Autoantibody-mediated IL-6-dependent endothelin-1 elevation underlies pathogenesis in a mouse model of preeclampsia

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy. Elevated circulating endothelin-1 (ET-1) is associated with the disease. However the molecular basis of increased ET-1 production and its role in PE are unknown. This study aimed to investigate the causative factors, pathological role of elevated ET-1 production in PE, and the underlying mechanisms. In this study, we found that IgG from women with PE, in contrast to IgG from normotensive pregnant women, induced preproET-1 mRNA expression via angiotensin II type 1 receptor activation in kidneys and placentas in pregnant mice. The ET-A receptor-specific antagonist BQ123 significantly attenuated autoantibody-induced hypertension, proteinuria, and renal damage in pregnant mice, demonstrating that autoantibody-induced ET-1 production contributes to pathophysiology. Mechanistically, we discovered that IL-6 functioned downstream of TNF-α signaling, contributing to increased ET-1 production in pregnant mice. IL-6 blockade inhibited preeclamptic features in autoantibody-injected pregnant mice. Extending the data to human studies, we found that IL-6 was a key cytokine underlying ET-1 induction mediated by IgG from women with PE in human placental villous explants and that endothelial cells are a key source of ET-1. Overall, we provide human and mouse studies showing that angiotensin II type I receptor-agonistic autoantibody is a novel causative factor responsible for elevated ET-1 production and that increased TNF-α/IL-6 signaling is a key mechanism underlying increased ET-1 production and subsequent maternal features. Significantly, our findings revealed novel factors and signaling cascades involved in ET-1 production, subsequent disease symptom development, and possible therapeutic intervention in the management of PE.     

Changes in cardiac structure and function in rats immunized by angiotensin type 1 receptor peptides

Angiotensin II (Ang II) is known to induce cardiomyocyte hypertrophy by activating the Ang II type 1 (AT1) receptor. Some studies have demonstrated that the autoantibodies against angiotensin AT1 receptor (AT1-AAs) cause functional effects, which is similar to those observed for the natural agonist Ang II. In this study, we investigated the effects of AT1-AAs on cardiomyocytes' structure and function. Male Wistar rats were immunized with synthetic peptides corresponding to the second extracellular loop of AT1 receptor and Freund's adjuvant. The titers of AT1-AAs in rat serum were detected by enzyme-linked immunosorbent assay every week. Hemodynamic analysis and heart weight (HW) indices were measured on the 4th and 8th months after initial immunization, respectively. Cultured neonatal rat cardiomyocytes were used to observe the hypertrophic effects of AT1-AAs. Results showed that systolic blood pressure and heart rate were significantly increased, the titers of AT1-AAs were also increased after 4 weeks of initial immunization. Compared with control group, the HW/body weight (BW) and left ventricular weight/BW of immunized rats were increased significantly and cardiac function was enhanced compensatively. The cultured neonatal rat cardiomyocytes respond to AT1-AAs stimulation with increased (3)H-leucine incorporation and cell surface area in a dose-dependent manner. These results suggest that the AT1-AAs have an agonist effect similar to Ang II in hypertrophy of cardiomyocytes in vivo and in vitro. AT1-AAs are involved in the pathogenesis of cardiovascular diseases and hypertension.     

IL-17-mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy

Preeclampsia is associated with autoimmune cells T(H)17, secreting interleukin-17, autoantibodies activating the angiotensin II type I receptor (AT1-AA), and placental oxidative stress (ROS). The objective of our study was to determine whether chronic IL-17 increases blood pressure by stimulating ROS and AT1-AAs during pregnancy. To answer this question four groups of rats were examined: normal pregnant (NP, n = 20), NP+IL-17 (n = 12), NP+tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) (n = 7) (a superoxide dismutase mimetic that scavenges ROS), and NP+IL-17+tempol (n = 11). IL-17 (150 pg/day) was infused into NP rats while tempol was administered via the drinking water ad libitum. On day 19 blood pressure (MAP) was recorded, and plasma, urine, and tissue were collected for isolation of ROS detected by chemilluminescent technique. Urinary isoprostane was measured by ELISA. AT1-AAs were determined via cardiomyocyte assay and expressed as beats per minute. MAP increased from 98 ± 3 mmHg in NP to 123 ± 3 mmHg in IL-17-infused NP rats. Urinary isoprostane increased from 1,029 ± 1 in NP to 3,526 ± 2 pg·mg(-1)·day(-1) in IL-17-infused rats (P < 0.05). Placental ROS was 436 ± 4 RLU·ml(-1)·min(-1) (n = 4) in NP and 702 ± 5 (n = 5) RLU·ml(-1)·min(-1) in IL-17-treated rats. Importantly, AT1-AA increased from 0.41 ± 0.05 beats/min in NP rats (n = 8) to 18.4 ± 1 beats/min in IL-17 rats (n = 12). Administration of tempol attenuated the hypertension (101 ± 3 mmHg) ROS (459 ± 5 RLU·ml(-1)·min(-1)) and blunted AT1-AAs (7.3 ± 0.6 beats/min) in NP+IL-17+tempol-treated rats. Additionally, AT1 receptor blockade inhibited IL-17-induced hypertension and placental oxidative stress. MAP was 105 ± 5 mmHg and ROS was 418 ± 5 RLU·ml(-1)·min(-1) in NP+IL 17-treated with losartan. These data indicate that IL-17 causes placental oxidative stress, which serves as stimulus modulating AT1-AAs that may play an important role in mediating IL-17-induced hypertension during pregnancy.     

Activin signalling and pre-eclampsia: From genetic risk to pre-symptomatic biomarker

Pre-eclampsia is a multi-system condition in pregnancy that is characterised by the onset of hypertension and proteinuria in women after the 20th week and it remains a leading cause of maternal and fetal mortality. Despite this the causative molecular basis of pre-eclampsia remains poorly understood. As a result, an intensive research effort has focused on understanding the molecular mechanisms involved in pre-eclampsia and using this information to identify new pre-symptomatic bio-markers of the condition. Activin A and its receptor, ACVR2A, have been extensively studied in this regard.Activin A is a member of the transforming growth factor (TGF)-β superfamily that has a wide range of biological functions depending on the cellular context. Recent work has shown that polymorphisms in ACVR2A may be a genetic risk factor for pre-eclampsia. Furthermore, both placenta and serum levels of Activin A are significantly increased in pre-eclampsia suggesting that Activin A may be a possible biomarker for the condition. Here we review the latest advances in this field and link these with new molecular data that suggest that the oxidative stress and pro-inflammatory cytokine production seen in pre-eclampsia may result in increased placental Activin A secretion in an attempt to maintain placental function.     

Agonistic Autoantibodies to the Angiotensin II Type I Receptor Cause Pathophysiologic Characteristics of Preeclampsia

BackgroundPreeclampsia (PE), new-onset hypertension with proteinuria during pregnancy, is associated with increased reactive oxygen species, the vasoactive peptide endothelin-1 (ET-1), T and B lymphocytes, soluble antiangiogenic factors sFlt-1 and sEndoglin (sFlt-1 and sEng), and agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA).ObjectivesOne important area of investigation for our laboratory was to determine what role AT1-AA plays in the pathophysiology associated with PE.MethodsTo achieve this goal, we examined the effect of AT1-AA suppression on hypertension in response to placental ischemia as well as the effect of AT1-AA on increased blood pressure, ET-1, reactive oxygen species, and sFlt-1 in normal pregnant rats (NP).ResultsWe demonstrated reductions in uterine perfusion pressure (RUPP) to be a stimulus for AT1-AA during pregnancy. We utilized the technique of B-cell depletion to suppress circulating AT1-AA in RUPP rats and found that AT1-AA suppression in RUPP rats was associated with lower blood pressure and ET-1 activation. To determine a role for AT1-AA to mediate hypertension during pregnancy, we infused purified rat AT1-AA (1:50) into NP rats, and analyzed blood pressure and soluble factors. We consistently found that AT1-AA infused rats had significantly increased AT1-AA and blood pressure above NP rats. This hypertension was associated with significantly increased ET-1 in renal cortices (11-fold) and placenta (4-fold), and there was an approximately 2- to 3-fold increase in placental oxidative stress. Furthermore, antiangiogenic factors sFlt-1 and sEng were significantly increased in the AT1-AA induced hypertensive group compared with the NP controls.ConclusionsCollectively, these data indicated an important role for AT1-AA stimulated in response to placental ischemia that caused hypertension during pregnancy.     

An unexpected tail of VEGF and PlGF in pre-eclampsia

PET (pre-eclamptic toxaemia), characterized by pregnancy-related hypertension and proteinuria, due to widespread endothelial dysfunction, is a primary cause of maternal morbidity. Altered circulating factors, particularly the VEGF (vascular endothelial growth factor) family of proteins and their receptors, are thought to be key contributors to this disease. Plasma from patients with PET induces numerous cellular and physiological changes in endothelial cells, indicating the presence of a circulating imbalance of the normal plasma constituents. These have been narrowed down to macromolecules of the VEGF family of proteins and receptors. It has been shown that responses of endothelial cells in intact vessels to plasma from patients with pre-eclampsia is VEGF-dependent. It has recently been shown that this may be specific to the VEGF???b isoform, and blocked by addition of recombinant human PlGF (placental growth factor). Taken together with results that show that sVEGFR1 (soluble VEGF receptor 1) levels are insufficient to bind VEGF-A in human plasma from patients with pre-eclampsia, and that other circulating macromolecules bind, but do not inactivate, VEGF-A, this suggests that novel hypotheses involving altered bioavailability of VEGF isoforms resulting from reduced or bound PlGF, or increased sVEGFR1 increasing biological activity of circulating plasma, could be tested. This suggests that knowing how to alter the balance of VEGF family members could prevent endothelial activation, and potentially some symptoms, of pre-eclampsia.     

Coagulation and Fibrinolytic Systems in Pre-eclampsia and Eclampsia

The coagulation and fibrinolytic mechanisms were investigated in a group of patients with severe pre-eclampsia and eclampsia and the findings were compared with those of healthy women in late pregnancy. In patients with pre-eclampsia the following significant differences were found: (1) greater depression of plasma fibrinolytic activity (euglobulin lysis time) than in normal pregnancy, (2) a higher level of inhibitor to urokinaseinduced lysis, (3) increased levels of serum fibrin degradation products, and (4) reduced platelet counts.In patients with eclampsia a progressive increase of the level of serum fibrin degradation products was found over the three days following eclamptic seizures. No such increase occurred after grand mal seizures in late pregnancy. The findings in this study support the view that intravascular clotting is taking place in pre-eclampsia and that this disturbance of the balance between coagulation and fibrinolysis may be localized to certain areas of the vascular compartment, particularly the placental and renal circulations. Fibrin deposition in the maternal vessels supplying the placenta would impair the placental blood flow, which may explain the placental insufficiency which occurs in pre-eclampsia. Likewise fibrin deposition in the renal vasculature will result in glomerular damage and proteinuria. Hypertension may be related to the renal ischaemic changes or a compensatory response to the presence of fibrin deposition in the vascular compartment. This evidence of intravascular fibrin deposition raises the question of the possible therapeutic value of antithrombotic agents to inhibit the clotting process. On a theoretical basis such treatment might be expected to improve blood flow to the placenta and thereby fetal growth.     

Effect of antihypertensive therapy with alpha methyldopa on levels of angiogenic factors in pregnancies with hypertensive disorders

Background

Antihypertensive drugs are believed to lower blood pressure in pre-eclampsia by direct or central vasodilatory mechanisms. However, they could also act by decreasing production of anti-angiogenic proteins involved in the pathophysiology of hypertension and proteinuria in pre-eclampsia (PE). The aim of our study was to evaluate the impact of antihypertensive therapy with alpha methyldopa on maternal circulating levels and placental production of soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in hypertensive disorders of pregnancy.

Methodology/Principal Findings

In a study conducted at University College Hospital and the Homerton University Hospital in London, we recruited 51 women with PE, 29 with gestational hypertension (GH), and 80 matched normotensive controls. Eight (16%) of the women with PE had severe disease. Placental samples were obtained from a further 48 women (14 PE, 10 GH and 24 matched controls). Serum levels of angiogenic factors were measured before and 24–48 hours after commencing antihypertensive therapy with alpha methyldopa for clinical indications. The same parameters were measured in placental extracts. In both PE (P<0.0001) and GH (P<0.05), serum sFlt-1 was increased and PlGF reduced at all gestations (P<0.001) compared to controls. Serum sEng levels were also increased in PE. Placental concentration of sFlt-1 and sEng was significantly higher in women with PE compared to controls and women with GH (P<0.0001). The concentration of PlGF was significantly lower in the placental tissue of women with PE compared to GH (P = 0.008). Antihypertensive treatment was associated with a significant fall in serum and placental content of sFlt1 and sEng in PE only.

Conclusions

Our data suggest that alpha methyldopa may have a specific effect on placental and/or endothelial cell function in pre-eclampsia patients, altering angiogenic proteins.     

Therapeutic potential of endothelin receptor antagonists for chronic proteinuric renal disease in humans

Diabetes and arterial hypertension continue to be the main causes of chronic renal failure in 2010, with a rising prevalence in part due to the worldwide obesity epidemic. Proteinuria is a main feature of chronic renal disease and mediated by defects in the glomerular filtration barrier and is as a good predictor of cardiovascular events. Indeed, chronic renal disease due to glomerulosclerosis is one of the important risk factors for the development of coronary artery disease and stroke. Glomerulosclerosis develops in response to inflammatory activation and increased growth factor production. Preclinical and first preliminary clinical studies provide strong evidence that endogenous endothelin-1 (ET-1), a 21-amino-acid peptide with strong growth-promoting and vasoconstricting properties, plays a central role in the pathogenesis of proteinuria and glomerulosclerosis via activation of its ET_A subtype receptor involving podocyte injury. These studies have not only shown that endothelin participates in the disease processes of hypertension and glomerulosclerosis but also that features of chronic renal disease such as proteinuria and glomerulosclerosis are reversible processes. Remarkably, the protective effects of endothelin receptors antagonists (ERAs) are present even on top of concomitant treatments with inhibitors of the renin–angiotensin system. This review discusses current evidence for a role of endothelin for proteinuric renal disease and podocyte injury in diabetes and arterial hypertension and reviews the current status of endothelin receptor antagonists as a potential new treatment option in renal medicine.     

Relationships of risk factors for pre-eclampsia with patterns of occurrence of isolated gestational proteinuria during normal term pregnancy

Background

Isolated gestational proteinuria may be part of the pre-eclampsia disease spectrum. Confirmation of its association with established pre-eclampsia risk factors and higher blood pressure in uncomplicated pregnancies would support this concept.

Methods

Data from 11,651 women from the Avon Longitudinal Study of Parents and Children who had a term live birth but did not have pre-existing hypertension or diabetes or develop gestational diabetes or preeclampsia were used. Proteinuria was assessed repeatedly (median 12 measurements per woman) by dipstick and latent class analysis was used to identify subgroups of the population with different patterns of proteinuria in pregnancy.

Results

Higher maternal pre-pregnancy body mass index (BMI), younger age, nulliparity and twin pregnancy were independently associated with increased odds of any proteinuria in pregnancy. Women who experienced proteinuria showed five patterns: proteinuria in early pregnancy only (≤20 weeks gestation), and onset at 21–28 weeks, 29–32 weeks, 33–36 weeks and ≥37 weeks gestation. There were higher odds of proteinuria onset after 33 weeks in obese women and after 37 weeks in nulliparous women compared with normal weight and multiparous women respectively. Smoking in pregnancy was weakly negatively associated with odds of proteinuria onset after 37 weeks. Twin pregnancies had higher odds of proteinuria onset from 29 weeks. In women with proteinuria onset after 33 weeks blood pressure was higher in early pregnancy and at the end of pregnancy.

Conclusions

Established pre-eclampsia risk factors were related to proteinuria occurrence in late gestation in healthy term pregnancies, supporting the hypothesis that isolated gestational proteinuria may represent an early manifestation of pre-eclampsia.     

Activation of renal angiotensin type 1 receptor contributes to the pathogenesis of progressive renal injury in a rat model of chronic cardiorenal syndrome

Although chronic cardiac dysfunction is known to progressively exacerbate renal injury, a condition known as type 2 cardiorenal syndrome (CRS), the mechanism responsible is largely unknown. The present study was undertaken to clarify the mechanism of renal injury in rats with both unilateral nephrectomy (NX) and surgically induced myocardial infarction (MI), corresponding to a model of type 2 CRS. Compared with a control group, rats with both MI and NX (MI+NX) exhibited progressive proteinuria during the experimental period (34 wk after MI surgery), whereas proteinuria was not observed in rats with MI alone and was moderate in rats with NX alone. The proteinuria in rats with MI+NX was associated with renal lesions such as glomerulosclerosis and infiltration of mononuclear cells and upregulation of the renal proinflammatory and -fibrotic cytokine and angiotensin II type 1a receptor (AT1aR) genes. In contrast, plasma renin activity was lowered in rats with MI+NX. Immunohistochemistry revealed that the increased AT1R protein was present mainly in renal interstitial mononuclear cells. Olmesartan medoxomil, an AT1R blocker, markedly reduced the proteinuria and infiltration of mononuclear cells, whereas spironolactone, a mineralocorticoid receptor blocker, did not. The present findings demonstrate the pathogenetic role of renal interstitial AT1R signaling in a model of type 2 CRS, providing evidence that AT1R blockade can be a useful therapeutic option for this syndrome.     

Plasma S1P and Sphingosine are not Different Prior to Pre-Eclampsia in Women at High Risk of Developing the Disease

Sphingolipids like sphingosine-1-phosphate (S1P) have been implicated in the pathophysiology of pre-eclampsia. We hypothesized that plasma S1P would be increased in women at high risk of developing pre-eclampsia who subsequently develop the disease. Low circulating placental growth factor (PlGF) is known to be associated with development of pre-eclampsia; so further, we hypothesized that increased S1P would be associated with concurrently low PlGF. This was a case-control study using stored maternal blood samples from 14 to 24 weeks of pregnancy, collected from 95 women at increased risk of pre-eclampsia. Pregnancy outcome was classified as uncomplicated, preterm pre-eclampsia (<37 weeks), or term pre-eclampsia. Plasma lipids were extracted and analyzed by ultraperformance liquid chromatography coupled to electrospray ionization MS/MS to determine concentrations of S1P and sphingosine. Median plasma S1P was 0.339 nmol/ml, and median sphingosine was 6.77 nmol/l. There were no differences in the plasma concentrations of S1P or sphingosine in women who subsequently developed pre-eclampsia, no effect of gestational age, fetal sex, ethnicity, or the presence of pre-existing hypertension. There was a correlation between S1P and sphingosine plasma concentration (P < 0.0001). There was no relationship between S1P or sphingosine with PlGF. Previous studies have suggested that plasma S1P may be a biomarker of pre-eclampsia. In our larger study, we failed to demonstrate there are women at high risk of developing the disease. We did not show a relationship with known biomarkers of the disease, suggesting that S1P is unlikely to be a useful predictor of the development of pre-eclampsia later in pregnancy.     

Role of AT₁ receptor-mediated salt retention in angiotensin II-dependent hypertension

Activation of type 1 angiotensin II (AT(1)) receptors in the kidney promotes blood pressure elevation and target organ damage, but whether renal AT(1) receptors influence the level of hypertension by stimulating sodium retention or by raising systemic vascular resistance has not been established. In the current studies, we used a kidney cross-transplantation strategy to determine whether increased sodium reabsorption by AT(1) receptors in the kidney mediates the chronic hypertensive response to angiotensin II. We found this to be true. In addition, we also identified a second, nontrivial component of blood pressure elevation induced by activation of renal AT(1) receptors that is sodium-independent. As the kidney has the capacity to limit the transmission of elevated systemic blood pressure into the renal microcirculation, prior studies struggled to clearly discriminate the relative contributions of blood pressure elevation vs. activation of AT(1) receptors to hypertensive kidney injury. In our model, we found that rapid surges in blood pressure, which may overcome the kidney's capacity to prevent perturbations in renal hemodynamics, correlate closely with kidney damage in hypertension. Moreover, maximal kidney injury in hypertension may require activation of a pool of nonrenal, systemic AT(1) receptors. These studies provide insight into precise mechanisms through which AT(1) receptor blockade influences the progression of hypertensive kidney disease.     

Predictors of ratio of placental weight to fetal weight in multiethnic community.

OBJECTIVE--To determine whether placental ratio is influenced by maternal ethnic origin, obesity, hypertension, and haematological indices of iron deficiency anaemia. DESIGN--Observational study. SETTING--District general hospital in Birmingham. SUBJECTS--692 healthy nulliparous pregnant women, of whom 367 were European, 213 Asian, 99 Afro-Caribbean, and 13 of other or undocumented ethnic origin. MAIN OUTCOME MEASURES--Placental ratio and maternal body mass index, blood pressure, and haematological indices. RESULTS--Though birth weight and placental weight were lower in Asian women than in other groups, mean placental ratio was similar in Asian (19.5% (SD 3.3%)), European (20.0% (4.0%)), and Afro-Caribbean women (20.4% (5.3%)). Gestational age at birth was the main predictor of placental ratio in the univariate analysis (r = -0.34, P < 0.001) and multivariate analysis. The only other significant predictor of placental ratio in multivariate analysis was maternal body mass index, which was positively associated with placental ratio (r = 0.1, P = 0.01). Mean (SD) placental ratio was not significantly higher in women who developed gestational hypertension (20.4% (4.5%)) and pre-eclampsia (23.3% (7.3%)) than in normal women (19.8% (3.8%)). No evidence of a relation between placental ratio and first antenatal visit haemoglobin concentration or mean cell volume was detected, and placental ratio was not associated with change in mean cell volume during pregnancy or with third trimester serum ferritin concentration. CONCLUSIONS--These data do not support the proposed association between poor maternal nutrition and increased placental ratio. The association between high placental ratio and adult hypertension may be confounded by genetic and environmental factors associated with maternal obesity (and possibly maternal hypertension).     

Impact of angiotensin II type 2 receptor blockade on experimental radiation nephropathy

In the rat, blockade of angiotensin II type 1 receptors diminishes the functional changes that occur after kidney irradiation. It has been hypothesized that some of the beneficial effects of angiotensin II type 1 blockers in renal disease are caused by a rise in angiotensin II that stimulates the angiotensin II type 2 receptor. If this hypothesis applied in this model, blockade of the type 2 receptor should exacerbate radiation nephropathy and/or counteract the beneficial effects of type 1 receptor blockade. To assess this hypothesis, rats were given total-body irradiation plus bone marrow transplantation and then treated for 12 weeks with a type 1 receptor blocker (L158,809), a type 2 blocker (PD123319), both blockers, or no blockers. Rats were assessed for renal function (proteinuria, hypertension, azotemia) and renal failure for up to 62 weeks. Contrary to the hypothesis, the type 2 blocker alone produced a temporary delay in the development of radiation nephropathy, and it substantially enhanced the efficacy of the type 1 blocker. This implies that both type 1 and type 2 angiotensin receptors need to be blocked to achieve the maximum level of prophylaxis of radiation nephropathy. We speculate that the beneficial effect of the angiotensin II type 2 receptor blocker is due to a reduction in radiation-induced renal cell proliferation or fibrosis.     

血管紧张素AT1受体抗体阳性孕鼠后代高盐饮食后血管功能障碍

血管紧张素AT1受体抗体(AT1-Ab)可损伤胎盘发育,进而导致胎儿宫内生长受限(intrauterine growth restriction,IUGR).根据胎儿源性成人疾病学说,IUGR会明显增加成人后患心血管疾病的几率.本研究旨在观察AT1-Ab阳性孕鼠后代生长至成年后血管功能有无异常.24只雌性Wistar大...     

Tumor necrosis factor α induces a model of preeclampsia in pregnant baboons (Papio hamadryas)

Preeclampsia is a common disease of pregnancy characterised by maternal hypertension and proteinuria. Abnormal placentation in early pregnancy and abnormal cytokine and anti-angiogenic factor expression are thought to contribute to the clinical syndrome of endothelial dysfunction evident in the second half of gestation. The mechanisms underlying both the placental pathology and its translation to the maternal clinical syndrome are not fully understood. A model of preeclampsia manifest by clinically evident endothelial dysfunction (increased blood pressure and proteinuria) was induced by administration of low-dose TNF-α for 2 weeks at mid-gestation in pregnant baboons (Papio hamadryas). Blood pressure was monitored continuously and remotely by intra-arterial radiotelemetry. Following TNF-α infusion, there was an increase in systolic and diastolic blood pressure and development of proteinuria in pregnant treated animals, but not in pregnant saline controls nor in non-pregnant TNF-α treated animals. The treated pregnant animals also developed elevated plasma soluble FMS-like tyrosine kinase-1 (sFLT-1) and increased placental mRNA expression of sFLT-1 and soluble endoglin (sEng). These results clearly demonstrate that the cytokine TNF-α can induce the clinical and biochemical features of human preeclampsia. The results identify a link between cytokines, placental dysfunction and endothelial dysfunction resulting in a loss of maternal blood pressure control.     

Angiotensin receptors, autoimmunity, and preeclampsia

Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contributes to pathophysiology associated with preeclampsia. The research reviewed here raises the intriguing possibility that preeclampsia may be a pregnancy-induced autoimmune disease.     

Angiotensin II receptor antagonist treatment during pregnancy

Angiotensin II (A-II) is the main effector of the renin-angiotensin system. A-II functions by binding its type 1 (AT1) receptors to cause vasoconstriction and retention of sodium and fluid. Several AT1 receptor antagonists-a group of drugs collectively called "sartans"-have been marketed during the past few years for treatment of hypertension and heart failure. At least 15 case reports describe oligohydramnios, fetal growth retardation, pulmonary hypoplasia, limb contractures, and calvarial hypoplasia in various combinations in association with maternal losartan, candesartan, valsartan, or telmisartan treatment during the second or third trimester of pregnancy. Stillbirth or neonatal death is frequent in these reports, and surviving infants may exhibit renal damage. The fetal abnormalities, which are strikingly similar to those produced by maternal treatment with angiotensin-converting enzyme (ACE) inhibitors during the second and third trimesters of pregnancy, are probably related to extreme sensitivity of the fetus to the hypotensive action of these drugs. Very little information is available regarding the outcome of human pregnancies in which the mother was treated with an AT1 receptor antagonist during the first trimester, but animal studies have not demonstrated teratogenic effects after maternal treatment with large doses of AT1 receptor antagonists during organogenesis. We conclude that pharmacological suppression of the fetal renin-angiotensin system through ACE inhibition or AT1 receptor blockade seems to disrupt fetal vascular perfusion and renal function. We recommend that maternal treatment with AT1 receptor antagonists be avoided during the second and third trimesters of pregnancy and that women who become pregnant while taking one of these medications be changed to an antihypertensive drug of a different class as soon as the pregnancy is recognized.     

Relationship between the changes in placental blood flow resistance assessed by Doppler technique and maternal serum placental aminopeptidases, which degrade vaso-active peptides, in pre-eclampsia.

Our study showed that there were statistically significant correlations between the systolic and diastolic ratio (S/D) of maternal uterine or umbilical artery and the levels of maternal serum aminopeptidase activities in pre-eclampsia. Kininase I was positively correlated with the S/D ratios, whereas placental leucine aminopeptidase (P-LAP) and aminopeptidase A were negatively correlated with the S/D ratios. It is known that the increased S/D ratios reflect the increased utero-placental blood flow resistance. Since our previous study showed that placental aminopeptidases degrade vasoactive peptides such as oxytocin, angiotensin and bradykinin, which the fetus actively produces, our present study suggests that the increased vascular resistance in feto-placental circulation in pre-eclampsia is partly controlled by changes in vaso-active peptides, via degradation by placental aminopeptidases.