. Calreticulin mRNA and protein expression in placenta were not changed between pre-eclampsia and control pregnancies. These novel results indicate that calreticulin is increased in peripheral maternal blood early in pregnancy and remains elevated throughout normal gestation and that there is a further increase in calreticulin in pre-eclampsia.     

Increased levels of pregnancy-associated plasma protein-A2 in the serum of pre-eclamptic patients

Pregnancy-associated plasma protein-A and -A2 (PAPP-A and -A2) are proteases that cleave insulin-like growth factor-binding proteins (IGFBPs), resulting in local activation of IGF signaling pathways. Here, we examined PAPP-A and -A2 mRNA and protein levels in placenta and maternal sera from women with pre-eclampsia and compared them with samples from uncomplicated pregnancy. PAPP-A2 but not PAPP-A mRNA and protein were elevated in pre-eclamptic placenta (P < 0.01). PAPP-A2 is normally produced in placental syncytiotrophoblast cells and maternal decidua. PAPP-A2 in syncytiotrophoblast cells was dramatically increased in pre-eclampsia. Maternal serum concentrations of PAPP-A2 but not PAPP-A were also significantly elevated in pre-eclampsia as compared with uncomplicated pregnancy. mRNA levels of IGFBP5, a specific substrate for PAPP-A2 protease activity, were also significantly increased, suggesting a potential role for IGFBP5 in fetal and placental growth suppression during pre-eclampsia. However, IGFBP5 protein levels were not increased in placenta from pre-eclampsia, possibly due to cleavage by up-regulated PAPP-A2. These data might imply that PAPP-A2 may be up-regulated in pre-eclamptic pregnancy to compensate for IGFBP5-mediated suppression of the IGF pathway, although final birthweights are still low in pre-eclamptic pregnancy.     

Relationships between maternal plasma leptin, placental leptin mRNA and protein in normal pregnancy, pre-eclampsia and intrauterine growth restriction without pre-eclampsia

Leptin, an adipocyte hormone involved in energy homeostasis, is important in reproduction and pregnancy. Questions yet to be addressed include the source of higher leptin during pregnancy and its relationship to pregnancy outcome and fetal growth. The objective of this study was to investigate the relationship between placental leptin gene expression, placental leptin protein concentration and maternal plasma leptin concentration among control pregnant women, women with pre-eclampsia and women with growth-restricted infants. We also investigated the relationship between placental leptin expression and the placental expression of enzymes involved in cellular lipid balance: fatty acid translocase (CD36), carnitine palmitoyltransferase I (CPT-1B) and lipoprotein lipase (LPL). Placental leptin expression, placental protein and maternal plasma concentration were higher in pre-eclampsia than in controls but not in women with growth-restricted infants. Placental leptin expression and placental protein were higher in the preterm pre-eclamptic subjects, whereas maternal leptin was higher in the term pre-eclamptic subjects. The placental gene expression of CD36, CPT-1B and LPL were not different among the groups. This study suggests that despite similar failed placental bed vascular remodelling in pre-eclampsia and intrauterine growth restriction (IUGR), leptin gene expression is higher only in preterm pre-eclampsia.     

Animal models of pre-eclampsia

The cardinal features of human pre-eclampsia, hypertension and proteinuria, are mimicked in animal models. Increasingly, the accuracy of inducing 'pure' systemic endothelial dysfunction is regarded as critical in differentiating mechanisms of pre-eclampsia from other conditions which induce hypertension (e.g. glomerulonephritis, renal denervation or manipulation of the renin-angiotensin system). A recent study in baboons has identified the timing of induction of maternal endothelial damage after acute uteroplacental ischaemia (UPI). The endothelial changes in the glomerulus are indicative of a direct endothelial toxin and mimic the lesions seen in human pre-eclampsia; the extent of hypertension and proteinuria are also similar. This animal model identifies systemic and placental sFLT-1 (soluble fms-like tyrosine kinase-1) as a potential mediator of endothelial damage. This research involving primates with haemomonochorial placentas makes translation of these results to humans very compelling for understanding the mechanisms of human disease. Similar endothelial dysfunction has been identified in baboons treated with anti-inflammatory inhibitors. Similar studies in rodents have identified a relationship between angiotensin II agonistic antibodies, UPI/reduced uteroplacental perfusion pressure, angiogenic markers, and cytokines. We can now identify vasoconstrictive mediators of the hypertensive and endothelial response such as endothelin 1, the renin-angiotensin system, or other hormones such as oestrogens in primate models.     

Endothelial cell activation by tumour necrosis factor-alpha (TNF-alpha) and the development of pre-eclampsia.

Pre-eclampsia may develop as a result of an endothelial activation. Tumour necrosis factor-alpha (TNF-alpha) activates endothelial cells which release soluble E-selectin, a putative circulating marker specific for endothelial damage. A retrospective longitudinal study of maternal blood samples, collected at different gestational ages in pregnancy, was undertaken to determine whether the development of pre-eclampsia is associated with TNF-alpha-mediated endothelial activation. This study included 19 women who developed pre-eclampsia and 22 women whose pregnancy outcome was normal. Ten women had blood samples taken before pre-eclampsia was clinically detected and, in all these, TNF-alpha was below the immunoassay limit of detection (< 80 pg/ml). Five had further samples taken after pre-eclampsia was clinically diagnosed and, initially, TNF-alpha was still below the lower limit of detection in all five pregnancies, but rose later in three (80, 156 and 250 pg/ml). In nine other patients with diagnosed pre-eclampsia, TNF-alpha was detected in only two (80 and 650 pg/ml). TNF-alpha was identified in only one of the 22 normal pregnancies (80 pg/ml), this being at term. There was no statistical difference in soluble E-selectin levels between normal and pre-eclamptic pregnancies, neither before nor after pre-eclampsia was diagnosed. Hence, blood TNF-alpha levels measured by immunoassay can be elevated in approximately 36% of cases of established pre-eclampsia, but this rise occurs only after the syndrome is detected clinically. Blood concentrations of TNF-alpha and soluble E-selectin are not related to severity of the disorder. These findings suggest that circulating TNF-alpha does not contribute to the initiation of endothelial cell activation that may be associated with the development of pre-eclampsia, but may rise as a consequence of the pathological processes of this disorder.