Vascular contraction of umbilical arteries of pregnant women with preeclampsia.

Objective: Potassium channels have an important role in the vascular adaptation during pregnancy and a reduction in the expression of adenosine triphosphate-sensitive potassium channels (Katp) has been linked to preeclampsia. Activation of Katp induces vasodilation; however, no previous study has been conducted to evaluate the effects of the inhibition of these channels in the contractility of preeclamptic arteries. Glibenclamide is an oral antihyperglycemic agent that inhibits Katp and has been widely used in vascular studies. Methods: To investigate the effects of the inhibition of Katp, umbilical arteries of preeclamptic women and women with healthy pregnancies were assessed by vascular contractility experiments, in the presence or absence of glibenclamide. The umbilical arteries were challenged with cumulative concentrations of potassium chloride (KCl) and serotonin. Results: There were no differences between the groups concerning the maternal age and gestational age of the patients. The percentage of smokers, caucasians and primiparae per group was also similar. On the other hand, blood pressure parameters were elevated in the preeclamptic group. In addition, the preeclamptic group presented a significantly higher body mass index. The newborns of both groups presented similar APGAR scores and weights. Conclusion: In the presence of glibenclamide, there was an increase in the KCl-induced contractions only in vessels from the PE group, showing a possible involvement of these channels in the disorder.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia.

Importance: Hypertensive disorders of pregnancy (HDPs), including gestational hypertension and preeclampsia, are important contributors to maternal morbidity and mortality worldwide. In addition, women with HDPs face an elevated long-term risk of cardiovascular disease. Objective: To identify proteins in the circulation associated with HDPs. Design, Setting, and Participants: Two-sample mendelian randomization (MR) tested the associations of genetic instruments for cardiovascular disease-related proteins with gestational hypertension and preeclampsia. In downstream analyses, a systematic review of observational data was conducted to evaluate the identified proteins' dynamics across gestation in hypertensive vs normotensive pregnancies, and phenome-wide MR analyses were performed to identify potential non-HDP-related effects associated with the prioritized proteins. Genetic association data for cardiovascular disease-related proteins were obtained from the Systematic and Combined Analysis of Olink Proteins (SCALLOP) consortium. Genetic association data for the HDPs were obtained from recent European-ancestry genome-wide association study meta-analyses for gestational hypertension and preeclampsia. Study data were analyzed October 2022 to October 2023. Exposures: Genetic instruments for 90 candidate proteins implicated in cardiovascular diseases, constructed using cis-protein quantitative trait loci (cis-pQTLs). Main Outcomes and Measures: Gestational hypertension and preeclampsia. Results: Genetic association data for cardiovascular disease-related proteins were obtained from 21 758 participants from the SCALLOP consortium. Genetic association data for the HDPs were obtained from 393 238 female individuals (8636 cases and 384 602 controls) for gestational hypertension and 606 903 female individuals (16 032 cases and 590 871 controls) for preeclampsia. Seventy-five of 90 proteins (83.3%) had at least 1 valid cis-pQTL. Of those, 10 proteins (13.3%) were significantly associated with HDPs. Four were robust to sensitivity analyses for gestational hypertension (cluster of differentiation 40, eosinophil cationic protein [ECP], galectin 3, N-terminal pro-brain natriuretic peptide [NT-proBNP]), and 2 were robust for preeclampsia (cystatin B, heat shock protein 27 [HSP27]). Consistent with the MR findings, observational data revealed that lower NT-proBNP (0.76- to 0.88-fold difference vs no HDPs) and higher HSP27 (2.40-fold difference vs no HDPs) levels during the first trimester of pregnancy were associated with increased risk of HDPs, as were higher levels of ECP (1.60-fold difference vs no HDPs). Phenome-wide MR analyses identified 37 unique non-HDP-related protein-disease associations, suggesting potential on-target effects associated with interventions lowering HDP risk through the identified proteins. Conclusions and Relevance: Study findings suggest genetic associations of 4 cardiovascular disease-related proteins with gestational hypertension and 2 associated with preeclampsia. Future studies are required to test the efficacy of targeting the corresponding pathways to reduce HDP risk.

Kisspeptin in the Prediction of Pregnancy Complications.

Kisspeptin and its receptor are central to reproductive health acting as key regulators of the reproductive endocrine axis in humans. Kisspeptin is most widely recognised as a regulator of gonadotrophin releasing hormone (GnRH) neuronal function. However, recent evidence has demonstrated that kisspeptin and its receptor also play a fundamental role during pregnancy in the regulation of placentation. Kisspeptin is abundantly expressed in syncytiotrophoblasts, and its receptor in both cyto- and syncytio-trophoblasts. Circulating levels of kisspeptin rise dramatically during healthy pregnancy, which have been proposed as having potential as a biomarker of placental function. Indeed, alterations in kisspeptin levels are associated with an increased risk of adverse maternal and foetal complications. This review summarises data evaluating kisspeptin's role as a putative biomarker of pregnancy complications including miscarriage, ectopic pregnancy (EP), preterm birth (PTB), foetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), gestational diabetes mellitus (GDM), and gestational trophoblastic disease (GTD).

The involvement of long noncoding RNA APOA1-AS in the pathogenesis of preeclampsia.

OBJECTIVE: Long noncoding RNAs (lncRNAs) are involved in preeclampsia (PE), and apolipoprotein A-1 antisense RNA (APOA1-AS) and has been found to be associated with a number of diseases. Our study aims to understand the involvement of APOA1-AS in PE. METHODS: Clinically, APOA1-AS expression in early-onset severe PE (EOSPE) patients and healthy controls was detected by real-time quantitative polymerase chain reaction. In vitro experiments were divided into control [coculturing trophoblasts with human uterine microvascular endothelial cells (UtMVECs)], TNF-α [coculturing trophoblasts with UtMVECs treated with tumor necrosis factor-α (TNF-α)], and TNF-α + control siRNA/APOA1-AS siRNA groups (UtMVECs transfected with control siRNA/APOA1-AS siRNA were cocultured with trophoblasts in the presence of TNF-α). The animals were divided into normal group, PE group (PE model was established by administrating nitro-L-arginine methyl ester (L-NAME) in rats), PE + control siRNA group (PE rats were treated with control siRNA), and PE + APOA1-AS siRNA group (PE rats were treated with APOA1-AS siRNA). RESULTS: Increased APOA1-AS was found in the placental tissues of EOSPE patients. APOA1-AS siRNA abolished the decreased integration of trophoblasts into UtMVEC networks induced by TNF-α. Furthermore, APOA1-AS siRNA improved pregnancy outcomes in PE rats with increased expression of vascular endothelial growth factor, placental growth factor, and fms-like tyrosine kinase receptor (Flt-1) but decreased expression of E-cadherin, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). CONCLUSION: Downregulation of APOA1-AS protected against TNF-α-induced inhibition of trophoblast integration into endothelial networks, thus exerting protective effects against PE rats.

Pregnancy-specific expression of protease-activated receptor 1: a therapeutic target for prevention and treatment of preeclampsia?

Neutrophils extensively infiltrate maternal blood vessels in preeclampsia. This could explain why multiple organs are affected in this enigmatic disorder. Lipid peroxides produced by the placenta are probably the first factors that activate neutrophils as they circulate through the intervillous space, but then a second factor specific to pregnancy comes into play, protease-activated receptor 1. The only time neutrophils express protease-activated receptor 1 is during pregnancy. This means that neutrophils can be activated by a mechanism specific to pregnancy, that is, by proteases. Two proteases that are elevated in preeclampsia and activate protease-activated receptor 1 are matrix metalloproteinase-1 and neutrophil elastase. There is an 8-fold increase in vascular protease-activated receptor 1 expression in women with preeclampsia, and protease-activated receptor 1 is also expressed on the placenta, a pregnancy-specific tissue. The question arises if the pregnancy-specific expression of protease-activated receptor 1 is essential to the pathophysiology of preeclampsia. Protease activation of protease-activated receptor 1 in neutrophils of women with normal pregnancies causes activation of RhoA kinase. RhoA kinase phosphorylates nuclear factor-kappa B causing its translocation from the cytosol into the nucleus, increasing the expression of inflammatory genes. This signaling pathway is blocked by inhibition of either protease-activated receptor 1 or RhoA kinase activity. In contrast, neutrophils obtained from preeclamptic women are already activated, with nuclear factor-kappa B localized in the nucleus. Surprisingly, inhibition of either protease-activated receptor 1 or RhoA kinase results in an efflux of nuclear factor-kappa B from the nucleus back into the cytoplasm. Cyclooxygenase-2 seems to be a downstream mediator between protease-activated receptor 1 and RhoA kinase because aspirin inhibits the nuclear translocation of nuclear factor-kappa B and inhibits neutrophil production of superoxide, thromboxane, and tumor necrosis factor alpha. Currently, low-dose aspirin is the standard of care to prevent preeclampsia in high-risk women. Generally, the actions of low-dose aspirin are attributed to selective inhibition of maternal platelet thromboxane production. However, a recent study showed that beneficial effects extend to the placenta, where aspirin corrected the imbalance of increased thromboxane and reduced prostacyclin and oxidative stress. Selective inhibition of placental thromboxane is possible because thromboxane and prostacyclin are compartmentalized. Thromboxane is produced by trophoblast cells and prostacyclin by endothelial cells, so as aspirin crosses the placenta, its levels decline, sparing prostacyclin. Placental oxidative stress is attenuated because cyclooxygenase-2 inhibition decreases the generation of reactive oxygen species to decrease the formation of isoprostanes. The clinical manifestations of preeclampsia can be explained by protease activation of protease-activated receptor 1 in different tissues. In neutrophils, it can account for their activation and inflammatory response. In vascular tissue, protease-activated receptor 1 activation leads to enhanced vascular reactivity to angiotensin II to cause hypertension. In the placenta, it leads to oxidative stress, increased soluble fms-like tyrosine kinase, and thromboxane production. Activation of protease-activated receptor 1 on endothelial cells causes contraction, leading to edema and proteinuria, and activation on platelets leads to coagulation abnormalities. As proteases that activate protease-activated receptor 1 are elevated in the circulation of women with preeclampsia, consideration should be given to the inhibition of protease-activated receptor 1 as a treatment. Recently, The Food and Drug Administration (FDA) approved a protease-activated receptor 1 inhibitor, creating an opportunity to test whether protease-activated receptor 1 inhibition can prevent and/or treat preeclampsia, but a standard dose of aspirin might be just as effective by blocking its downstream actions.

The etiology of preeclampsia.

Preeclampsia is one of the "great obstetrical syndromes" in which multiple and sometimes overlapping pathologic processes activate a common pathway consisting of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. This article reviews the potential etiologies of preeclampsia. The role of uteroplacental ischemia is well-established on the basis of a solid body of clinical and experimental evidence. A causal role for microorganisms has gained recognition through the realization that periodontal disease and maternal gut dysbiosis are linked to atherosclerosis, thus possibly to a subset of patients with preeclampsia. The recent reports indicating that SARS-CoV-2 infection might be causally linked to preeclampsia are reviewed along with the potential mechanisms involved. Particular etiologic factors, such as the breakdown of maternal-fetal immune tolerance (thought to account for the excess of preeclampsia in primipaternity and egg donation), may operate, in part, through uteroplacental ischemia, whereas other factors such as placental aging may operate largely through syncytiotrophoblast stress. This article also examines the association between gestational diabetes mellitus and maternal obesity with preeclampsia. The role of autoimmunity, fetal diseases, and endocrine disorders is discussed. A greater understanding of the etiologic factors of preeclampsia is essential to improve treatment and prevention.

Suppression of FPR2 expression inhibits inflammation in preeclampsia by improving the biological functions of trophoblast via NF-κB pathway.

PURPOSE: The dysfunction of trophoblast during inflammation plays an important role in PE. Formyl peptide receptor 2 (FPR2) plays crucial roles in the development of inflammation-associated disease. This present study aimed to explore the effect of FPR2 on a trophoblast cellular model of preeclampsia. METHODS: The expression of FPR2 in placenta was detected by immunohistochemical staining and western blotting. Transfection of siRNA was used to knockdown FPR2 in HTR-8/SVneo cells. Inflammatory cytokines were detected by ELISA. CCK8, Transwell, wound healing, FACS and tube formation assays were performed to observe the abilities of cell proliferation, migration, invasion, apoptosis and angiogenesis. Western blotting was implemented to clarify that NF-κB signaling pathway was downstream of FPR2. RESULTS: The expression levels of FPR2 were higher in placental tissues of patients with PE. Knockdown of FPR2 expression by siFPR2 or inhibition of its activity by WRW4 decreased the release of proinflammatory cytokines in HTR8/SVneo cells treated with LPS. Knockdown of FPR2 expression or inhibition of its activity further reversed the LPS-induced attenuation of the proliferation, migration, invasion and angiogenesis and increase in apoptosis in HTR8/SVneo cells. Moreover, the NF-κB signaling pathway was activated in both placental tissues of patients with PE and LPS-treated HTR8/SVneo cells. However, the activation was attenuated when FPR2 was knocked down or inhibited. CONCLUSION: Suppression of FPR2 expression alleviated the effects of inflammation induced by LPS on trophoblasts via the NF-κB signaling pathway, which provided a novel and potential strategy for the treatment of PE.

Prediction of preeclampsia throughout gestation with maternal characteristics and biophysical and biochemical markers: a longitudinal study.

BACKGROUND: The current approach to predict preeclampsia combines maternal risk factors and evidence from biophysical markers (mean arterial pressure, Doppler velocimetry of the uterine arteries) and maternal blood proteins (placental growth factor, soluble vascular endothelial growth factor receptor-1, pregnancy-associated plasma protein A). Such models require the transformation of biomarker data into multiples of the mean values by using population- and site-specific models. Previous studies have focused on a narrow window in gestation and have not included the maternal blood concentration of soluble endoglin, an important antiangiogenic factor up-regulated in preeclampsia. OBJECTIVE: This study aimed (1) to develop models for the calculation of multiples of the mean values for mean arterial pressure and biochemical markers; (2) to build and assess the predictive models for preeclampsia based on maternal risk factors, the biophysical (mean arterial pressure) and biochemical (placental growth factor, soluble vascular endothelial growth factor receptor-1, and soluble endoglin) markers collected throughout pregnancy; and (3) to evaluate how prediction accuracy is affected by the presence of chronic hypertension and gestational age. STUDY DESIGN: This longitudinal case-cohort study included 1150 pregnant women: women without preeclampsia with (n=49) and without chronic hypertension (n=871) and those who developed preeclampsia (n=166) or superimposed preeclampsia (n=64). Mean arterial pressure and immunoassay-based maternal plasma placental growth factor, soluble vascular endothelial growth factor receptor-1, and soluble endoglin concentrations were available throughout pregnancy (median of 5 observations per patient). A prior-risk model for preeclampsia was established by using Poisson regression based on maternal characteristics and obstetrical history. Next, multiple regression was used to fit biophysical and biochemical marker data as a function of maternal characteristics by using data collected at 8 to 15+6, 16 to 19+6, 20 to 23+6, 24 to 27+6, 28 to 31+6, and 32 to 36+6 week intervals, and observed values were converted into multiples of the mean values. Then, multivariable prediction models for preeclampsia were fit based on the biomarker multiples of the mean data and prior-risk estimates. Separate models were derived for overall, preterm, and term preeclampsia, which were evaluated by receiver operating characteristic curves and sensitivity at fixed false-positive rates. RESULTS: (1) The inclusion of soluble endoglin in prediction models for all preeclampsia, together with the prior-risk estimates, mean arterial pressure, placental growth factor, and soluble vascular endothelial growth factor receptor-1, increased the sensitivity (at a fixed false-positive rate of 10%) for early prediction of superimposed preeclampsia, with the largest increase (from 44% to 54%) noted at 20 to 23+6 weeks (McNemar test, P<.05); (2) combined evidence from prior-risk estimates and biomarkers predicted preterm preeclampsia with a sensitivity (false-positive rate, 10%) of 55%, 48%, 62%, 72%, and 84% at 8 to 15+6, 16 to 19+6, 20 to 23+6, 24 to 27+6, and 28 to 31+6 week intervals, respectively; (3) the sensitivity for term preeclampsia (false-positive rate, 10%) was 36%, 36%, 41%, 43%, 39%, and 51% at 8 to 15+6, 16 to 19+6, 20 to 23+6, 24 to 27+6, 28 to 31+6, and 32 to 36+6 week intervals, respectively; (4) the detection rate for superimposed preeclampsia among women with chronic hypertension was similar to that in women without chronic hypertension, especially earlier in pregnancy, reaching at most 54% at 20 to 23+6 weeks (false-positive rate, 10%); and (5) prediction models performed comparably to the Fetal Medicine Foundation calculators when the same maternal risk factors and biomarkers (mean arterial pressure, placental growth factor, and soluble vascular endothelial growth factor receptor-1 multiples of the mean values) were used as input. CONCLUSION: We introduced prediction models for preeclampsia throughout pregnancy. These models can be useful to identify women at risk during the first trimester who could benefit from aspirin treatment or later in pregnancy to inform patient management. Relative to prediction performance at 8 to 15+6 weeks, there was a substantial improvement in the detection rate for preterm and term preeclampsia by using data collected after 20 and 32 weeks' gestation, respectively. The inclusion of plasma soluble endoglin improves the early prediction of superimposed preeclampsia, which may be valuable when Doppler velocimetry of the uterine arteries is not available.

Downregulation of cathepsin C alleviates endothelial cell dysfunction by suppressing p38 MAPK/NF-κB pathway in preeclampsia.

Endothelial cell dysfunction is an essential pathophysiological feature of preeclampsia (PE). It has been reported that cathepsin C is upregulated in the maternal vascular endothelium of PE patients. The excessive activation of p38 MAPK leads to various diseases, including PE. NF-κB pathway can promote uteroplacental dysfunction, endothelial stress and development of PE. Moreover, it has been verified that cathepsin C can activate p38 MAPK/NF-κB pathway. In the present work, hypoxia/reoxygenation (H/R) injury model of HUVECs was established to discuss the biological functions of cathepsin C in endothelial cell dysfunction and to elucidate the underlying molecular mechanism. The correlation between cathepsin C and p38 MAPK/NF-κB pathway in H/R-stimulated HUVECs as well as the effects of cathepsin C and p38 MAPK/NF-κB pathway on viability, apoptosis, invasion, in vitro angiogenesis of HUVECs and oxidative stress were assessed. The results revealed that H/R injury elevated cathepsin C expression and activated p38 MAPK/NF-κB pathway in HUVECs and cathepsin C knockdown inhibited the activity of p38 MAPK/NF-κB pathway in H/R-stimulated HUVECs. Downregulation of cathepsin C improved viability, inhibited apoptosis and enhanced invasion of H/R-stimulated HUVECs. In addition, downregulation of cathepsin C alleviated oxidative stress and induced stronger HUVEC angiogenesis in vitro. Furthermore, the protective effects of cathepsin C knockdown against endothelial cell dysfunction were reversed by p38 MAPK activator anisomycin. In other words, downregulation of cathepsin C could improve HUVEC viability and enhance anti-apoptotic capacity, anti-oxidative capability, invasive ability, as well as angiogenic potential of H/R-stimulated HUVECs by repressing p38 MAPK/NF-κB pathway.

Maternal Cardiac Function at Midgestation and Development of Preeclampsia.

BACKGROUND: Preeclampsia (PE) is an independent risk factor for adverse maternal cardiovascular outcomes. The role of maternal cardiac function in the pathophysiology of PE remains unclear. OBJECTIVES: This study sought to describe differences in cardiac function at midgestation between women who develop PE and those with uncomplicated pregnancy and to establish whether routine cardiac assessment at midgestation can improve performance of screening for PE achieved by established biomarkers. METHODS: Mean arterial pressure was measured, medical history was obtained, and left ventricular (LV) systolic and diastolic functions were assessed using standard echocardiography and speckle tracking imaging. Uterine artery pulsatility index and serum placental growth factor and soluble fms-like tyrosine kinase-1 were measured. RESULTS: In 4,795 pregnancies, 126 (2.6%) developed PE. Following multivariable analysis, peripheral vascular resistance was significantly higher and LV global longitudinal systolic strain, ejection fraction, cardiac output, and left atrial area were mildly lower in women who developed PE compared to those who did not. There was a weak association between maternal cardiovascular indices and biomarkers of placental perfusion and function. Cardiac indices did not improve the performance of screening for PE on top of maternal risk factors, mean arterial pressure, and biomarkers of placental perfusion and function. CONCLUSION: Women who develop PE have an increase in peripheral vascular resistance and a mild reduction in LV functional cardiac indices long before PE development. However, cardiac indices do not improve the performance of screening for PE; thus, their routine clinical use is not advocated.

Do modifiable risk factors for cardiovascular disease post-pregnancy influence the association between hypertensive disorders of pregnancy and cardiovascular health outcomes? A systematic review of observational studies.

Hypertensive disorders of pregnancy (HDP) are associated with increased risk of developing cardiovascular disease (CVD) in later life. This systematic review aimed to evaluate the impact of modifiable risk factors for CVD following pregnancy on the relationship between HDP and cardiovascular health outcomes. Seven databases (Medline, CENTRAL, CINAHL, Cochrane Reviews, Embase, PsycINFO and Scopus) were searched from date of inception to July 24, 2019. Observational studies that included female adults with a history of HDP and analysed whether modifiable risk factors for CVD following pregnancy (dietary intake, physical activity, smoking status, alcohol intake, body weight and mental health status) influenced associations between HDP and cardiovascular health outcomes (morbidity, mortality or related risk markers) were eligible for inclusion. In total, 4704 articles were identified, with 11 studies included. The modifiable risk factors measured included body weight (11 studies), physical activity and dietary intake (one study) and smoking (one study). Overall, five of seven studies provided convincing evidence that the relationship between HDP and blood pressure was adversely impacted by excess body weight post-pregnancy. The current systematic review provides evidence that excess body weight post-pregnancy impacts associations between HDP and hypertension in later life. However, there is a lack of evidence exploring the impact of a variety of modifiable risk factors for CVD on associations between HDP and cardiovascular health outcomes. This evidence is imperative to inform development of effective CVD prevention interventions for women with a history of HDP.

Decidualization resistance in the origin of preeclampsia.

Preeclampsia is a major obstetrical complication with short- and long-term life-threatening consequences for both mother and child. Shallow cytotrophoblast invasion through the uterine decidua into the spiral arteries is implicated in the pathogenesis of preeclampsia, although the cause of deficient arterial invasion remains unknown. Research that is focused on the "soil"-the maternal decidua-highlights the importance of this poorly understood but influential uterine layer. Decidualization of endometrial cells regulates embryo invasion, which is essential for spiral artery remodeling and establishing the maternal-fetal interface. Exploration of the association between impaired decidualization and preeclampsia revealed suboptimal endometrial maturation and uterine natural killer cells present in the decidua before preeclampsia development. Furthermore, decidualization defects in the endometrium of women with severe preeclampsia, characterized by impaired cytotrophoblast invasion, were detected at the time of delivery and persisted 5 years after the affected pregnancy. Recently, a maternal deficiency of annexin A2 expression was found to influence aberrant decidualization and shallow cytotrophoblast invasion, suggesting that decidualization resistance, which is a defective endometrial cell differentiation during the menstrual cycle, could underlie shallow trophoblast invasion and the poor establishment of the maternal-fetal interface. Based on these findings, the transcriptional signature in the endometrium that promotes decidualization deficiency could be detected before (or after) conception. This would serve to identify women at risk of developing severe preeclampsia and aid the development of therapies focused on improving decidualization, perhaps also preventing severe preeclampsia. Here, we discuss decidualization deficiency as a contributor to the pathogenesis of pregnancy disorders with particular attention to severe preeclampsia. We also review current diagnostic strategies and discuss future directions in diagnostic methods based on decidualization.

An integrated model of preeclampsia: a multifaceted syndrome of the maternal cardiovascular-placental-fetal array.

Maternal tolerance of the semiallogenic fetus necessitates conciliation of competing interests. Viviparity evolved with a placenta to mediate the needs of the fetus and maternal adaptation to the demands of pregnancy and to ensure optimal survival for both entities. The maternal-fetal interface is imagined as a 2-dimensional porous barrier between the mother and fetus, when in fact it is an intricate multidimensional array of tissues and resident and circulating factors at play, encompassing the developing fetus, the growing placenta, the changing decidua, and the dynamic maternal cardiovascular system. Pregnancy triggers dramatic changes to maternal hemodynamics to meet the growing demands of the developing fetus. Nearly a century of extensive research into the development and function of the placenta has revealed the role of placental dysfunction in the great obstetrical syndromes, among them preeclampsia. Recently, a debate has arisen questioning the primacy of the placenta in the etiology of preeclampsia, asserting that the maternal cardiovascular system is the instigator of the disorder. It was the clinical observation of the high rate of preeclampsia in hydatidiform mole that initiated the focus on the placenta in the etiology of the disease. Over many years of research, shallow trophoblast invasion with deficient remodeling of the maternal spiral arteries into vessels of higher capacitance and lower resistance has been recognized as hallmarks of the preeclamptic milieu. The lack of the normal decrease in uterine artery resistance is likewise predictive of preeclampsia. In abdominal pregnancies, however, an extrauterine pregnancy develops without remodeling of the spiral arteries, yet there is reduced resistance in the uterine arteries and distant vessels, such as the maternal ophthalmic arteries. Proponents of the maternal cardiovascular model of preeclampsia point to the observed maternal hemodynamic adaptations to pregnancy and maladaptation in gestational hypertension and preeclampsia and how the latter resembles the changes associated with cardiac disease states. Recognition of the importance of the angiogenic-antiangiogenic balance between placental-derived growth factor and its receptor soluble fms-like tyrosine kinase-1 and disturbance in this balance by an excess of a circulating isoform, soluble fms-like tyrosine kinase-1, which competes for and disrupts the proangiogenic receptor binding of the vascular endothelial growth factor and placental-derived growth factor, opened new avenues of research into the pathways to normal adaptation of the maternal cardiovascular and other systems to pregnancy and maladaptation in preeclampsia. The significance of the "placenta vs heart" debate goes beyond the academic: understanding the mutuality of placental and maternal cardiac etiologies of preeclampsia has far-reaching clinical implications for designing prevention strategies, such as aspirin therapy, prediction and surveillance through maternal hemodynamic studies or serum placental-derived growth factor and soluble fms-like tyrosine kinase-1 testing, and possible treatments to attenuate the effects of insipient preeclampsia on women and their fetuses, such as RNAi therapy to counteract excess soluble fms-like tyrosine kinase-1 produced by the placenta. In this review, we will present an integrated model of the maternal-placental-fetal array that delineates the commensality among the constituent parts, showing how a disruption in any component or nexus may lead to the multifaceted syndrome of preeclampsia.

Cellular immune responses in the pathophysiology of preeclampsia.

Preeclampsia, defined as new-onset hypertension accompanied by proteinuria occurring at 20 weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi-systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti-angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal-fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.

Prospective Evaluation of International Prediction of Pregnancy Complications Collaborative Network Models for Prediction of Preeclampsia: Role of Serum sFlt-1 at 11-13 Weeks' Gestation.

The study aimed to investigate whether serum sFlt-1 (soluble fms-like tyrosine kinase-1) at 11-13 weeks' gestation in pregnancies that subsequently developed preeclampsia was different from those without preeclampsia and compare screening performance of the International Prediction of Pregnancy Complications (IPPIC) reported models, which include various combinations of maternal factors, systolic blood pressure, diastolic blood pressure, PlGF (placental growth factor) and sFlt-1 and the competing risk (CR) models, which include various combinations of maternal factors, mean arterial pressure (MAP) and PlGF for predicting any-onset, early-onset, and late-onset preeclampsia. This was a prospective multicenter study in 7877 singleton pregnancies. The differences of the predictive performance between the IPPIC and CR models were compared. There were 141 women (1.79%) who developed preeclampsia, including 13 cases (0.17%) of early-onset preeclampsia and 128 cases (1.62%) of late-onset preeclampsia. In pregnancies that developed preeclampsia compared to unaffected pregnancies, median serum sFlt-1 levels and its MoMs were not significantly different (p>0.05). There was no significant association between gestational age at delivery and log10 sFlt-1 and log10 sFlt-1 MoM (p>0.05). The areas under the curve of CR models were significantly higher than the IPPIC models for the prediction of any-onset and late-onset preeclampsia but not for early-onset preeclampsia. In conclusion, there are no significant differences in the maternal serum sFlt-1 levels at 11-13 weeks' gestation between women who subsequently develop preeclampsia and those who do not. Moreover, the CR models for the prediction of any-onset and late-onset preeclampsia perform better than the IPPIC reported model.

Changes in Circulating Kisspeptin Levels During Each Trimester in Women With Antenatal Complications.

CONTEXT: Antenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all 3 trimesters in women with antenatal complications. OBJECTIVE: We aimed to assess whether kisspeptin levels are altered in women with antenatal complications. METHODS: Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed. RESULTS: Third-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P < 0.0001), and of FGR were reduced by 28% (95% CI, 4-46%; P = 0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (P = 0.014) and lower in those with GDM (P = 0.020), but not significantly on multivariable analysis. CONCLUSION: We delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.

Relationship between the sFlt-1/PlGF ratio and the optical coherence tomographic features of chorioretina in patients with preeclampsia.

This study aimed to evaluate the correlation between ophthalmologic factors and the serologic indicator soluble fms-like tyrosine kinase 1 (sFlt-1): placental growth factor (PlGF) ratio in patients with preeclampsia using optical coherence tomography (OCT) and OCT angiography (OCT-A). A total of 52 pregnant patients (104 eyes) diagnosed with preeclampsia were recruited during their hospital stay. The associations between the sFlt-1/PlGF ratio and chorioretinal measurements, including the choroidal thickness (CT), foveal avascular zone, vascular density, and ganglion cell layer+ were evaluated. Central and nasal subfield CT of the left eye (p = 0.039; p = 0.010) and nasal subfield CT of the right eye (p = 0.042) were lower in the high sFlt-1/PlGF ratio group (≥38). Pearson's correlation test showed a negative correlation between the sFlt-1/PlGF ratio and central subfield CT; however, this was not statistically significant (p = 0.648). Linear regression analysis revealed a significant association between the sFlt-1/PlGF ratio and central subfield CT (ß coefficient, -6.66; p = 0.01) and between sFlt-1 and central subfield CT (ß coefficient, -5.65; p = 0.00). Thus, an increase in the sFlt-1/PlGF ratio resulted in a decrease in central subfield CT.

Biomarkers of Inflammation and Redox Imbalance in Umbilical Cord in Pregnancies with and without Preeclampsia and Consequent Perinatal Outcomes.

OBJECTIVE: To compare redox imbalance and inflammation biomarkers in umbilical cords from pregnancies with and without preeclampsia (PE) and to analyse their relationships with perinatal outcomes. METHODS: A controlled cross-sectional study was conducted in Maceió, Alagoas, Brazil, that involved pregnant women with PE and a group of women without the disease, through the application of a standardized questionnaire. After delivery, umbilical cord samples were collected to measure antioxidant defense, products from oxidative damage, and inflammation biomarkers such as myeloperoxidase (MPO), interleukin- (IL-) 6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α). Statistical analyses were performed using Stata version 13.0 software and IBM Statistical Package for the Social Sciences (SPSS) 20.0, adopting a 95% confidence level (α = 0.05), with the chi-square test, the Wilcoxon-Mann-Whitney test, and the multinomial and Poisson regression tests. RESULTS: One hundred PE pregnant women and 50 women without the disease were studied. The umbilical cords from PE pregnancies showed higher levels of reduced glutathione (GSH) (p ≤ 0.001), glutathione peroxidase (GPx) (p = 0.016), and malondialdehyde (MDA) (p = 0.028) and lower levels of IL-6 (p = 0.030) and TNF-α (p ≤ 0.001) than the other group, with some associations among these biomarkers with perinatal outcomes. CONCLUSION: The higher levels of GSH and GPx, in addition to the lower levels of IL-6 and TNF-α, found in the PE umbilical cord, may result from adaptive mechanisms to maintain the oxidative and inflammatory balance; however, despite these changes, the damage to the cell membranes was not minimized, as the MDA level was higher in women with PE than in women without the disease. This implies that a redox imbalance is present, confirming that other physiological and adaptive mechanisms are being activated to preserve foetal health. Therefore, the present work unveils an important role of the umbilical cord in controlling redox imbalance and inflammation in PE pregnancies. Our results reinforce the necessity for continuous research on GSH as a protective compound for the perinatal outcome, especially in PE women.