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. 2025 Oct 8;17(17):1293–1302. doi: 10.1080/17501911.2025.2568364

Role of epigenetic markers in cardiovascular disease following hypertensive disorders of pregnancy

Kimiya Padidar a, Shaun Brennecke b,c, John Blangero d, Eric K Moses a, Phillip E Melton a,e,✉
PMCID: PMC12674235  PMID: 41060197

ABSTRACT

Cardiovascular disease (CVD) is the leading cause of death among women globally. Pregnancy complications, such as hypertensive disorders of pregnancy (HDP), are known to increase the risk of developing CVD. Over 10% of pregnancies globally are affected by HDP, a condition characterized by increased blood pressure and a multiorgan disorder (preeclampsia) associated with a 2- to 8-fold higher risk of hypertension, ischemic heart disease, stroke, and heart failure. Altered epigenetic regulation of angiogenesis, endothelial function, and gene expression may help explain the link between HDP and later-life CVD risk. However, studies investigating how epigenetic modifications mediate the progression from HDP to CVD remain limited. This review provides an overview on how epigenetic mechanisms may influence the long-term cardiovascular consequences of HDP. It also highlights key research gaps, including the need for long-term longitudinal studies to show causality. Further research on this topic may result in better screening, prevention strategies, and personalized therapies for women’s cardiovascular health. However, epigenetic markers should be viewed as complementary to established clinical predictors, with near-term value in mechanistic risk refinement rather than as replacements for current approaches.

KEYWORDS: Epigenetic markers, cardiovascular disease, hypertensive disorders of pregnancy, preeclampsia, DNA methylation, histone modifications, non-coding RNAs

1. Introduction

Cardiovascular disease (CVD) remains a major contributor to female mortality worldwide, with pregnancy complications significantly increasing lifetime CVD risk [1,2]. Adverse pregnancy outcomes, such as hypertensive disorders of pregnancy (HDP), preterm delivery, gestational diabetes, and fetal growth restriction, are linked to a higher risk of CVD later in life [3]. Compared to men, women with CVD have worse overall health, greater rates of hospitalization, higher morbidity, and more frequent symptoms of chronic angina [4]. One of the most notable examples of HDP, preeclampsia (PE), increases the risk of later-life hypertension by two- to eightfold compared to normotensive pregnancies [5,6]. Emerging evidence suggests that epigenetic mechanisms may bridge the gap between pregnancy-related complications and long-term cardiovascular outcomes [7].

Epigenetic changes including DNA methylation and histone modifications have been proposed to help explain this association. They are heritable alterations in gene expression that do not involve changes to the underlying DNA sequence. Among these mechanisms, DNA methylation is the most extensively studied and has been connected to the etiology of several chronic illnesses. In pregnancy, aberrant epigenetic regulation has been associated with the development of PE, possibly because genes related to vascular control, immunological response, and placental development are disrupted [8].

Recent studies suggest that epigenetic patterns recognized during HDP or possibly even earlier in pregnancy may persist long after delivery and contribute to the elevated CVD risk observed in affected women. Notably, specific methylation signatures, including differentially methylated regions (DMRs), have been linked to both the severity of HDP and subsequent cardiometabolic outcomes. However, disparities among studies have diminished the potential for therapeutic use of these findings [9]. This review investigates epigenetic alterations in women with a history of HDP, with a particular focus on their potential as prognostic biomarkers for long-term CVD risk. We also discuss current limitations in the field and outline future directions for integrating DNA methylation markers into maternal health care strategies.

Given the clinical and biological heterogeneity of HDP, as well as their varying associations with long-term CVD outcomes, clearly defining HDP subtypes helps to frame epigenetic studies and properly identify possible biomarkers.

2. Classification of HDP

HDP are categorized into four main subtypes: chronic hypertension (CH), gestational hypertension (GH), PE, and CH with superimposed preeclampsia (sPE) [10–12]. A summary of definitions, prevalence, and associated clinical outcomes of HDP subtypes is presented in Table 1 [12].

Table 1.

HDP subtypes with ISSHP definitions, prevalence, and associated maternal risks.

HDP Subtype Definition/ISSHP Criteria Prevalence in pregnancy Risks & Considerations
CH BP ≥ 140/90 mmHg diagnosed before pregnancy or before 20 weeks of gestation 5% Increases risk of sPE and later-life CVD
GH New-onset hypertension (≥140/90 mmHg) occurring after 20 weeks of gestation without proteinuria or other signs of organ dysfunction. 1.8–4.4% Progress to PE, increases risk of chronic hypertension postpartum.
PE BP ≥ 140/90 mmHg after 20 weeks of gestation, accompanied by proteinuria or signs of multi-organ involvement. 2–8% Preterm cases especially linked to later-life CVD risk.
sPE Worsening hypertension in a woman with preexisting CH, plus new-onset proteinuria or organ dysfunction after 20 weeks. 20% of CH cases High risk for maternal and fetal complications
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Abbreviation: EOPE: Early-Onset Preeclampsia.

2.1. Chronic hypertension

CH in pregnancy is defined as systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mmHg diagnosed before pregnancy or before 20 weeks of gestation or persisting beyond 12 weeks postpartum [12]. It affects 5% of pregnant women and increases the risk of complications to the mother and fetus such as preterm birth, intrauterine growth restriction, placental abruption, intrauterine fetal death. The severity and duration of hypertension correlate with the risk of adverse outcomes. Severe hypertension in early pregnancy increases the likelihood of developing sPE by more than 50% [13]. Women with CH during pregnancy exhibit at least a two-fold elevated risk of subsequent CVD, highlighting CH as a significant lifelong CVD risk factor [14].

2.2. Gestational hypertension

GH is diagnosed when BP reaches ≥140/90 mmHg on two separate occasions at least four hours apart after 20 weeks of pregnancy in a previously normotensive individual without proteinuria or systemic involvement. Severe GH confirm GH if it persists after a short interval, warranting immediate antihypertensive treatment. Clinical symptoms are more likely to manifest when BP exceeds 160/110 mmHg, indicating possible end-organ damage [15]. GH has been significantly associated with altered hepatic, renal, and coagulation function in mothers, as well as preterm birth [16]. Furthermore, women with GH have approximately a 1.7-fold increased risk of developing future CVD, indicating a moderately elevated long-term CVD risk compared to normotensive pregnancies [12,17].

2.3. Preeclampsia

PE is a multisystem hypertensive disorder characterized by SBP ≥140 mmHg and/or DBP ≥90 mmHg) after 20 weeks of gestation, accompanied by proteinuria (≥300 mg per 24 hours) and/or evidence of maternal organ dysfunction or uteroplacental abnormalities and neurological symptoms [12]. Women with a history of PE have an approximately twofold increased risk of later-life coronary heart disease, stroke, and cardiovascular-related mortality, and a fourfold increased risk of developing heart failure [18].

2.4. Superimposed PE

sPE occurs in approximately 20% of CH pregnancies and is associated with greater maternal and fetal risks than either CH or PE alone. Diagnosis can be particularly challenging, as hypertension and proteinuria may already be present prior to pregnancy, making it difficult to distinguish sPE from baseline chronic disease [19]. sPE increases the risk of future CVD by about twofold compared to normotensive pregnancies [12,20].

3. Epigenetic mechanisms linking HDP to later-life CVD

Epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs play a critical role in mediating the long-term CVD effects of HDP, through regulation of genes related to blood pressure, inflammation, vascular remodeling, and lipid metabolism as shown in Figure 1 [21]. While maternal blood is the most practical substrate for prognostic biomarker development, placental epigenetic studies were included because the placenta is the primary site of HDP pathology and provides mechanistic context for interpreting blood-based findings. These insights are essential for understanding the biological pathways that connect HDP to long-term CVD risk. Paternal genetic and epigenetic contributions are acknowledged as important but fall outside the scope of this review, which focuses on maternal and placental pathways to maternal CVD outcomes.

Figure 1.

Figure 1.

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Key epigenetic mechanisms regulating gene expression.(A) DNA methylation: Addition of methyl groups by DNA methyltransferases (DNMTs, writers), removal by TET enzymes (erasers), and recognition by methyl-CpG – binding proteins (MBDs, readers) typically results in transcriptional silencing.(B) Non-coding RNAs (ncRNAs): Small nuclear RNAs (snRNAs), small interfering RNAs (siRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) regulate gene expression through transcriptional and post-transcriptional mechanisms.(C) Histone modifications: Histone acetyltransferases (HATs) and histone methyltransferases (HMTs) act as writers, histone deacetylases (HDACs) and histone demethylases (HDMs) as erasers, while reader proteins recognize specific modifications to alter chromatin structure and activate or repress transcription.Created in BioRender. Padidar, K. (2025) https://BioRender.com/0hw8333.

Table 2 summarizes the key epigenetic mechanisms implicated in HDP and their potential contributions to long-term CVD. It highlights studies relevant to maternal cardiovascular outcomes and pathways, with inclusion based on the following criteria: (1) investigation of any HDP, (2) use of biological samples related to maternal health (maternal blood or placenta), (3) exploration of epigenetic mechanisms, (4) application of genome-wide or well-validated approaches, and (5) explicit mention of mechanistic or pathway-level links to CVD.

Table 2.

Epigenetic studies of hypertesnsive disorders of pregnancy linking to maternal CVD risk, based on maternal blood or placental samples.

Gene(s) Epigenetic mechanism Disorder type Tissue type Sample size Sample origin Analysis type Re ference
IL12B, FAS, PIK3R1, IGF1 DNA methylation EOPE Cord blood (neonatal) 12: EOPE,
8: controls		 Offspring Illumina 450K [22]
SORD, DGKI, ICA1 DNA methylation PE Maternal peripheral blood 1: eclampsia, 6 PE, 4: controls, 2 male relatives Maternal WGBS [23]
TBXAS1 DNA methylation PE Maternal blood vessels 7: PE, 5: controls Maternal Illumina 27K, bisulfite assay [24]
GNAS, ZNF331, NAP1L5, FLT4, ZNF831 DNA methylation PE, chronic HT cfDNA PE :5, HT :5, controls: 5 Maternal WGBS [25]
COL12A1 DNA methylation GH, PE Placenta 288: Controls, 8: GH, 5: PE Offspring Illumina 450K; expression data [26]
HIST1H3E, TICAM2, ZNF417 DNA methylation PE and severe PE Placenta 5:PE: 8: severe PE 13:controls Offspring Illumina EPIC (850K) BeadChip [27]
Multiple miRNAs
(e.g., miR-17-5p,
miR-20b-5p, miR-29a-3p
, miR-126-3p, miR-133a-3p
, miR-145-5p, miR-125b-5p,
miR-100-5p)		 Non-coding RNAs   Peripheral blood (maternal, postpartum) 50;GH, 101:PE,35:FGR 89:controls Maternal qRT-PCR [28]
miR-126-3p/miR-146a-5p miR-122-5p Non-coding RNAs PE blood 30:PE
146:controls		 Maternal qRTPCR [29]
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Abbreviations: FGR: Fetal growth restriction, HT: Hypertension, qRT-PCR: Quantitative real-time polymerase chain reaction.

3.1. Epigenetic regulation by DNA methylation in HDP and CVD

DNA methylation, which is a key epigenetic mechanism involved in gene regulation and genomic stability maintenance is the enzymatic addition of methyl groups to cytosines, mainly at CpG dinucleotides by DNA methyltransferases (DNMTs). Dysregulation of genes related to oxidative stress, inflammation, and vascular function has been linked to altered methylation patterns in maternal blood and placental tissue in women with HDP. These epigenetic changes may not only contribute to the pathogenesis of HDP during pregnancy, but also persist postpartum, potentially predisposing affected women to long-term cardiovascular complications [30].

It has been discovered that significant genes in HDP show both global DNA hypomethylation and promoter-specific hypermethylation. Interestingly, a number of these methylation patterns are like those observed in CVD, supporting the idea that a shared epigenetic pathway connects prenatal issues and future CVD [24].

3.1.1. Maternal cfDNA methylation profiles in CH pregnancies and PE

The methylation of maternal cell-free DNA (cfDNA) has been examined recently as a possible early biomarker for HDP. Whole-genome bisulfite sequencing for first-trimester cfDNA profiling has identified DMRs in women who had CH and developed PE in comparison to controls. The considerable overlap in DMRs between these two groups suggests a shared epigenetic vulnerability to vascular dysfunction. Numerous DMRs were mapped to genes like GNAS, ZNF331, and NAP1L5, which are all involved in cardiovascular regulation, imprinting, and epigenetic memory. It was discovered that most methylation signals came from the maternal compartment. The recurrence of these loci across pregnancy-related and CVD highlights their potential as early noninvasive biomarkers. Women who are more susceptible to HDP and CVD may be identified with the help of these cfDNA methylation profiles [25]. The affected twins consistently showed twelve DMRs with methylation variations more than 50%, indicating that epigenetic variability regardless of genetic background may affect susceptibility and long-term CVD risk [9]. A methylation panel was applied to placental DNA from pregnancies with early-onset preeclampsia (EOPET), late-onset preeclampsia (LOPET), intrauterine growth restriction (IUGR), and controls. In the study, discovered that 34 loci were hypomethylated in EOPET, whereas no significant differences were observed in LOPET and only a few in IUGR placentas. Hypomethylation was confirmed by bisulfite pyrosequencing for a variety of sites, with TIMP3 promoter hypomethylation revealing the highest correlation with gene expression. This implies that the primary epigenetic signature of EOPET may be gene-specific hypomethylation, primarily at TIMP3, which is very interesting as a novel biomarker for risk prediction and early diagnosis. Moreover, considering that TIMP3 controls vascular remodeling, angiogenesis, and extracellular matrix turnover, its deregulation may be the connecting point between impaired placentation and the high risk of long-term CVD in women with a history of PE [31].

3.1.2. Placental and offspring DNA methylation changes associated with GH and PE

Placenta- and offspring-derived DNA methylation signatures have increasingly been studied as potential mediators of the developmental origins of cardiometabolic risk in pregnancies complicated by GH. One of the earliest epigenome-wide association studies (EWAS) investigating this link analyzed placental DNA methylation in a cohort of 301 women and identified 24 novel CpG sites associated with SD-BP across pregnancy. Eight of these participants had GH and five had PE, while the others had normotension, it was possible to identify subtle epigenetic variations. Notably, elevated first-trimester BP was linked to hypermethylation near COL12A1, which linked to increased gene expression in the third trimester suggesting a potential functional role in vascular regulation and later cardiometabolic disease [26]. The largest EWAS to date assessed the impact of HDP, including GH and PE, on neonatal DNA methylation. A meta-analysis of 5,242 neonates from 10 cohorts in the Pregnancy and Childhood Epigenetics (PACE) Consortium revealed substantial differential methylation at 26 CpG sites for PE and 43 sites for HDP, with hypermethylation in most cases. These CpG sites were enriched in genes involved in cardiovascular and metabolic pathways. Pathway analysis revealed significant enrichment in biological processes including organ development, regulation of cell communication, and cell differentiation. Key genes included MYLK, IGF2BP1, RARA, ARID5B, and SPARC, suggesting that maternal hypertension may epigenetically influence fetal development and later disease susceptibility [32]. A postnatal study by Julian et al. evaluated peripheral blood mononuclear cells (PBMCs) from children born to hypertensive pregnancies (n = 5) versus normotensive pregnancies (n = 19). Three of the six DMRs that were found inside the genes SMOC2, CTHRC1, and ARID1B, are linked to vascular biology. ARID1B is a chromatin remodeling factor involved in transcriptional control and cardiovascular development, whereas SMOC2 and CTHRC1 are recognized for their roles in angiogenesis and extracellular matrix remodeling [33]. EWAS of 666 term placentas identified 64 DMRs linked to systolic, diastolic, and mean arterial pressure (MAP), with MAP showing the strongest associations. Some effects were mediated by altered stromal-to-syncytiotrophoblast ratios, and functional enrichment revealed genes related to inflammation and lung development, suggesting potential intergenerational impacts [34]. Given that maternal MAP and pulse pressure are established independent predictors of future CVD, this placental methylation signatures may represent an early-life molecular link between HDP and later CVD risk.

3.1.3. DNA methylation alterations in maternal blood in PE

DNA methylation changes in maternal blood have been increasingly recognized as contributors to the development and progression of PE. A study by Mousa et al. identified hypomethylation in the promoter region of the TBXAS1 (thromboxane synthase) gene in maternal vascular tissues from women with PE. This reduction in methylation was associated with elevated TBXAS1 expression, particularly in vascular smooth muscle cells, endothelial cells, and infiltrating neutrophils. Functional assays confirmed that hypomethylation upregulated TBXAS1 in neutrophil-like cells, and that TNF-α exposure further enhanced its expression in vascular smooth muscle cells. These findings suggest a synergistic interaction between inflammatory signaling and epigenetic dysregulation in promoting vascular dysfunction in PE [24]. These findings may also offer a mechanistic explanation for the increased long-term CVD risk seen in women with a history of PE, given the known function of thromboxane pathways in regulating vascular tone and platelet aggregation.

Whole-genome bisulfite sequencing (WGBS) in multiplex families with PE has identified three novel candidate genes SORD, DGKI, and ICA1 that confirmed differential methylation in previously implicated genes such as COL4A1, FLT1, and TGFB3. These genes are involved in oxidative stress regulation, vascular remodeling, and metabolic signaling pathways highlighting their potential relevance to the pathophysiology of PE. This family-based epigenetic approach emphasizes how crucial it is to combine environmental exposures and genetic background in order to identify new methylation targets linked to PE risk [23]. Notably, the biological functions of SORD, DGKI and ICA1 suggest potential mechanistic links between the epigenetic alterations linked to PE and the subsequent risk of CVD.

3.1.4. DNA methylation signatures in placental tissue or cord blood from preeclamptic pregnancies

Extensive DNA methylation alterations have been observed in placental tissue affected from PE. One genome-wide analysis reported 303 DMRs between PE and normotensive placentas, including 214 hypermethylated and 89 hypomethylated regions. These DMRs were associated with transcriptional regulation, Wnt signaling, and cell adhesion genes through functional enrichment. WNT2, SPESP1, NOX5, and ALCAM were among the genes whose hypermethylation was further validated by pyrosequencing, underscoring their significance in PE pathogenesis [35]. These pathways may serve as a mechanistic link between PE alterations and subsequent CVD because they are also essential for vascular dysfunction and hypertension. Fetal endothelial colony-forming cells (ECFCs) from PE pregnancies have also shown stable methylation differences even after in vitro expansion. The affected genes were involved in metabolic regulation, cell cycle control, and cell-cell communication, particularly in pathways overlapping with vascular development. These persistent alterations may contribute to endothelial dysfunction and increased CVD risk later in life [36]. VEGF promoter hypomethylation is associated with increased expression in preterm PE placentas, indicating a compensatory epigenetic response to placental hypoxia. However, methylation was not associated with alterations in FLT1 or KDR expression [37]. Given that these pathways also regulate may be an additional mechanism linking PE to CVD in later life, since these pathways also control vascular tone and endothelial integrity in the systemic circulation. Additionally, there have been repeated reports of changes in the TGF-β signaling system. Genome-wide methylation analysis of placental tissues from women with and without PE showed that more than 80% of important CpG sites were hypomethylated in PE, with the majority exhibiting variations of more than 5% from controls. The substantial enrichment of TGF-β-related genes in these CpGs suggests that this pathway is a key mediator of PE-associated epigenetic alteration [38]. Since angiogenesis-related pathways and TGF-β signaling are essential for both systemic vascular homeostasis and placental vascular remodeling, their epigenetic dysregulation in PE may offer a mechanistic explanation for the developed maternal CVD later in life.

In PE placentas, subtype-specific methylation profiling has also identified transcriptional clusters with unique epigenetic signatures. DMR in canonical and immunological subtypes was found to link to gene expression in pathways like TGF-β signaling, immune response, and metabolism after controlling for fetal sex and gestational age. Nevertheless, a large number of CpG sites did not directly correlate with expression, suggesting the involvement of other regulatory mechanisms [39]. In PE, epigenetic dysregulation of immune-endothelial signaling, angiogenesis, and TGF-β-related pathways not only support placental pathology but also reflect the mechanisms triggering vascular dysfunction in later-life CVD.

3.2. Histone modifications in HDP: epigenetic mediators of vascular and cardiac dysfunction

Histone modifications involved in regulating chromatin structure and gene expression. These post-translational modifications including acetylation, phosphorylation, ubiquitination, and ADP-ribosylation occur mostly on histone tails and modify interactions with transcriptional regulators to change nucleosome positioning and chromatin accessibility [40,41].

Histone acetylation, particularly on lysine residues of histones H3 and H4, is typically associated with transcriptional activation chromatin structure. This process is catalyzed by histone acetyltransferases (HATs) and reversed by histone deacetylases (HDACs). Dysregulated histone acetylation has been linked to a range of cardiovascular pathologies, including coronary artery disease, cardiomyopathy, and cardiac hypertrophy [42,43]. The therapeutic modulation of HATs and HDACs has gained attention as a strategy to reverse epigenetically driven vascular and cardiac dysfunction [44].

3.2.1. Histone modifications in the preeclamptic placenta

Histone alterations brought on by hypoxia have been identified as important modulators of gene expression in the preeclamptic placenta. Histone demethylases, including JMJD1A, are increased under hypoxic stress when HIF-1α binds to hypoxia response elements (HREs). This demethylates H3K9me2, which then triggers the transcription of genes related to placental development and vascular control. Conversely, HIF-1α also induces histone deacetylase 2 (HDAC2), promoting H3 deacetylation and transcriptional repression of genes vital for endothelial homeostasis. Together, these epigenetic shifts under hypoxia contribute to impaired trophoblast invasion, increased inflammation, and increased maternal vascular resistance hallmarks of PE pathophysiology [45]. highlighting a shared epigenetic mechanism that could be responsible for the progression of CVD from PE. Further supporting the role of histone regulation in PE, The epigenetic regulatory role of PPARγ is demonstrated by its modulation in vitro, where its activation results in lower levels of H3K4me3 and H3K9ac, indicating a non-linear interaction with chromatin [46]. The epigenetic changes may not only explain impaired trophoblast invasion but also offer a mechanistic explanation for the increased risk of later-life CVD associated with impacted women, given the known functions of PPARγ in vascular remodeling, inflammation, and lipid metabolism.

Dynamic alterations in histone modifications have also been identified using epigenetic profiling of cytotrophoblasts (CTBs) throughout gestation. Repressive (H3K9me3, H3K27me3) and active (H3K4me3, H3K27ac) changes both decrease approach term in healthy pregnancies, suggesting a natural epigenetic silencing mechanism. In contrast, severe PE is characterized by elevation of H3K27ac in CTBs, particularly at promoters of genes that are normally downregulated later in gestation. This abnormal retention of active chromatin states may lead to prolonged overexpression of inflammatory and angiogenic genes, contributing to placental dysfunction and maternal vascular complications in severe PE [47]. This study revealed that changes in CTBs histone modifications, specifically abnormal overexpression of H3K27ac, are associated with severe PE. This suggests a potential epigenetic link between placental disease linked to PE and consequent higher maternal CVD.

3.3. Noncoding RNAs as epigenetic regulators in HDP and CVD

Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), are increasingly recognized as key regulators in the pathogenesis of HDP and its impact on CVD [48]. These molecules regulate gene expression through various mechanisms such as chromatin remodeling, epigenetic alteration, and transcriptional and post-transcriptional regulation [49]. As post-transcriptional modulators of gene expression, miRNAs play a crucial role in the development, hypertrophy, fibrosis, and regeneration of the heart [50,51]. Their expression in cardiovascular tissues is tightly regulated and can be influenced by upstream epigenetic mechanisms such as histone modifications and DNA methylation [52]. For CVD, particularly myocardial infarction and heart failure, miRNAs have become feasible diagnostic and prognostic biomarkers due to their stability and disease-specific expression patterns [53]. Furthermore, preclinical studies suggest that therapeutic targeting of specific miRNAs, including miR-21, miR-133, and miR-28 May propose novel approaches to the treatment of diseases like dyslipidemia and heart failure [49,54]. In placental tissue from PE, miR-155 has been discovered to be markedly elevated. It inhibits endothelial nitric oxide synthase (eNOS), which hinders trophoblast migration and encourages placental vascular dysfunction. MiR-155 overexpression decreases cell migration and invasion, but its inhibition partially restores these activities through eNOS upregulation, according to in vitro experiments utilizing HTR8/SVneo human trophoblast cells. This provides mechanistic insight into placental failure in PE [55]. Even though this study focused on placental pathology in severe PE, the mechanism by which miR-155 suppresses eNOS and impairs endothelial function is particularly interesting because decreased eNOS activity and the resulting endothelial dysfunction are well-established contributors to increase the risk of CVD in women in the long term. circRNAs measured in early pregnancy may serve as promising noninvasive biomarkers for predicting GH. In a two-cohort study, first-trimester plasma levels of miR-208b-3p and miR-26a-1-3p, when combined with MAP, improved the predictive performance for GH compared to clinical parameters alone. Both miRNAs are implicated in cardiovascular-related signaling pathways, suggesting their involvement not only in early risk stratification but also in the pathophysiological mechanisms linking GH with future CVD [56]. Dysregulation of miRNA expression has also been reported in decidua-derived mesenchymal stem cells (dMSCs). A study identified at least nine miRNAs showed a > 2-fold increase in expression, whereas 21 miRNAs were upregulated and 28 downregulated in PE samples [57]. Although this study focused on decidual MSC dysfunction in PE, the miRNA-mediated suppression of VEGFA and related angiogenic pathways emphasizes mechanisms of vascular remodeling that probably link PE to long-term CVD risk. Hromadnikova et al. identified seven miRNAs (e.g., miR-20a-5p, miR-143-3p, and miR-146a-5p) that were upregulated in women with GH [28]. Additionally, four miRNAs miR-17-5p, miR-20b-5p, miR-29a-3p, and miR-126-3p were found to be upregulated in both GH and PE [28]. Dysregulation in women with a history of GH or PE revealed a mechanistic bridge to the elevated risk of CVD later in life.

4. Epigenetic age acceleration: a composite biomarker of long-term CVD

There is growing evidence that the long-term cardiovascular effects of HDP are mediated in large part by the epigenetic landscape. One of the most promising advances in this field is the development of epigenetic clocks, which estimate biological age based on DNA methylation patterns across the genome.

Unlike the chronological age, the epigenetic age captures the cumulative impact of genetic, environmental, and physiological stressors. The difference between an individual’s epigenetic and chronological age has been associated with increased risk of various age-related diseases, including CVD, even in relatively young populations. Comparing second-generation clocks like PhenoAge and GrimAge to older models, the former have demonstrated better prediction power for physical decline, morbidity, and mortality. Accelerated epigenetic aging may reflect persistent vascular and metabolic stress that underlies the elevated CVD observed years after pregnancy. Thus, epigenetic age holds potential not only as a risk stratification tool, but also as a mechanistic biomarker that informs individualized monitoring and preventive strategies [58]. Although the chronological ages of the women in this study were identical, those with PE showed a significantly accelerated DNA methylation age in comparison to normotensive controls. The PE group consistently showed higher ΔDNAmAge and more epigenetic and intrinsic age acceleration among epigenetic clock models, including Hannum, PhenoAge, and Wu. These alterations were further accompanied by changed epigenetic estimations of vascular biomarkers as well as immune cell profiles, including decreased B cells and natural killer (NK) cells. These results collectively imply that epigenetic age acceleration may represent early immunological and vascular changes that predispose women with HDP to CVD in the future, in addition to reflecting long-term biological stress. This demonstrates DNAmAge’s potential as a comprehensive biomarker for the long-term cardiovascular health of mothers [59].

5. Limitations and challenges

Despite their potential, several limitations hinder the immediate clinical application of epigenetic markers for CVD risk assessment following HDP.

5.1. Limited longitudinal evidence

Most existing studies linking epigenetic changes to cardiovascular outcomes are cross-sectional, limiting the ability to infer temporal dynamics or causality. Long-term prospective cohorts are required to determine whether these epigenetic alterations are stable over time or vary in response to physiological or environmental changes [60,61].

5.2. Lack of reproducibility

Epigenetic profiles are inherently tissue-specific, as gene regulation varies according to cellular function and development. While such variation is biologically expected, it presents methodological challenges when comparing findings across studies that utilize different sample types. Integrating sample selection and interpretation frameworks is necessary to improve clinical translation and reproducibility [62].

5.3. Lack of standardized analytical methods

The evaluation of epigenetic alterations, particularly DNA methylation, can be carried out using a variety of laboratory platforms, including bisulfite sequencing and methylation arrays. These data are often analyzed through approaches like EWAS. However, the lack of standardized protocols and reliable validation across different populations hinders the routine clinical application of epigenetic biomarkers [63].

5.4. Limited therapeutic interventions

Although promising, epigenetic-based treatments in cardiology are still in the early stages of development. To confirm the safety and effectiveness of epigenetic-based therapies for postpartum CVD risk, more clinical studies are necessary [64].

5.5. Limited integration with conventional clinical markers

Traditional predictors like pregnancy history, blood pressure, lipid levels, and family history are still essential for the stratification of CVD. At present, epigenetic biomarkers probably will not be able to solely replace these well-known tools in clinical practice. On the other hand, the potential of such markers could be in aiding the existing models by uncovering the molecular signatures of the pathways that connect hypertensive disorders in pregnancy to CVD. Recent evidence supports this complementary role. For instance, Desiderio et al. reported that DNA methylation – based scores (e.g., DNAmCVDscore, EpiScore) might exceed the performance of standard models such as SCORE2 and Framingham when predicting CVD [65]. Similarly, Gao et al. underlined that including epigenetic data along with traditional risk factors not only improved but also made the prediction of cardiometabolic outcomes more accurate [66].

5.6. Lack of consistent evidence

The latest research has shown that the occurrence and extent of epigenetic age acceleration after HDP vary, depending on the tissue and the type of epigenetic clock. For instance, using placental tissue reported no significant differences in biological age, however, research on maternal blood revealed an increase in the rate of aging with second-generation DNA methylation clocks. These differences emphasize the importance of longitudinal validation and sample types for which they have been standardized, before dependable clinical translation can be assured [67,68].

6. Conclusion

Understanding the CVD disparity landscape is vital, especially in women had HDP. Such women are at increased risk for long-term effects of CVD that need special strategies including early detection and intervention. Epigenetics shows promise in determining the most relevant genes that are activated during vascular dysfunction, inflammation, and metabolic pathways, all of which are critical players in the pathogenesis of CVD. In the foreseeable future, DNA methylation and related markers are most likely to enhance, rather than supplant, conventional risk stratification after HDP. The combination of epigenomic screening strategy and other omics-level technologies like transcriptomics, proteomics, and metabolomics serve as a strong platform for a more precise diagnosis in medicine. Additionally, the progression of epigenome editing especially those of CRISPR-related technologies, exemplify the certainty of transforming the disease-related epigenetic markers, consequently, opens up the possibilities of having highly targeted therapeutic interventions. Moreover, it’s possible that epigenetic therapy stands out as the primary driving force of the epigenetic influence to simulate the traditional CVD risk factors and facilitate for the personalized medicine treatments. This change in the concept brings the power to change CVD prevention and treatment by applying a more targeted and proactive approach to women’s heart health. However, several critical aspects need to be in place before epigenetic applications become a commonplace clinical tool. Significant challenges include the requirement for thorough validation, methodological standardization, and the development of reasonable plans for widespread implementation. To overcome these obstacles and convert epigenetic discoveries into useful clinical applications, long-term research will be crucial. Insights into site-specific methylation patterns can be obtained through large-scale epigenomic screening, allowing for earlier interventions and more tailored treatment plans.

7. Future perspective

Future studies should prioritize prospective cohort designs or nested case-control studies within a cohort over retrospective approaches to establish causal relationships and minimize biases. Additionally, a standardized classification of HDP should be consistently used across studies to improve comparability. To properly select the control group for any given study, gestational age is not the only factor to be considered but also the health condition of the subjects (normal blood pressure pregnancy), and the presence or absence of individuals with preexisting chronic hypertension and other co-morbidities (e.g., diabetes) which are the main issues that distort the interpretation of epigenetic alterations [69].

The dynamic nature of DNA methylation patterns along with their potential variation over time indicates that the collection of biological samples (longitudinal research) from maternal peripheral blood at different stages of pregnancy (first, second and third trimesters), delivery, and postpartum will play a crucial role in distinguishing transient from persistent epigenetic changes [25]. Therefore, the correct selection of tissues and the control of cellular and clinical heterogeneity will be the main part of finding the best way to increase the accuracy of the study and make the obtained results further reproducible [70].

EWAS that use bead-chip array technologies to research the methylation pattern of HDP-relevant genes can be of great help in the discovery of new hypotheses. Another method, targeted bisulfite sequencing, involves the examining of specific sites of methylation in the DNA and can be very helpful in these studies where such regions are relevant to HDP pathophysiology. The integration of gene expression analyses alongside DNA methylation data will provide valuable insights into the functional consequences of epigenetic modifications and their role in the progression from HDP to long-term CVD risk. Furthermore, validation of the findings in distinct independent and ethnically diverse cohorts is necessary to the enhancement of the generalizability and clinical applicability consequences of results [25,70]. Transparency in research is necessary to make a study repeatable and support subsequent meta-analyses. The technical aspects of the study should be covered in full, the raw datasets should be made available to open-access data platforms, and batch effects and other metadata information should be explicitly introduced if needed. Future studies can improve the relevance of epigenetic biomarkers in predicting CVD risk after HDP by putting these ideas into practice. This will pave the way for early screening methods and tailored therapies for women who are at risk [34,71].

Funding Statement

This manuscript was funded by the Australian National Health and Medical Research Council (NHMRC) [APP2001203] and Tasmania Graduate Research Scholarship (TGRS) from the University of Tasmania, Hobart, Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article highlights

Women with HDP, mainly PE, have a higher long-term risk of CVD, which emphasizes the need for early detection and prevention strategies.

  • Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNAs, play critical roles in linking HDP to future CVD risk through pathways regulating inflammation, vascular function, immune regulation, and metabolic homeostasis pathways through epigenetics.

  • EWAS have identified DMRs and CpG sites link to HDP and cardiovascular traits, offering candidate biomarkers for early stage and disease monitoring.

  • Accelerated epigenetic aging, as measured by DNA methylation-based clocks (GrimAge, PhenoAge), is linked to HDP and increased CVD risk, which indicate systemic and vascular age.

  • Several noncoding RNAs (miR-210, miR-155, miR-26a-1-3p, lncRNA MALAT1) are altered in HDP and are involved in endothelial dysfunction, inflammation, placental insufficiency, and cardiovascular remodeling.

  • Interpretation of epigenetic findings remains challenging due to tissue specificity, batch effects, inter-individual variability, and methodological heterogeneity in sample types, platforms, and statistical pipelines.

  • Future studies should use standard HDP classification, choose correct control groups, and make use of the longitudinal design to figure out the stable and functional epigenetic biomarkers that are also clinically significant.

Author contributions

Kimiya Padidar: Resources: Investigation, Visualization, Writing – original draft, Writing – review.

Eric K. Moses: Conceptualization: Funding Acquisition, Supervision, Writing – review & editing

John Blangero: Conceptualization, Funding Acquisition, Writing – review & editing

Shaun Brennecke: Conceptualization, Funding Acquisition, Writing – review & editing

Phillip E. Melton: Conceptualization, Funding Acquisition, Resources, Supervision, Writing – review & editing

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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