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Igenomix Foundation, INCLIVA Instituto de Investigación Sanitaria, Valencia, SpainDepartment of Obstetrics and Gynecology, School of Medicine, University of Valencia, Valencia, SpainDepartment of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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.
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Introduction
Preeclampsia (PE) is characterized by hypertension, proteinuria, and other signs of maternal vascular damage, such as edema. It affects 8% of first-time pregnancies, each year affecting 8 million mother-infant pairs
Severe PE (sPE) is diagnosed based on the further elevation of blood pressure (systolic ≥160 mm Hg or diastolic of ≥100 mm Hg) or any of the following: thrombocytopenia, impaired liver function, progressive renal insufficiency, pulmonary edema, and the onset of cerebral or visual disturbances that may end in hemolysis, elevated liver enzymes, and low platelet count syndrome
American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
PE is an important public health issue, because of not only the short-term life-threatening complications for both mother and child but also the long-term increased risk of cardiovascular
Screening women at high risk is key in the prevention and management of PE, but early detection is limited by uncertainty about the pathogenesis of PE.
The pathogenesis of PE is conceptualized in a 2-stage model proposing that abnormal placental perfusion leads to clinical manifestation of PE.
especially in cases of early-onset disease and preterm delivery before 34 weeks’ gestation. As a consequence of shallow CTB invasion, the placenta undergoes ischemia and structural damage owing to uteroplacental malperfusion. The placenta releases factors into the systemic circulation and causes oxidative stress to the syncytiotrophoblast, resulting in the release of proinflammatory cytokines, antiangiogenic factors, and exosomes into the systemic circulation.
Inadequate placental perfusion is also associated with other pregnancy complications. Pregnancies with intrauterine growth-restricted infants and one-third of preterm births involve defective vascular remodeling resulting from shallow trophoblast invasion.
Therefore, inadequate placental perfusion is not sufficient to cause PE. The contribution of maternal-impaired decidualization to the pathophysiology of PE is receiving increasing attention in the field of reproductive medicine.
Decidualization is essential for the regulation of CTB invasion and thus establishment of maternal-fetal interface during placentation. Accordingly, a deficiency in decidualization could lead to shallow CTB invasion implicated in PE. Here, we present the latest advances in the maternal contribution to the pathophysiology of PE focusing on the role of decidualization deficiency. We also discuss current diagnostic strategies and how a decidualization perspective could inform diagnoses.
The Placental Perspective
By postconception day 10 in a normal pregnancy, the human embryo is completely enveloped within the endometrial lining. The blastocyst is nourished by secretions from the endometrial glands (via histotrophic support) under hypoxic and hypoglycemic conditions until the maternal-placenta circulation is fully established.
At approximately 8 to 10 weeks’ gestation, the placental extravillous trophoblasts (EVTs) transform into invasive cells through a partial epithelial-mesenchymal transition, in which the epithelial-like adhesion molecules are replaced by vascular-like adhesion molecules and the EVTs mimic a vascular adhesion phenotype.
Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?.
Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: new insights from contrast-enhanced ultrasound and tissue histopathology.
This process, known as the second wave of trophoblast invasion, is usually complete by 18 weeks’ gestation and is critical for the establishment of definitive uteroplacental circulation. As pregnancy progresses, the 120 to 140 small maternal spiral arteries that supply the placenta dilate to accommodate the increasing demands of the fetoplacental unit (Figure 1).
The placenta is a high-volume, low-resistance organ, and at term, almost one-fifth of the maternal cardiac output (approximately 800 mL) passes through the placenta each minute.
Extravillous trophoblast cells (EVTs) transform into invasive cells through a partial epithelial-mesenchymal transition in which epithelial-like adhesion molecules are replaced by vascular-like adhesion molecules. EVT migrations occur through the decidua until reaching the inner third of the myometrium to invade the maternal spiral artery. Optimal EVT invasion is required to adapt the maternal vasculature to pregnancy and maintain blood flow to the placenta.
Garrido-Gómez. Decidualization resistance in severe preeclampsia.Am J Obstet Gynecol 2022.
Defective remodeling of maternal spiral arteries may result in a narrow lumen, a thick muscle layer, wide or thin-walled arteries, or funnel-shaped vessels, all of which are pathologic hallmarks of PE and are termed shallow endovascular invasion.
Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?.
However, this is not sufficient to cause PE, because other pregnancy complications such as intrauterine growth restriction and one-third of preterm births involve defective vascular remodeling.
Defective remodeling causes oxidative stress in the syncytiotrophoblast and the release of proinflammatory cytokines, such as tumor necrosis factor alpha and interlukin-1, and antiangiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFLT1).
Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia.
Interestingly, assessing changes associated with PE at a genetic level provides a second perspective. CTBs freshly isolated from preeclamptic placentas were found to present a different transcriptional profile compared with control placentas.
When CTBs were cultured for 48 hours, enabling differentiation and invasion, the abnormal pattern of gene expression in preeclamptic cells was reverted to control levels. This surprising finding pointed to the relevance of the maternal decidua in influencing CTB invasiveness.
Key questions in the role of the decidua in PE remain, including why shallow CTB endovascular invasion occurs and how the maternal decidua induces shallow CTB invasion. Answers to these questions will enable the development of preventative measures and possible cures for PE.
The Decidua Perspective
Remarkably, removing the decidua in the immediate postpartum period by uterine curettage accelerates the speed of recovery in patients with PE.
Decidual removal was first explored in 1993 in a pilot study with 32 patients with sPE. Significantly decreased mean arterial pressure at each 2-hour point for the first 24 hours after delivery was observed compared with patients who were not curetted. The platelet count increased in the curettage group, whereas the noncurettage group had decreased platelet count.
consolidated the concept of accelerated recovery in a randomized controlled study involving 420 women with PE or eclampsia who underwent immediate postpartum curettage (n=220) compared with patients without this intervention (n=200). This study showed significant improvement in mean arterial blood pressure in the curettage group for the first 6, 12, and 24 hours after delivery. Likewise, there was an improvement in the platelet count in the curettage group compared with the control group.
The process involves the differentiation of human endometrial stromal cells (hESCs) in response to hormonal stimuli beginning in the midsecretory phase of the menstrual cycle.
This differentiation includes changes at the morphologic and secretory level. Morphologically, it is characterized by the transformation of elongated fibroblast-like cells into an enlarged polygonal- or round-shaped cell population involving ultrastructural modifications through complex cytoskeletal rearrangements.
Decidualization also involves the transition to a secretory phenotype. Decidualized hESCs secrete molecules such as prolactin and insulin-like growth factor binding protein 1, which are signaling molecules for CTB invasion and used as markers of decidualization.
We recently characterized both static and dynamic characteristics of the human endometrium across the menstrual cycle with single-cell resolution at the transcriptomic level.
We transcriptionally demonstrated that decidualization is initiated gradually before the opening of the window of implantation (the brief time during which the endometrium is receptive to the embryo), and stromal decidualized features and endothelial and resident immune cells (macrophages and uterine natural killer [uNK] and T cells) are widespread.
During early pregnancy, progressive endometrial decidualization forms the decidua, a tissue with the capacity to detect and respond to placental and embryonic stimuli, protecting the fetus from the maternal immune system and oxidative stress.
Overall, the decidua plays a vital role in coordinating embryo implantation and subsequently EVT interactions within the uterus, making decidualization essential for establishing the maternal-fetal interface.
Decidualization resistance is an aberrant response of the endometrium to hormone-driven differentiation signals. This defect can lead to complications at any pregnancy stage, including late-onset conditions, even though decidualization failure occurs before implantation. In intrauterine growth restriction, failures in decidualization result in the uterovascular remodeling disruptions observed in this complication.
Aberrant decidua may not support the dramatic changes in oxidative stress produced in response to active maternal perfusion of the placenta, and miscarriage may occur.
These and other pregnancy disorders are typically classified into distinct categories, but much of this classification is arbitrary because these conditions occur along a continuum and have common and interrelated risk factors with overlapping biomarkers.
Deficient spiral artery remodeling is well associated with PE and is also described in a spectrum of obstetrical syndromes, including intrauterine growth restriction, preterm labor, premature rupture of membranes, miscarriage, and fetal death.
Healthy pregnancy is likely established before implantation and placentation and influenced by the correct formation of the decidua. Decidualization resistance, entailing the inability of the maternal “soil” to undergo tissue modifications, leads to aberrations in placental invasion and adverse pregnancy outcomes. Modifications in optimal decidualization are usually cellular changes in hESCs (morphologic, biochemical, and secretory phenotypes) and the recruitment of immune cells (uNK and regulatory T cells).
In decidualization resistance, the process fails at some point resulting in a deficient decidua, impaired EVT invasion, and arterial remodeling. Thus, decidualization resistance could be considered a maternal risk factor for pregnancy complications, including PE. As a consequence, the contribution of impaired decidualization to the pathogenesis of PE is receiving increasing attention.
Below, we review the evolution of decidualization deficiency theory.
This hypothesis for the involvement of decidualization failure in the pathogenesis of PE started as a logical deduction based on the cross-talk between the EVT and the decidua during placentation.
However, uncovering any potential etiological factors occurring early in pregnancy, such as inadequate EVT invasion, would require an assessment of the relevant tissue, and obtaining first-trimester placenta and decidua is difficult. Thus, many studies are performed using third-trimester placentas and basal plate decidua. Transcriptional analysis of the decidua basalis in PE revealed 455 differentially expressed genes (DEGs) likely to play an important role in the pathogenesis of PE.
Gene expression analysis of chorionic villous samples identified 396 DEGs at 11.5 weeks’ gestation in patients who developed sPE symptoms 6 months later compared with normal pregnancies. Using bioinformatics to compare transcriptomic data from different studies, many of the dysregulated genes (154) overlapped with normal endometrial maturation before and after implantation. Furthermore, 116 of the 154 DEGs overlapped with DEGs related to decidualization in the absence of EVT. The expression 112 of the 154 DEGs was in the opposite direction from the expression expected in normal decidualization, including 16 DEG down-regulated in decidual natural killer cells. These findings motivated further inquiry into the concept that deficiency or defects in predecidualization gene expression and uNK cells are precursors to PE.
by analyzing the decidualization process in hESCs isolated from nonpregnant donors with a previous sPE diagnosis compared with control women with a previous normal pregnancy. Samples were collected between 1 and 5 years after pregnancy, and decidualization of hESCs was induced in the culture. The ability to differentiate was analyzed by stage-specific antigens, morphology, and transcriptional profile and revealed that hESCs from patients with previous sPE were unable to decidualize. Transcriptomic analysis identified 129 genes differentially expressed in sPE compared with controls (Figure 2, A). We also investigated whether impaired decidualization was present at the time of delivery in women with sPE by isolating portions of decidua (basalis and parietalis) from maternal-fetal interface sections using laser microdissection. Samples were collected at the time of delivery from women with sPE and women who had a spontaneous preterm birth with no signs of infection. Transcriptomic profiling revealed >200 dysregulated genes in sPE related to decidual dysfunctionality. Isolated decidual cells from patients with sPE dedifferentiated in vitro and failed to redecidualize in the culture. Finally, we explored whether decidualization resistance might affect CTB invasion in a model mimicking aspect of the uterine environment in PE. This model was performed using CTBs isolated from second-trimester human placentas and cultured on a Matrigel substrate. The conditioned medium for these cultures was obtained from stromal cells isolated from decidual samples mentioned earlier. The conditioned medium from sPE patient cells did not support CTB invasion, suggesting that decidualization resistance is associated with shallow CTB invasion, a common feature in sPE.
A, Women with preeclampsia present decidualization failure years after childbirth. hESCs isolated from patients with PE and cultured in vitro to promote decidualization showed an inert transcriptomic profile and were unable to decidualize. Among the 129 dysregulated genes, ANXA2 was down-regulated. B, In an in vitro model, ANXA2 was silenced in hESCs isolated from women with previous severe preeclampsia. The consequences of ANXA2 deficiency were confirmed with the use of an ANXA2-null mouse model. Together, these results suggest that a deficiency in ANXA2 is associated with the decidualization resistance observed in preeclamptic patients, highlighting the maternal contribution in the pathogenesis of severe preeclampsia.
ANXA2, annexin A2; DEG, differential expression genes; hESCs, human endometrial stromal cells; siRNA, small interfering RNA.
Garrido-Gómez. Decidualization resistance in severe preeclampsia.Am J Obstet Gynecol 2022.
Global transcriptional profiling revealed alterations in gene expression during in vitro decidualization of hESCs from former patients with sPE. In particular, annexin A2 (ANXA2) expression was lower
ANXA2 is abundantly expressed in the placenta, and its impaired activity could cause fibrinolytic deficiency associated with increased thrombosis, predisposing to PE.
We investigated the relevance of ANXA2 in decidualization defects to assess its value as a putative preconception maternal biomarker with translational potential for sPE risk prediction.
We assessed endometrial deficiency using a small interfering RNA and a knockout mouse model. This model produced a decidualization resistance phenotype with a shallow trophoblast invasion into the decidua, causing placentation defects associated with sPE (Figure 2, B). Together, our results support decidualization resistance in women with sPE at the time of delivery and persisting for years as mediated, at least in part, by ANXA2 deficiency.
We hypothesize that the development of sPE begins before pregnancy, with an altered baseline profile of decidualization resistance that could be identified during the menstrual cycle, even though clinical features are evident only at later stages of pregnancy.
Placenta- or Decidua-Based Diagnostic Strategies
PE carries a high economic burden. Healthcare costs of short-term complications developed during the first year after delivery reach $2.18 billion in the United States.
These costs increase further with long-term complications.
Early identification of women at risk of PE is necessary to mitigate both the short- and long-term adverse effects. The challenge to prevention and diagnostic strategies is that the etiology of PE is widely separated in time from the onset of disease symptoms. Thus, diagnostic strategies based on biomarkers of placental dysfunction have limited success, and no single marker or model combining markers has performed well enough to be suitable for routine. The most promising screening methods with a high sensitivity and specificity are with combined biomarkers sFLT1 and placental growth factor (PlGF).
A meta-analysis of 15 studies with 534 cases of PE and 19,587 controls after 19 weeks’ gestation evaluated the diagnostic value of the sFlt-1 to PlGF ratio as a screening method of PE and found a sensitivity of 80% and a specificity of 92%. However, there was a considerable heterogeneity between studies, including a lack of uniformity in the cutoff to rule out disease risk.
Meta-analysis and systematic review to assess the role of soluble FMS-like tyrosine kinase-1 and placenta growth factor ratio in prediction of preeclampsia: the SaPPPhirE Study.
In a multicenter study, a cutoff sFLT1 to PlGF ratio was established in 38, representing a sensitivity of 66.2% and a specificity of 83.1% for the diagnosis of PE within 4 weeks in patients at 24 to 37 weeks’ gestation. The same ratio was used to rule out the disease within 1 week with a negative predictive value of 99.9%.
Finally, multiparametric models were developed to detect pregnancies at risk of PE by screening at 11 to 13 weeks’ gestation. These models combine data from medical history with biophysical and biochemical markers. However, when applied to different populations, they showed poor performance. A multivariate Gaussian distribution model was recently proposed including maternal factors, early PlGF determination, and biophysical variables, but this model is not validated in different populations.
The goal is obtaining an effective early screening for prevention and prediction because placental alterations become evident in the second trimester of pregnancy. Current therapies are based on careful monitoring, antihypertensive therapy, low-dose aspirin, healthy diet, exercise, and stress reduction,
Significant findings have already been made in the maternal contribution to PE and in the role of decidualization resistance in its pathophysiology. However, further investigations are needed to better understand and evaluate the detection of decidualization resistance before pregnancy in women without a history of PE. In particular, research on the underlying mechanisms that lead to deficient decidualization would be especially valuable. Decidua-based diagnostic strategies for PE could be applied even before pregnancy, because decidualization is a process that occurs during the menstrual cycle, regardless of the presence of a conceptus. Developing a molecular test for application to the endometrial tissue at the time of decidualization—before pregnancy—could enable a prospective risk screening for this pathologic condition. Such testing would have promising clinical potential in the characterization of risk, which is the first step in achieving effective prevention (Figure 3).
Figure 3Maternal contribution to severe preeclampsia and the potential for prevention strategies
The pathogenesis of sPE could result from decidualization resistance, which begins before implantation, followed by shallow CTB invasion resulting in abnormal spiral remodeling, aberrant placentation, and impaired blood flow to the placenta, causing the placenta to release inflammatory factors resulting in systemic endothelial dysfunction. PE symptoms appear after 20 weeks’ gestation. Clinical translation of the maternal contribution to the pathogenesis of sPE could provide novel strategies to prevent the disease.
Decidualization resistance in the pathophysiology of PE solidifies a maternal contribution to the development of the condition. However, further investigations are needed to determine how to detect decidualization resistance before pregnancy in women without a history of PE. In particular, research on the underlying mechanisms leading to deficient decidualization would be especially valuable. Ideally, decidua-based diagnostic strategies for PE could be applied before pregnancy, because decidualization occurs during the menstrual cycle regardless of the presence of conceptus. Such testing would have promising clinical potential in the characterization of risk.
Acknowledgments
We thank phD student Irene Muñoz (Instituto de Investigación Sanitaria INCLIVA-Igenomix Foundation, Valencia, phD grant PRE2019-090770 from Spanish Ministry of Science and Innovation) for assistance in compiling data. This work was supported by a fellowship Program grant FDEGENT/2019/008 from the Generalitat Valenciana (to N.C.-M.); an Institute of Health Carlos III Grant PI19/01659 (to T.G.-G); and the Spanish Ministry of Science and Innovation Grant RTI2018-094946-B-100 (to C.S).
Glossary
Glossary
Abbreviation
Term
Definition
CTB
Cytotrophoblast
Unfused trophoblast cells that cover the implanting blastocyst surface. During implantation, CTBs invade the decidua and this invasion is shallow in preeclampsia.
CVS
Chorionic villous samples
Villi that sprout from the chorion to provide maximal contact area with maternal blood can be sampled to assess gene expression.
DEGs
Differentially expressed genes
Genes showing statistically significant different expression between 2 conditions.
EVTs
Extravillous trophoblasts
Cells that invade the maternal spiral arteries forming a chimeric vasculature. In preeclampsia, this invasion is shallow.
hESCs
Human endometrial stromal cells
Fibroblast-like cells in the endometrial stroma that differentiate during decidualization, an essential process for decidua formation.
PE
Preeclampsia
A major obstetrical complication with short-term and long-term life-threatening consequences for both mother and child.
PlGF
Placental growth factor
An angiogenic factor whose concentration is low in patients who subsequently develop preeclampsia.
sFLT1
Soluble fms-like tyrosine kinase-1
An antiangiogenic factor whose concentration in maternal plasma is high before and at the time of preeclampsia diagnosis.
—
Single-cell resolution
Sequence information from individual cells with optimized next-generation sequencing.
sPE
Severe preeclampsia
Preeclampsia with severe symptoms and signs.
—
Transcriptomics
The study of transcriptome, which is the complete set of RNA molecules within a cell.
Garrido-Gómez. Decidualization resistance in severe preeclampsia.Am J Obstet Gynecol 2022.
American College of Obstetricians and Gynecologists
Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?.
Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: new insights from contrast-enhanced ultrasound and tissue histopathology.
Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia.
Meta-analysis and systematic review to assess the role of soluble FMS-like tyrosine kinase-1 and placenta growth factor ratio in prediction of preeclampsia: the SaPPPhirE Study.
T.G-G. and T.C. are employees of Igenomix SL. C.S. is the Head of the Scientific Advisory Board at Igenomix SL. Igenomix SL does not sell any products related to preeclampsia. The remaining authors report no conflict of interest.
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