Andja Cirkovic1†
Dejana Stanisavljevic1†Jelena Milin-Lazovic1Nina Rajovic1Vedrana Pavlovic1Ognjen Milicevic1Marko Savic1
Jelena Kostic Peric2Natasa Aleksic3Nikola Milic4Tamara Stanisavljevic4Zeljko Mikovic5
Vesna Garovic6*
Natasa Milic1,6- 1Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- 2Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
- 3Center for Molecular Biology, University of Vienna, Vienna, Austria
- 4Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- 5Clinic for Gynecology and Obstetrics Narodni Front, Belgrade, Serbia
- 6Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
Introduction: Preeclampsia (PE) is a pregnancy-associated, multi-organ, life-threatening disease that appears after the 20th week of gestation. The aim of this study was to perform a systematic review and meta-analysis to determine whether women with PE have disrupted miRNA expression compared to women who do not have PE.
Methods: We conducted a systematic review and meta-analysis of studies that reported miRNAs expression levels in placenta or peripheral blood of pregnant women with vs. without PE. Studies published before October 29, 2021 were identified through PubMed, EMBASE and Web of Science. Two reviewers used predefined forms and protocols to evaluate independently the eligibility of studies based on titles and abstracts and to perform full-text screening, data abstraction and quality assessment. Standardized mean difference (SMD) was used as a measure of effect size.
Results: 229 publications were included in the systematic review and 53 in the meta-analysis. The expression levels in placenta were significantly higher in women with PE compared to women without PE for miRNA-16 (SMD = 1.51,95%CI = 0.55–2.46), miRNA-20b (SMD = 0.89, 95%CI = 0.33–1.45), miRNA-23a (SMD = 2.02, 95%CI = 1.25–2.78), miRNA-29b (SMD = 1.37, 95%CI = 0.36–2.37), miRNA-155 (SMD = 2.99, 95%CI = 0.83–5.14) and miRNA-210 (SMD = 1.63, 95%CI = 0.69–2.58), and significantly lower for miRNA-376c (SMD = –4.86, 95%CI = –9.51 to –0.20). An increased level of miRNK-155 expression was found in peripheral blood of women with PE (SMD = 2.06, 95%CI = 0.35–3.76), while the expression level of miRNA-16 was significantly lower in peripheral blood of PE women (SMD = –0.47, 95%CI = –0.91 to –0.03). The functional roles of the presented miRNAs include control of trophoblast proliferation, migration, invasion, apoptosis, differentiation, cellular metabolism and angiogenesis.
Conclusion: miRNAs play an important role in the pathophysiology of PE. The identification of differentially expressed miRNAs in maternal blood creates an opportunity to define an easily accessible biomarker of PE.
Introduction
Preeclampsia (PE) has been shown to affect 1–7.5% of all pregnancies, making it one of the leading causes of maternal and fetal morbidity and mortality worldwide (Abalos et al., 2013; Witcher, 2018; Garovic et al., 2020). PE is a multi-factorial, multi-systemic pregnancy specific condition found typically after 20 weeks of gestation or early post-delivery (American College of Obstetricians and Gynecologists, 2019). Although clinical symptoms appear relatively late in pregnancy, PE pathology begins early, making the identification of potential biomarkers during the first trimester a possible strategy for identifying predictors of PE (McElrath et al., 2020). Several potential biomarkers already have been evaluated: C reactive protein (CRP), cytokines (IL-6, IL-8, TNF-α), microparticle proteins (C1RL, GP1BA, VTNC, and ZA2G), oxidative stress markers (malondialdehyde - MDA), and genetic factors (PAI-1 4G/5G polymorphism) (Black and Horowitz, 2018; Giannakou et al., 2018; Taravati and Tohidi, 2018; McElrath et al., 2020). There are few known biomarkers, however, that can accurately predict the risk for PE. The use of combinations of several biomarkers previously has been proposed as a diagnostic or predictive parameter, such as the ratio of soluble fms-like tyrosine kinase-1 to placental growth factor ratio (sFlt-1/PlGF) (Lecarpentier and Tsatsaris, 2016). A study by Garovic et al. reported podocyturia, defined as the presence of podocin-positive cells in urine sampled ≤24 h of delivery, as a 100% sensitive and specific diagnostic marker for PE (Garovic et al., 2007).
Significant progress has been made in the past decade in the assessment of epigenetic mechanisms that might be involved in the pathophysiology of PE, and which aim to identify potential diagnostic and/or predictive epigenetic markers of PE. More specifically, short non-coding microRNAs (miRNAs) are involved in post-transcriptional gene expression and play a role in numerous diseases, modulating regulatory pathways that control development, differentiation, and organ function. MiRNAs are single-stranded RNA molecules consisting of 19–24 nucleotides, and their mode of action is primarily by degrading targeted mRNA transcripts or inhibiting translation of mRNA into a protein product (Hombach and Kretz, 2016). It is also known that miRNA molecules are involved in the physiological regulation of major processes of placentation (Mouillet et al., 2015). It might therefore be anticipated that dysfunction of miRNA expression could be important for the development of PE. Studies recently published explored a possible causal relationship between miRNA expression and PE (Youssef and Marei, 2019; Hemmatzadeh et al., 2020). It has been demonstrated that expression levels of miRNAs in different tissues play a role in physiological pregnancy as regulators of trophoblast proliferation, migration, invasion, apoptosis, differentiation, cellular metabolism and placental angiogenesis (Hayder et al., 2018). The placenta is one of the main sources of miRNAs, but they also can be found in the circulation (Mouillet et al., 2015). Placental miRNA-210 expression has been the most studied in PE and other pregnancy related complications, and increased levels have been demonstrated (Muralimanoharan et al., 2012; Awamleh and Han, 2020). Results from evaluations of other frequently analyzed miRNAs, such as miRNA-155, -223, -126, -183, -182, -281b, -154, -139-5p, -29b, -181a, -15b (Mayor-Lynn et al., 2011; Yang et al., 2011; Zhao et al., 2013; Sheikh et al., 2016; Hemmatzadeh et al., 2020), suggest that miRNA expression differs according to the severity of PE (Jairajpuri et al., 2017), and also differs throughout the course of normal pregnancy (Cai et al., 2017). While some research has been done to investigate the association between miRNA expression levels and PE, there is still a lack of evidence to support the common use of miRNAs as functional biomarkers related to PE. The aim of this study was to perform a systematic review and meta-analysis to determine whether women with PE have disrupted miRNA expressions compared to women without PE.
Materials and Methods
This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and MOOSE guidelines (Stroup et al., 2000; Liberati et al., 2009).
Study Selection
Publications were screened for inclusion in the systematic review in two phases, and all disagreements were resolved by discussion at each stage with inclusion of a third reviewer. We included studies that compared miRNA expression levels between women with and without PE. Studies were eligible for inclusion if the miRNA expression levels were measured in both groups. Studies were excluded if they: 1) investigated other outcomes, 2) did not make comparisons between PE and control groups, 3) examined other populations (animal, cell lines), 4) assessed other epigenetic markers, 5) were abstracts, or 6) were not original articles.
Database Search
Two biostatisticians with expertise in conducting systematic reviews and meta-analyses (NM, AC) developed the search strategy. A systematic review of peer-reviewed publications was performed through searches of PubMed, Web of Science (WoS) and embase electronic databases until October 29, 2021. Search queries differed according to the database. Key words for the PubMed search were: preeclampsia and (epigenetic or epigenetics or miRNA or microRNA or DNA methylation or DNA methylation or long non coding RNA); for Wos: TS = *eclampsia and TS= (epigenetic* or microRNA or DNA methylation or gene imprinting or long non coding RNA), and for embase: preeclampsia and (epigenetics or microRNA or DNA methylation or genome imprinting or long untranslated RNA). Only publications in English were considered. In addition, reference lists of articles identified through electronic retrieval were manually searched, as well as relevant reviews and editorials. Experts in the field were contacted to identify other potentially relevant articles.
Authors of relevant articles were contacted to obtain missing data. Studies with combined data of gestational hypertension and/or chronic hypertension in pregnancy and PE were only eligible if data for the subset of women who developed preeclampsia were available.
Article Screening and Selection
Two reviewers (AC, JML) independently evaluated the eligibility of all titles and abstracts. Studies were included in the full text screening if either reviewer identified the study as being potentially eligible, or if the abstract and title did not include sufficient information. Studies were eligible for full text screening if they included comparisons of miRNA expression levels between women with and without PE. Preeclampsia included more severe, less severe, and not specified forms. The same reviewers independently performed full text screening to select articles for inclusion according to the criteria listed under Inclusion and Exclusion Criteria. Disagreements were resolved by consensus (AC, JML) or arbitration (NM, DS).
Data Abstraction and Quality Assessment
Two reviewers independently abstracted the following data: author(s), country of research, year of publication, study design, sample size, study population, maternal age, preeclampsia definitions, disease severity (more severe, less severe or not-specified PE), inclusion and exclusion criteria used in the original articles, sample type and time of sampling, matching, evaluated miRNAs, method for miRNA expression quantification, miRNA expression value, housekeeping gene for internal control, conclusion in original article. Each reviewer independently evaluated the quality of selected manuscripts using an adapted version of the Newcastle-Ottawa tool for observational studies (Wells et al., 2014). Reviewers used a standardized previously defined miRNA protocol when selecting and abstracting data. All detailed information about quality assessment, data extraction, variables, miRNA expression quantification methods and housekeeping gene for internal normalization are available at https://osf.io/g42ze/.
Statistical Analysis
The primary outcome was expression levels of miRNAs, presented as means with standard deviation. GetData Graph Digitizer version 2.26.0.20 was used to read miRNA values when figures presenting miRNA expression levels were available (Digitize graphs and plots, 2013). Median was used as an approximation of the arithmetic mean, and IQR/1.35 was used as an approximation of standard deviation. If standard error was used in the original article, standard deviation was calculated as sd = se*√n, and if the range was presented, standard deviation was estimated as (max-min)/4.
Methodologies for measuring miRNA expression levels varied; therefore, the standardized mean difference (SMD) was used as a measure of effect size to examine differences between the preeclampsia and non-preeclampsia groups. SMD expresses the difference between group means in units of standard deviation and was estimated by pooling individual trial results using random-effects models via the Der Simonian-Laird method. Heterogeneity was assessed using the Chi-square Q and I2 statistic. I2 presents the inconsistency between the study results and quantifies the proportion of observed dispersion that is real, i.e., due to between-study differences and not due to random error. The categorization of heterogeneity was based on the Cochrane Handbook (Higgins et al., 2019) and states that I2<30%, 30–60% or >60%, correspond to low, moderate and high heterogeneity, respectively. Forest plots were constructed for each analysis showing the SMD (box), 95% confidence interval (lines), and weight (size of box) for each trial. The overall effect size was represented by a diamond. Meta-analysis was performed for all miRNAs with available data from at least three relevant studies.
Sensitivity analyses were conducted to examine the effects of: 1) replacement of studies that measured miRNA expression levels in the chorionic plate with studies exploring the basal plate, 2) inclusion of measurements performed in more severe, less severe or not-specified PE forms only (instead of all PE forms), 3) replacement of miRNA expression levels obtained in term controls with miRNA expression levels in preterm controls, 4) inclusion of studies exploring miRNA expression levels in moderate or mild proteinuria PE groups, instead of severe proteinuria as in the PE group in the first analysis. A p value < 0.05 was statistically significant. Analyses were performed using Review Manager Version 5.4 (Cochrane, 2021).
Results
Systematic Review
A total of 1773 potentially eligible articles were found. 1,517 articles were excluded because they were duplicates, not original articles, were without PE as the outcome, did not compare PE and control groups, examined populations other than women (animals, cell lines), did not explore miRNA expression levels, or were abstracts. Of the 256 reviewed full text articles, 229 were selected for inclusion in the systematic review. A flow diagram illustrating this selection process is presented in Figure 1.
FIGURE 1. Flow diagram.
Characteristics of all 229 publications included in the systematic review are presented in detail in Table 1. They were published between 2007 and 2021, with a total of 13043 participants; 6,459 women with and 6584 without PE. The minimum sample size of the PE group was four, and a minimum of one for the control group. The maximum sample size was 200 in PE and 321 in the control group. Four publications did not report the number of participants. 139 studies were cross-sectional, 64 were case-control, 11 were nested case-control studies, while only six were prospectively followed cohorts. Five studies included two or three sub-studies with the same or different study designs. In eighteen publications, the study design was not clearly stated. Most studies were from China (138), United States (19), and Czech Republic (8). Study groups were matched in 73 (32%) of all articles, and gestational age at the time of delivery was the most used variable for matching (in 53 of 73 publications). Maternal age at the time of delivery was used for matching in 35 publications. Other matching variables were BMI at the time of delivery, parity, race and/or ethnicity, gravidity, delivery, fetal gender, family history of PE, smoking history, additional comorbidities, systolic blood pressure at the time of inclusion, diastolic blood pressure at the time of inclusion, proteinuria at the time of inclusion, infant weight, pre-pregnancy indices, duration of storage of plasma samples, and maternal body weight at the time of delivery. Regression analysis was used to account for confounders in 14 publications. Ethnicity was reported in eight and race in eleven publications. Fetal gender was reported in 25 publications. The expression levels of miRNA were explored according to fetal gender in just three studies, and a regression model was adjusted for fetal gender in one publication. The most examined source of miRNAs was placenta, reported in 155/229 publications. Ninety-eight studies used maternal peripheral blood: plasma in 46, serum in 28, plasma exosomes in 9, mononuclear cells in 2, serum exosomes in 2, whole blood in 2, and leukocytes and buffy coat in one study each. Twelve studies analyzed miRNA expression levels in umbilical cord cell populations: mesenchymal stem cells in 4, and HUVECs, vein cells, maternal blood, exosomes, endothelial progenitor cells, serum, fetal blood, and umbilical cord tissue in one study each. Other rarely sampled tissues were myometrium, urine, maternal subcutaneous fat tissue endothelium, and placental blood vessel endothelium. Tissue was sampled at the time of delivery in 149 (65%) studies. In 60 studies, sampling was done prior to delivery and, in two studies, after delivery; 1 year after (Murphy et al., 2015), and 3–11 years after delivery (Hromadnikova et al., 2019b). Time of sampling was not reported in 34 (15%) publications. Most articles did not differentiate the type of PE (70%). Inclusion and exclusion criteria were not reported in most studies assessing miRNA in preeclamptic pregnancies. Only primiparous women were included in six studies, only non-smokers in 17, and only women without chronic hypertension in 89 publications. Detailed additional inclusion and exclusion criteria are presented in Supplementary Table S1. The presence of renal disease was the most common (50/229). The presence of diabetes mellitus (49/229) and the presence of cardiovascular disease (32/229) were reported less often. The presence of obesity was reported in six and preeclampsia in the previous gestation in five publications.
TABLE 1. Systematic review.
Disease severity was reported in 70/229 publications. Details regarding PE definitions and the diagnostic criteria used in the original articles are presented in Supplementary Tables S2, S3. qRT-PCR as the detection method with U6 as an internal control was utilized in almost all studies, and the details regarding quantification methods and housekeeping genes used are presented in Supplementary Table S4. A list of all explored miRNAs from the included publications according to PE severity (more severe, less severe, and not-specified PE) is presented in Supplementary Tables S5–S7.
Meta-Analysis
A meta-analysis was performed for the following fourteen miRNAs: miRNA-16, miRNA-17, miRNA-17-5p, miRNA-20b, miRNA-23a, miRNA-29a-3p, miRNA-29b, miRNA-30a-3p, miRNA-155, miRNA-155-5p, miRNA-181a, miRNA-195, miRNA-210, and miRNA-376c.
The expression levels were significantly higher in the placentas of women with PE compared to women without PE for miRNA-16 (SMD = 1.51, 95%CI = 0.55–2.46, p = 0.002) (Figure 2), miRNA-20b (SMD = 0.89, 95%CI = 0.33–1.45, p = 0.002) (Figure 3), miRNA-23a (SMD = 2.02, 95%CI = 1.25–2.78, p < 0.001) (Figure 4), miRNA-29b (SMD = 1.37, 95%CI = 0.36–2.37, p = 0.008) (Figure 5), miRNA-155 (SMD = 2.99, 95%CI = 0.83–5.14, p = 0.007) (Figure 6) and miRNA-210 (SMD = 1.63, 95%CI = 0.69–2.58, p < 0.001) (Figure 7). Subgroup analysis showed increased levels of miRNA-210 expression in placentas of women with more severe (SMD = 2.01, 95%CI = 0.31–3.71, p = 0.020), but not in women with a less severe form of PE (SMD = 0.39, 95%CI = –8.14 = 8.92, p = 0.930), compared to women without PE (Figure 7). The expression levels in placenta were significantly lower in women with PE compared to women without PE for miRNA-376c (SMD = –4.86, 95%CI = –9.51 to –0.20, p = 0.040) (Figure 8).
FIGURE 2. Meta-analysis of differences in expression level of miRNA-16 in placenta between women with vs. without preeclampsia.
FIGURE 3. Meta-analysis of differences in expression level of miRNA-20b in placenta between women with vs. without preeclampsia.
FIGURE 4. Meta-analysis of differences in expression level of miRNA-23a in placenta between women with vs. without preeclampsia.
FIGURE 5. Meta-analysis of differences in expression level of miRNA-29b in placenta between women with vs. without preeclampsia.
FIGURE 6. Meta-analysis of differences in expression level of miRNA-155 in placenta between women with vs. without preeclampsia.
FIGURE 7. Meta-analysis of differences in expression level of miRNA-210 in placenta between women with vs. without preeclampsia.
FIGURE 8. Meta-analysis of differences in expression level of miRNA-376c in placenta between women with vs. without preeclampsia.
The expression level was significantly higher in the maternal peripheral blood of women with PE compared to women without PE for miRNA-155 (SMD = 2.06, 95CI = 0.35–3.76, p = 0.020) (Figure 9), but it was lower for miRNA-16 (SMD = –0.47, 95%CI = –0.91 to –0.03, p = 0.040) (Figure 10).
FIGURE 9. Meta-analysis of differences in expression level of miRNA-155 in peripheral blood between women with vs. without preeclampsia.
FIGURE 10. Meta-analysis of differences in expression level of miRNA-16 in peripheral blood between women with vs. without preeclampsia.
The functional roles of all significant miRNAs are presented in detail in Table 2. Although the roles of the evaluated miRNAs are confusing, special emphasis should be placed on the interpretation of the miRNAs known roles in controlling trophoblast proliferation, migration, invasion, apoptosis, differentiation, cellular metabolism, and angiogenesis.
TABLE 2. Functional roles of significant miRNAs.
Placental expression levels were not significantly different in women with PE compared to women without PE for miRNA-17 (SMD = 0.22, 95%CI = -1.35 to –1.79, p = 0.790) (Supplementary Figure S1), miRNA-30a-3p (SMD = 1.00, 95%CI = –0.50–2.50, p = 0.190) (Supplementary Figure S2), miRNA-181a (SMD = 0.05, 95%CI = –0.99–1.08, p = 0.930) (Supplementary Figure S3), and miRNA-195 (SMD = –0.16, 95%CI = –1.35–1.02, p = 0.780) (Supplementary Figure S4). The expression level was not significantly different in maternal peripheral blood in women with PE compared to women without PE for miRNA-17-5p (SMD = 0.08, 95%CI = –0.74–0.90, p = 0.850) (Supplementary Figure S5), miRNA-29a-3p (SMD = –0.29, 95%CI = –1.22–0.64, p = 0.540) (Supplementary Figure S6), miRNA-155-5p (SMD = –0.37, 95%CI = –1.07–0.33, p = 0.300) (Supplementary Figure S7), miRNA-181a (SMD = 0.22, 95%CI = –0.42–0.86, p = 0.500) (Supplementary Figure S8), and miRNA-210 (SMD = 0.48, 95%CI = –0.66–1.62, p = 0.410) (Supplementary Figure S9).
The same results were obtained when sensitivity analyses were performed to exclude studies with unspecified types of PE, to replace expression data obtained from the chorionic plate with those obtained from the basal plate, including/excluding different forms (more/less severe) of PE where possible (Supplementary Figures S10–S22).
Discussion
We identified in this study seven differentially expressed miRNAs in the placentas of women with vs without PE. miRNA-16, miRNA-20b, miRNA-23a, miRNA-29b, miRNA-155, and miRNA-210 were significantly increased in the placentas of PE women, while the levels of miRNA-376c were significantly decreased in PE placentas. We found no differences in the expression levels of miRNA-17, miRNA-30a-3p, miRNA-181a, and miRNA-195 in placentas of PE vs. non-PE women. A meta-analysis of the miRNA expression levels in the peripheral blood of PE women compared to women without PE was performed for miRNA-16, miRNA-17-5p, miRNA-29a-3p, miRNA-155, miRNA-155-5p, miRNA-181a and miRNA-210. A significant decrease in miRNA-16 expression levels in maternal peripheral blood of PE women was found, and no differences were found for other evaluated miRNAs. A sensitivity analysis did not change the results of the primary analysis.
Placentation is thought to be the basis for normal physiological pregnancy and is required for fetal growth and development, as well as the expectation of term labor. Several sensitive, precisely dictated, vascular processes involving angiogenesis at the fetal-maternal interface and adequate cytotrophoblast invasion with spiral-artery remodeling are essential for placentation (Weedon-Fekjær et al., 2014). At the very beginning of a pregnancy in which PE will develop, the transformation of proliferative endothelium into invasive endothelium is absent, and the expected extensive invasion of cytotrophoblasts into the spiral arteries does not occur. This results in pathologic remodeling of the placental arterioles, which become narrow, with reduced flow and sclerotic changes in the arteriolar walls (Mouillet et al., 2015). Placental ischemia promotes an inflammatory state that is characterized by increased production of inflammatory cytokines by pro-inflammatory T cells, and a decrease in regulatory and anti-inflammatory cytokines (Hanna et al., 2000). Decreased levels of anti-inflammatory cytokines (IL-10, IL-4) and increased pro-inflammatory cytokines (TNF-α, IL-6) in the circulation and placental tissue support the inflammatory background of preeclampsia (Keiser et al., 2009; Spence et al., 2021). These processes lead to placental malnutrition, and subsequent development of PE. The placenta is known to be an organ in which a large number of miRNAs are expressed (Mouillet et al., 2015). Several miRNAs contribute to the processes of trophoblast proliferation, invasion, and differentiation. miRNA-125b-1-3p and miRNA-210 inhibit trophoblast proliferation and invasion, while miRNA-155 inhibits trophoblast invasion only. In contrast, miRNA-376c enhances trophoblast proliferation and invasion (Mouillet et al., 2015). Fu et al. demonstrated that miR-376c promotes trophoblast cell proliferation, survival, migration, and invasion, and postulated that inhibition of Nodal and TGF-β signaling by miR-376c is important for adequate placentation (Fu et al., 2013). Primate-specific C19MC miRNAs, which are almost exclusively expressed in placenta, were described as important factors influencing adequate trophoblast invasion and arterial remodeling (Hromadnikova et al., 2013; Mouillet et al., 2015). As knowledge of the functional importance of miRNAs in adequate placentation and the development of PE increases (Hayder et al., 2018), it becomes important to determine whether miRNA expression levels are disrupted in PE, and which specific miRNA contributes predominantly to disease pathogenesis.
Meta-analysis in this study revealed significantly higher miRNA-16 expression in the placentas of women with PE compared to those without PE. Confirmation of the possible association between altered expression of miRNA-16 and PE was first described by Hu et al. who showed that there is increased expression of miRNA-16 in the placentas of women with severe PE (Hu et al., 2009). This was followed by Vu et al. who found increased expression of miRNA-16 in the sera of women with PE compared with healthy controls (Wu et al., 2012). The pathologic significance of miRNA-16 lies in its function in regulating the cell cycle. Liu et al. have shown that miRNA-16 stops the cell cycle in G1 phase by regulating the expressions of the CCND3, CCNE1 and CDK6 genes. Based on these physiological roles, it is supposed that miRNA-16 acts as a tumor suppressor (Yan X. et al., 2013). It also is known that the target of miRNA-16 is the Vascular Endothelial Growth Factor (VEGF) gene, whose product is an extremely important protein that initiates vasculogenesis in the placenta and induces proliferation and migration of endothelial cells in blood vessels (Wang and Zhao, 2010). In a study by Wang et al., miRNA-16 was found to have the potential to inhibit proliferation, migration and angiogenesis in mesenchymal stem cells (Wang Y. et al., 2012). The significantly lower miRNA-16 expression levels in the maternal peripheral blood of women with PE compared to those without PE led epigenetic analysis in another direction. It is proposed, but not proven, that miRNA-16 plays a significant role in the progression of human cardiac cell injury in ischemic dilated cardiomyopathy through endoplasmic reticulum stress, inflammation, autophagy, and apoptosis (Calderon-Dominguez et al., 2021). Down regulation of this miRNA, known as an anti-apoptotic factor, also was registered in ischemic myocardial cells, as a reaction to hypoxia in order to protect the tissue (Zhang H. J. et al., 2019). Therefore, miRNA-16 may play a role in both ischemic cardiomyopathy and preeclampsia, which similarly represent hypoxia induced pathological states. Original research articles have reported differing results regarding miRNA-16 levels in pregnancy complications. miRNA-16 levels were elevated in fetal macrosomia, but decreased in severe preeclampsia (Wu et al., 2012; Ge et al., 2015).
Increased expressions of miRNA-20b and miRNA-29b in the placentas of women with PE compared to women without PE were also found in our study. It is well known that the target gene for both miRNA-20 and miRNA-16 is VEGF, thus affecting placental vasculogenesis (Hayder et al., 2018). miRNA-20b binds to the Ephrin Type-B Receptor 4 (EPHB4) and Ephrin Type-B Receptor 2 (EPHB2), important receptors for intercellular communication, which have functions in the regulation of cellular morphology, binding, migration, proliferation, differentiation, and survival. These processes are assumed to be involved in the miRNA-20b contribution to placental blood vessel remodeling (Pasquale, 2005; Lisabeth et al., 2013). miRNA-29b is involved in the processes of trophoblast proliferation and invasion (Harapan and Andalas, 2015). miRNA-29b contributes to preeclampsia through dysregulation of the extracellular signal-regulated protein kinase and focal adhesion kinase (ERK/FAK) signaling pathway that allows the expression of matrix metalloproteinase-2 (MMP2), which is in turn an important factor for migration and invasion of trophoblast cells. Increased expression of miRNA-29b in severe PE has been previously shown to be associated with reduced expressions of MMP2 and integrin β1(ITGβ1) (Li H. et al., 2013).
The increased miRNA-23a levels in PE placentas support previously reported results that the level of this miRNA is upregulated in conditions related to abnormal angiogenesis (Chhabra et al., 2010). The main role of miRNA-23a, as part of the miR-23a∼27a∼24–2 cluster, is to mediate blood vessel genesis. It is included, except in PE, in pathological states such as muscle atrophy, cardiac hypertrophy, and cancers (Chhabra et al., 2010). Data in vitro, as well as in vivo, indicate that miRNA-23a and miR-23b may have opposite roles, with the former regulating angiogenesis and cellular junctions, and hence inhibiting vascular permeability, while miRNA-23b promotes permeability (Li et al., 2016).
MiRNA-155 expression levels were significantly increased in the placentas and maternal peripheral blood of women with PE compared to those without PE. The increased expression of miRNA-155 and resultant lower levels of cysteine-rich protein 61 (CYR61) and cyclin D1, have been associated with the inhibition of trophoblast invasion (Zhang et al., 2010; Dai et al., 2012). It also has been previously demonstrated that a significant increase in miRNA-155 decreases endothelial nitric oxide synthase (eNOS) expression and thus contributes to development of severe PE (Li X. et al., 2014). This result is consistent with findings from previous studies (Zhang et al., 2010; Gan et al., 2017). This immunomodulatory miRNA, induced in activated T lymphocytes, B lymphocytes and macrophages (Bernstein et al., 2003), is also disrupted in maternal peripheral blood. Its increased expression level was associated with a decreased level of pro-angiogenic factor, VEGF, in an experimental rat model of PE (Cheng et al., 2011). Newly performed studies have reported significantly higher levels of miRNA-155 in the maternal peripheral blood of women with compared to women without PE (Ayoub et al., 2019; Youssef and Marei, 2019; Witvrouwen et al., 2021).
MiRNA-210 has been the most evaluated small non-coding RNA. It is known that miRNA-210 is induced under hypoxic conditions which exist prior to, as well as during the clinical manifestations of PE. Hypoxia stimulates the production of NF-kB 1 (nuclear factor kappa-B 1) and HIF-1A (hypoxia inducible factor 1 α), which induce the expression of miRNA-210 (Muralimanoharan et al., 2012). Previous research has confirmed significantly increased expression of miRNA-210 in both the placentas and sera of women with PE and suggests that miRNA-210 obtained from serum may be a useful biomarker even months before diagnosis (Anton et al., 2013). Micro RNA-210 plays a role in several processes, such as inhibition of cytotrophoblast migration and invasion, differentiation, apoptosis, inflammation, angiogenesis, as well as in the regulation of cellular metabolism. miRNA-210 partially inhibits trophoblast invasion via the ERK/MAPK signaling pathway (Anton et al., 2012). Cell metabolism is dictated by miRNA-210 in that increased expression leads to decreased mitochondrial respiration and vice versa (Hayder et al., 2018). miRNA-210 also plays a role as a suppressor of EFNA3, a member of the ephrin ligand family which is important for cell migration, and HOXA9, an important angiogenesis regulator (Zhang et al., 2012; Luo et al., 2014). Overall, inadequate trophoblast invasion and impaired cellular metabolism are confirmed factors that can lead to the development of PE. Anton et al. found that for each 5-U increase in miR-210 in sera of previously healthy women at the beginning of the second trimester, the odds of PE development later in pregnancy increased fourfold (Anton et al., 2013).
MiRNA-376c plays a role in trophoblast proliferation and differentiation (Hayder et al., 2018). We found significantly lower levels of expression in the placentas of women with PE compared to women without PE, which is consistent with the findings of other studies (Fu et al., 2013; Yang H.-l. et al., 2019). Only Yang et al. showed no significant difference in the levels of miRNA-376c expression in the placentas of women with preterm preeclampsia and gestational age matched controls without PE (Yang H.-l. et al., 2019). Fu at al. showed that a decrease in miR-376c expression results in excessive apoptosis, insufficient cell proliferation, and shallow invasion of trophoblasts in the uterus in preeclampsia (Fu et al., 2013).
In summary, our results clearly identify a subset of miRNAs that are dysregulated in preeclampsia and clearly point towards the underlying mechanisms that may be contributing to the pathophysiology of preeclampsia. Our results set the stage for several venues for future research with an overall goal to facilitate early diagnosis and optimize fetal and maternal outcomes. First, given the clinical heterogeneity of preeclampsia (severe vs. mild, late vs. early, and “placental” vs. “maternal”), adequately designed and powered studies may detect differences in miRNA and related specific underlying mechanisms responsible for specific clinical subtypes. Second, clinical studies may identify a marker (or set of markers) with either predictive or diagnostic role. Third, further discovery of signaling pathways affected by miRNA may lead to mechanism-based therapies.
Our study has several limitations. They originate from the unavailability of all/some data from the original publications, uninformative figures presented in the articles, and selection of the housekeeping gene used for internal controls. The consequences of the data unavailability are possible exclusion of relevant data and a smaller number of included studies, as well as miRNAs, in the meta-analysis that may lead to an overestimation/underestimation of the effects of miRNA expression level on PE development. The importance of adequate selection of the housekeeping gene should be emphasized to standardize miRNA evaluation methodology and to provide comparability between studies. The definition of PE is not the same in each of the included studies which may lead to inclusion of heterogeneous cases that can change the assessment of the effect. Through the systematic review, it was realized that cases and controls were rarely matched for gestational age at the time of sampling. It is necessary to highlight the importance of comparing matched groups because it is known that there are physiological changes in miRNAs expression levels throughout pregnancy. The miRNA source in plasma may be maternal, fetal, or both, yet only a small number of studies reported these data.
Conclusion
MiRNAs play an important role in the pathophysiology of PE. The functional roles of the microRNAs found to be disrupted in preeclamptic pregnancies include control of trophoblast proliferation, migration, invasion, apoptosis, differentiation, cellular metabolism, and angiogenesis. The identification of differentially expressed miRNAs in maternal blood creates an opportunity to define an easily accessible biomarker of PE. A better understanding of the role of microRNAs in the development of PE offers great potential for developing diagnostic and therapeutic targets for PE.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Author Contributions
Conceptualization: AC, VG, ZM, DS, NM; Data curation: AC, JM, MS, NR, JK, NA, TS, VP, DS, NM; Formal analysis: AC, JM, MS, NR, DS, NM; Investigation: AC, VG, JM, OM, MS, NR, JK, NA, NM, TS, VP, DS, NM; Methodology: AC, VG, JM, DS, NM; Project administration: VG, DS, NM; Supervision: VG, DS, NM; Visualization: AC, JM, MS, DS, NM; Writing – original draft: AC, VG, JM, OM, MS, NR, NA, TS, JK, VP, DS, NM; Writing – review & editing: AC, VG, JM, OM, MS, NR, NA, NM, TS, JK, VP, DS, NM. All authors read and approved the final manuscript.
Funding
Funding: NIH R01-HL136348 (VG).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fbioe.2021.782845/full#supplementary-material
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Keywords: epigenetics, miRNA, preeclampsia, pathophysiology, meta-analysis
Citation: Cirkovic A, Stanisavljevic D, Milin-Lazovic J, Rajovic N, Pavlovic V, Milicevic O, Savic M, Kostic Peric J, Aleksic N, Milic N, Stanisavljevic T, Mikovic Z, Garovic V and Milic N (2021) Preeclamptic Women Have Disrupted Placental microRNA Expression at the Time of Preeclampsia Diagnosis: Meta-Analysis. Front. Bioeng. Biotechnol. 9:782845. doi: 10.3389/fbioe.2021.782845
Received: 24 September 2021; Accepted: 22 November 2021;
Published: 24 December 2021.
Edited by:
Umberto Galderisi, University of Campania Luigi Vanvitelli, ItalyReviewed by:
Liv Cecilie Vestrheim Thomsen, University of Bergen, NorwayMartin Mueller, University Hospital Bern, Switzerland
Copyright © 2021 Cirkovic, Stanisavljevic, Milin-Lazovic, Rajovic, Pavlovic, Milicevic, Savic, Kostic Peric, Aleksic, Milic, Stanisavljevic, Mikovic, Garovic and Milic. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Vesna Garovic, garovic.vesna@mayo.edu
†These authors share first authorship