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Review

Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction)

by
Ja-Young Kwon
1,2 and
Yong-Sun Maeng
1,2,*
1
Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University Health System, Seoul 03722, Republic of Korea
2
Department of Obstetrics and Gynecology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 03722, Republic of Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(8), 4444; https://doi.org/10.3390/ijms25084444
Submission received: 14 March 2024 / Revised: 12 April 2024 / Accepted: 17 April 2024 / Published: 18 April 2024
(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
Browse Figure
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Abstract

:
Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in circulation have been linked to human cardiovascular disorders. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, the present literature suggests that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system as they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare—through the assessment of their quantity, differentiation potency, angiogenic activity, and senescence—the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems (preeclampsia, gestational diabetes mellitus, and fetal growth restriction). This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development.

1. Introduction

A new paradigm for endothelial regeneration involving angiogenesis and vasculogenesis was established in 1997 with the identification of endothelial progenitor cells (EPCs) by Asahara et al. [1]. According to reports, endothelial progenitor cells (EPCs) are essential for the development of new blood vessels and the restoration of endothelial dysfunction [2,3]. EPCs are mostly found in the stem cells of bone marrow, while some are also present in the peripheral blood and cord blood [4,5]. EPCs are mobilized from bone marrow cells into the blood circulation in response to chemokine stimulation following a peripheral blood vessel injury or ischemic stroke. After injury, ischemia, or hypoxia, EPCs deposit in the endothelium to aid in tissue healing, as seen in both human and animal models [6,7,8]. Research has revealed the involvement of EPC in the processes of postnatal vasculogenesis, wound healing, myocardial infarction, and limb ischemia [9,10]. Growth factors such as vascular endothelial growth factor (VEGF)/KDR, granulocyte colony-stimulating factor (G-CSF), insulin-like growth factor 2 (IGF2), stromal cell-derived factor-1 (SDF1), hepatocyte growth factor, soluble intercellular adhesion molecule, interleukin-6 (IL-6), and endothelial nitric oxide synthase (eNOS) mediate EPC mobilization and differentiation in ischemic regions [11,12,13,14].
A crucial finding is that the quantity and function of endothelial progenitor cells (EPCs) are reduced as a result of senescence in conditions involving endothelial dysfunction, such as diabetes mellitus and cardiovascular disease [15,16,17,18], where the EPC count is a reliable indicator of future cardiovascular events [19]. Accelerated aging of these cells has also been linked to decreased EPC activity and number [20,21,22]. These data led to the hypothesis that diseases associated with endothelial dysfunction might be caused by the reduction of circulating EPCs.
Preeclampsia (PE) and intrauterine growth restriction in particular are regarded to be pathogenesis-related conditions that are influenced by aberrant vasculature and impaired endothelial function on both the maternal and fetal sides. The etiology of abnormal vessel development could perhaps result from decreased EPC function or bioavailability. Consequently, these pregnancy problems may be a result of impaired EPC function.
Pregnancies affected by preeclampsia or fetal growth restriction have been found in multiple studies to have a decreased number and abnormal function of cord blood-derived EPCs [23,24,25].
When the fetus’s growth-constrained, PE is linked to poor chorionic villous development and poor fetoplacental angiogenesis [26]. Significant decreases in cord blood EPCs and cord plasma free VEGF, which is known to be involved in EPC mobilization, were observed in severe preeclampsia [27]. Furthermore, in comparison with the normally derived EPCs, the preeclampsia-derived CD133+/C-kit+/Lin− EPCs (CKL− EPC) showed reduced out-growing endothelial cell (OEC) migration, adhesion, and tube formation activities, as well as delayed differentiation times and a significant decrease in the number of generated OEC colonies [23].
Maternal hyperglycemia caused by glucose intolerance that initially manifests during pregnancy is known as gestational diabetes mellitus (GDM). Hyperglycemia inhibits the clonogenic growth of cord blood endothelial colony-forming cells (ECFCs) by causing premature senescence [28]. Additionally, ECFCs exposed to a diabetic environment during pregnancy display lower proliferation and premature senescence [29,30].
One pregnancy condition that is clinically relevant is fetal growth restriction (FGR). A birth weight that is at or below the third centile for gestational age and abnormal dopplers are commonly used to determine FGR [31]. When compared with the normal control group, the fetal EPC numbers in the FGR group were considerably lower. The FGR group had a longer EPC differentiation period and significantly fewer OEC colonies [32,33].
These pregnancy diseases are linked to both maternal and perinatal morbidity as well as poor long-term results for the offspring, making them one of the major concerns for fetal development and the health of the offspring. Numerous research studies have demonstrated that children exposed to prenatal disorders are more vulnerable to long-term conditions such as obesity, metabolic syndrome, type 2 diabetes, and hypertension, all of which are subtypes of cardiovascular disease (CVD) [23,27,34,35,36,37,38].
In this review, we highlighted the role that fetal EPCs may play in the increased life-long cardiovascular risk that is associated with preeclampsia (PE), gestational diabetes (GDM), and fetal growth restriction (FGR), as well as their number, senescence, differentiation, and angiogenic function in the pathophysiology of these conditions.

2. Preeclampsia

2.1. Number of EPC in Preeclampsia

About 5–8% of pregnancies are complicated by preeclampsia (PE), a pregnancy disease with unclear etiology that greatly increases maternal and neonatal morbidity and mortality [39]. When the fetus is growth-constrained, PE is linked to poor chorionic villous development and fetoplacental angiogenesis [26,40]. Normal fetal growth is associated with increased branching angiogenesis and hyperramified capillary loops with uneven and narrow lumina [41,42]. It is appropriate to speculate that disturbances in EPCs may be implicated in this vasculopathy given their involvement in vascular homeostasis.
Recent research by Fadini et al. [43] revealed a decreased number of circulating EPCs in patients with chronic hypoxia with severe lung disease, and the reduction was related to impaired alveolo-arterial diffusion. Studies by Vasa et al. [15] and Hill et al. [44] also demonstrated a negative correlation between circulating EPCs and coronary artery disease risk factors. These data led to the hypothesis that diseases associated with endothelial dysfunction might be caused by the reduction of circulating EPCs. Additionally, a number of animal studies and modest clinical trials have shown the therapeutic efficacy of EPC transplantation in tissue ischemia, indicating a potential role for EPCs in the management of vascular disease [45,46,47,48].
We examined the circulating EPC number of umbilical cord blood in the normal and preeclamptic groups in earlier research. Table 1 displays the features of the patient. There were no discernible variations between the two groups’ gestational ages at delivery or patient ages. On the other hand, the severe preeclampsia group had a much greater rate of small for gestational age (SGA), lower birth weight and a significantly higher maternal systolic blood pressure. When compared with the normal group, the preeclampsia group’s circulating EPC number in the umbilical cord blood significantly decreased. [27,49,50]. Concurrently, the same group’s umbilical cord plasma showed a decline in the free VEGF level. Nevertheless, the rise in sVEGFR-1 did not attain statistical significance [27]. Additionally, Xia et al. demonstrated that, in the preeclampsia group as opposed to the normal group, there is a significant decrease in the placental/fetal circulating EPC numbers (median, 200; range, 100–440 cells/mL vs. 390; 270–440 cells/mL, p < 0.001) [51]. Following the in vitro culture, the preeclampsia group’s EPC counts likewise declined (19.5; 5.0–32.0 vs. 39.5; 31.2–52.0 EPC/ × 200 field; p < 0.001). There was an inverse correlation between the level of soluble fms-like tyrosine kinase 1 (sFlt-1) in cord blood and both circulating and cultured EPC [51].
These results imply that in cases of severe preeclampsia, ineffective EPC mobilization from the bone marrow due to a reduction in free VEGF as a consequence of increased binding to excess sVEGFR-1 is the cause of the decreased EPCs in the umbilical cord blood. We were unable to show a correlation between decreased cord plasma free VEGF and increased cord plasma sVEGFR-1 despite the fact that the EPC count was lower in the cord blood from preeclamptic pregnancy.

2.2. Senescence of EPC in Preeclampsia

Senescent cell burden in adipose, skeletal muscle, kidney, and skin tissues is low in young people but rises with age [52,53,54]. Specifically, among the many diseases linked to elevated senescent cell load are parts of the metabolic syndrome, such as diabetes, atherosclerosis, hypertension, and abdominal obesity [55,56,57].
Maternal vascular/endothelial malfunction and placental deficient angiogenesis are the hallmarks of preeclampsia [58,59]. Numerous investigations revealed that vascular endothelial dysfunction is significantly influenced by cellular senescence [60,61,62,63].
Senescence of EPC in maternal circulation associated with preeclampsia has been recently observed. Patients (maternal age: 32.4 ± 1.4) with preeclampsia had a considerably higher rate of cellular senescence (33.9%) than controls (maternal age: 31.8 ± 2.1) (22.9%; p < 0.05) [64]. Furthermore, patients diagnosed with preeclampsia were separated into two subgroups: those with C-reactive protein (CRP) levels less than or equal to 0.1 mg/dL (n = 4) and those with CRP levels greater than or equal to 0.1 mg/dL (n = 4). Cellular impairment of EPCs was linked to serum levels of C-reactive protein (CRP), a sign for systemic inflammation. It is interesting to note that the CRP-positive group had higher median values for cellular senescence than the CRP-negative group did; however this difference did not reach statistical significance (43.5% and 33.3%, respectively; p = 0.12) [64].
Additionally, the in vitro features of EPC cellular aging were evaluated using the senescence-associated β-galactosidase (SA-β-gal) activity assay for fetal EPCs obtained from women with preeclampsia and normal pregnancies.
Compared with normal pregnant women (32.4%; range, 25.2–39.6%; p < 0.001), patients with PE had a considerably higher number of SA-β-gal-positive cells (55.8%; range, 49.5–62.1%) [49]. These results show that endothelial dysfunction may be linked to the cellular aging of fetal EPCs in preeclamptic individuals.

2.3. Differentiation Activity and Angiogenic Function of EPC in Preeclampsia

In addition to the immediate implications on the fetus, such as preterm or fetal growth restriction, maternal preeclampsia may also result in potential problems with the fetus’s vascular health due to effects sustained in utero. The findings of several additional studies, which have previously documented a higher prevalence of adult-onset metabolic and cardiovascular disorders, including hypertension, cardiovascular disorders, cerebrovascular disorders, impaired neural development, type 2 diabetes, metabolic syndrome, and hypercortisolism in people born to preeclamptic women, provide support to this [65,66,67,68,69].
Because EPCs are endothelial cell progenitors and can therefore regulate angiogenesis, neovascularization, and vasculogenesis postnatally [46,70], it is likely that a variety of vascular disorders are caused by their malfunction. Indeed, previous research has demonstrated a decrease in the quantity of circulating EPCs in vascular and metabolic conditions, including metabolic syndrome, coronary artery disease, diabetic vasculopathy, atherosclerosis, and systemic lupus erythematosus [71,72,73,74,75]. It has been demonstrated that preeclampsia, which can be defined as a hypertensive disease, is linked to a lower level of circulating EPCs in peripheral blood vessels [76].
Because cord blood is a part of the fetal circulation, the angiogenic property of cord blood EPCs most likely resembles the fetus’s total angiogenic potential. The findings of an earlier investigation, which demonstrated that OECs differentiated from cord blood EPCs and had angiogenic potential [77], are consistent with this. It is known that there are fewer cord blood-derived EPCs in preeclamptic pregnancies and that the few EPCs that are found are primarily senescent, despite the fact that little research has been conducted to date to examine the function of fetal EPCs exposed to preeclampsia [27,49,78,79].
Proliferation, migration, and vasculogenesis were all markedly compromised in the AC133+/KDR+ EPC from the cord blood of preeclamptic individuals [51]. Furthermore, compared with cord blood-derived CKL− EPCs from normal pregnancy, preeclampsia pregnancy-derived cord blood CKL− EPCs and the resulting differentiated OECs showed decreased differentiation capacity and angiogenic function, respectively [23]. Immature differentiation of OEC for angiogenesis is shown by diminished migration, adhesion, and tube formation function of preeclampsia-generated OECs in comparison with normal OECs. Moreover, exposure to normal serum conditions (17 days) did not restore the preeclampsia-derived CKL− EPCs’ reduced differentiation potency, indicating that their impaired function might be irreversible [23]. Conversely, CKL− EPCs produced from normal donors were able to differentiate even in the presence of preeclamptic serum (13 days) in culture media (vs. control serum: 8 days) [23]. Therefore, via influencing fetal vasculogenic/angiogenic function, the preeclamptic intrauterine environment appears to permanently alter pathways that significantly regulate and maintain fetal vascular health.
Environmental factors can induce permanent alterations in gene expression and/or protein function through a common process known as epigenetic modifications. A high frequency of transcriptionally competent yet changed genes, characterized by both active and repressive histone modifications linked to significant processes of differentiation and development, is a defining feature of stem and progenitor cells [80]. H3K4me3 and H3K9me3 levels were observed to be lower in the CKL− EPCs obtained from preeclampsia in the previous investigation [23]. Histone alterations have the potential to trigger pro-angiogenic (H3K4me3) and/or repressive (H3K9me3) signaling pathways, perhaps signifying a change in the proangiogenic/antiangiogenic balance in favor of anti-angiogenesis.
Collectively, these results demonstrated that the differentiation potency of cord blood EPCs produced from preeclampsia was irreversibly lower than that of EPCs derived from normal cases. Also, there was a notable reduction in the angiogenic potential of OECs that differentiated from EPCs produced from preeclampsia. To determine if the reduced function of preeclampsia-derived cord blood EPCs lasts after delivery and to clarify the mechanisms by which preeclampsia-induced effects on EPCs affect the exposed fetus’s long-term vascular health, more research is necessary.

3. Gestational Diabetes Mellitus (GDM)

3.1. Number of EPC in GDM

Maternal hyperglycemia caused by glucose intolerance that initially manifests during pregnancy is known as gestational diabetes mellitus or GDM. It has been steadily rising globally along with the increase in obesity among women of reproductive age and older mothers, complicating 5–31.5% of pregnancies [81,82]. Europe had the lowest prevalence of GDM (median 5.8%; range 1.8–22.3%), while the Middle East and North Africa had the highest overall, with a median estimate of 12.9% (range 8.4–24.5%). Southeast Asia, Western Pacific, South and Central America, Africa, and North America and the Caribbean followed with 11.7%, 11.2%, 8.9, and 7.0%, respectively, as the next highest prevalence regions. Different GDM diagnosis criteria were applied to the prevalence estimates, which varied greatly across the Western Pacific area, ranging from 4.5% in Japan to 25.1% in Singapore. The prevalence of GDM varied greatly throughout Europe as well; according to the WHO 1999 and the modified International Association of Diabetes and Pregnancy Study Groups criteria, Norway had the highest prevalence (median 22.3%; range 13.0–31.5%), while Ireland had the lowest prevalence (1.8%, according to the National Institute for Health and Care Excellence criteria) [82].
Offspring of women with gestational diabetes mellitus (GDM) are more likely to develop obesity, metabolic syndrome, and cardiovascular disease. A growing amount of research indicates that intrauterine hyperglycemia affects endothelial function in several fetal tissues and permanently changes genes’ epigenetic alterations.
Reduced number and impaired function of EPCs were shown in patients with endothelial dysfunction, and impaired EPC-mediated vascular repair allows for further progression of vascular disease. This is because the number of EPCs and their functional capacity determine the maintenance of endothelial homeostasis and de novo vessel formation [83,84,85,86]. Cord blood-derived EPCs, which are also referred to as fetal EPCs, can play a role in the development of the fetal vasculature and preservation of vascular integrity. As a result, dysfunction of these fetal EPCs may be a reflection of stem cell damage, which may lead to vascular dysfunction in the offspring later in life. Nevertheless, it is still unclear if fetal EPC dysfunction is a result of intrauterine hyperglycemia driven on by gestational diabetes mellitus (GDM) and what the underlying mechanisms involve.
EPCs have been demonstrated to be reduced in diabetes [16] and play an essential role in the neovascularization process that occurs following damage. When comparing the amount of maternal EPCs isolated from GDM with a normal pregnancy, Penno G et al. found that there was a substantial decrease in circulating EPCs in GDM [83]. Additionally, compared with non-diabetic patients, GDM patients had a statistically significant decrease in the percentage of circulating EPC from maternal blood (0.26% vs. 0.41%, respectively; p < 0.05) [87]. According to Gui J et al., there was a decrease in the number of progenitor cells called endothelial colony-forming cells (ECFCs) generated from umbilical cord blood in an intrauterine environment that was diabetic as compared with healthy pregnancies [88]. In GDM pregnancies, the average number of cord blood ECFC colonies appearing in culture was substantially lower (GDM: 2.94 ± 1.66, uncomplicated pregnancies: 5.83 ± 3.41, p = 0.04). In GDM pregnancies, the average days to first appearance of colonies appeared slightly later (GDM: 11.06 ± 4.14, n = 18; uncomplicated pregnancies: 9.95 ± 4.31), but not substantially later (p = 0.43). For ECFCs from GDM pregnancies, the population doubling period was much longer (GDM: 4.17 ± 1.23 days, uncomplicated pregnancies: 2.31 ± 0.43 days, p = 0.02). Colony count, colony appearance time, and population doubling times did not significantly correlate with any other patient variables [88].
Although there was a difference in umbilical cord EPCs between GDM patients and control patients, it was not statistically significant (1.76% vs. 1.46%, respectively) [87]. Furthermore, in our earlier research, the quantity of fetal EPCs produced from cord blood did not alter in GDM pregnancies. These results suggest that prenatal exposure to GDM does not affect the quantity of fetal EPCs, and more research is required.

3.2. Senescence of EPC in GDM

The function of EPCs may be reduced by premature senescence associated with gestational diabetes mellitus (GDM) [89,90]. In tissue stem cells, aging is a universal, progressive, and irreversible loss of function [91]. Furthermore, diabetes has been frequently linked to lower levels of circulating EPCs [92,93,94,95]. Endothelial progenitor cells (EPCs) in circulation are crucial for vascular regeneration. Nevertheless, it is still unclear how high hyperglycemia (HG) causes cord blood EPC aging. According to Wu et al. and Ingram et al., HG markedly raised the proportion of cord blood CD34+ EPC senescent cells [90] and cord blood endothelial colony-forming cells (ECFCs) that underwent premature senescence [29], respectively. Additionally, we examined the impact of GDM on fetal EPC senescence in our earlier research, and the results indicated a considerable rise in SA-β-gal positive CKL− EPCs. These results show that endothelial dysfunction may be linked to the cellular aging of fetal EPCs in GDM patients.

3.3. Differentiation and Angiogenic Function of EPC in GDM

Because GDM is linked to both maternal and perinatal morbidity as well as unfavorable long-term effects in offspring, it is one of the major issues for fetal development and offspring health. Numerous studies have revealed that children exposed to gestational diabetes mellitus (GDM) are more vulnerable to long-term conditions such obesity, metabolic syndrome, type 2 diabetes, and hypertension, all of which are subtypes of cardiovascular disease (CVD) [34,35,36,96,97].
Several investigations have indicated that pregnancies complicated by preeclampsia or fetal growth restriction were associated with a lower number and abnormal function of cord blood-derived EPCs [23,24]. Nevertheless, it is yet unclear if intrauterine hyperglycemia brought on by GDM influences fetal EPC development and angiogenic activity.
According to Gui J et al., compared with those from healthy pregnancies, the number and function of endothelial colony-forming cells (ECFCs) produced from umbilical cord blood were decreased in a diabetic intrauterine environment, including proliferation, migration, and tube formation [88,98]. They further showed that long-term cardiovascular disorders in the offspring of GDM pregnancies may be linked to lower sirtuin (SIRT) expression and activity in fetal ECFCs and human umbilical vein endothelial cells (HUVECs) from GDM pregnancies [99].
Based on prior research, we postulate that intrauterine exposure to gestational diabetes mellitus (GDM) induces endothelial dysfunction by modifying the function of fetal endothelial progenitor cells (EPCs) via epigenetic modifications in gene expression, eventually affecting the offspring’s subsequent developmental processes [30,87,100,101].
Growing data indicate that the development of diabetes-related vascular disease in progeny is influenced by epigenetic changes through DNA methylation in GDM [102,103,104,105,106]. Genomic stability and gene expression are controlled by DNA methylation. In our investigation, we discovered a negative correlation between hypomethylation and PCDH10 mRNA expression in OECs produced from GDM EPCs and OECs derived from N-EPCs subjected to high glucose levels. According to these findings, promoter hypomethylation is the main regulatory mechanism for fetal EPCs exposed to high glucose levels or GDM to express PCDH10 more than normal, which ultimately results in abnormal vascular health in the progeny. Furthermore, additional cohort studies are required to verify if these modifications continue to influence the offspring’s vascular health later in life. Also, additional research on angiogenesis-related genes like ROBO1, IGFBP1, and PCDH7 may be attempted in regard to the gene expression study of OECs from GDM EPCs. The objective of our study was to explore the programming effects of GDM on fetal EPCs and clarify the underlying mechanisms that may be associated with unfavorable outcomes in progeny. We used a cell migration, adhesion, tube formation, and proliferation assay to measure the angiogenic activity of OECs that were differentiated from cord blood-derived EPCs in order to investigate at how GDM affected the fetal EPCs. When compared with normal EPCs, GDM EPCs showed comparable differentiation activity in terms of both number and time of differentiation to OECs [107]. However, GDM OECs demonstrated significantly lower migration capacity, fibronectin adherence, tube formation, and proliferative activity [107].
Fetal EPCs from normal pregnancies were grown in high glucose (30 mM) during differentiation into OECs in order to mimic an intrauterine hyperglycemic circumstance. These cultures were then compared with those cultured in normal glucose (5 mM). Similar to GDM EPCs and GDM OECs, OECs differentiated by exposure to high glucose (HG) had reduced capacity in cell migration, adhesion, tube formation, and proliferation compared with those under normal glucose (NG) conditions, even though there was no discernible difference in the differentiation from EPCs to OECs between NG and HG conditions [107].
In addition, we identified a number of genes linked to decreased fetal EPC function in GDM and discovered epigenetic modifications affecting gene expression to further comprehend the pathology of endothelial dysfunction in GDM-exposed offspring.
These results showed that, whereas fetal EPCs exposed to GDM can differentiate into OECs under normal circumstances, in utero exposure to GDM reduces the angiogenic potential of OECs, including migration, adhesion, tube formation, and proliferation. It makes sense to assume that an intrauterine hyperglycemic environment at crucial stages of fetal vascular development causes persistent damage to the offspring’s vascular system.

4. Number and Senescence of EPC in FGR

One pregnancy complication that is clinically relevant is fetal growth restriction (FGR). A birth weight that is at or below the third centile for gestational age and abnormal dopplers is commonly used to determine FGR. [31] The fact that 13% of instances do not exhibit postnatal catch-up growth is the reason for the growing interest in FGR [108]. Up to 5% of pregnancies may be affected by the common condition known as FGR, which has a significant morbidity and mortality rate. Low birth weight for gestation babies are more likely to have long-term developmental disorders as well as neonatal morbidity and mortality [37]. A significant risk of perinatal problems is often linked to FGR [109,110]. An increasing amount of research on animals and epidemiology has shown that the effects of FGR persist throughout adulthood [38]. The majority of FGR cases are idiopathic, meaning their cause is unclear, and treatment approaches are ineffective [111]. However, an important proportion of cases, most cases defined as fetal growth restriction, are related to placental insufficiency and dysfunction. Adult disorders like diabetes mellitus and cardiovascular disease have been the focus of EPC-related research up to now. In actuality, fetal blood contains a higher concentration of EPCs than adult blood does, and pathologic diseases related to endothelial cells, such as FGR and preeclampsia, provide a serious clinical problem during pregnancy.
In adulthood, an increasing amount of research indicates that endothelial dysfunction-related disorders such as cardiovascular disease [15], diabetes mellitus [16], and preeclamptic pregnancy [64] are associated with impairments in the number and function of EPCs. Similar to this, numerous studies have proposed a link between children born with FGR and the development of the metabolic syndrome in adulthood, which includes diabetes, cardiovascular disease, asthma, intellectual disabilities such as depression and schizophrenia, and a lower intelligence quotient. This link has been considered as “fetal programming” [112,113,114]. Therefore, if there was any impairment of the fetal EPCs in FGR, it may have affected future adult life as well as intrauterine fetal growth, even if it is unclear whether the depletion and enhanced aging of EPCs in these diseases are causes or outcomes.
The cord blood from the FGR group had a mean EPC count per 50 mL that was considerably lower (4.3 ± 1.0 × 104/50 mL) than that of the normal group (6.6 ± 1.2 × 104/50 mL), as demonstrated by Hwang et al. [32]. Furthermore, the FGR group’s 8.8 ± 1.5-day differentiation period from EPC to OEC was longer than the normal group’s 6.0 ± 1.2-day differentiation period (p < 0.001). The staining intensity of SA-β-gal-positive cells was relatively higher in the FGR group compared with the normal group (141.3 ± 13.6% vs. 100.0 ± 14.82%; p < 0.001), and the OEC colony number from 1 × 105 fetal EPCs in each group was significantly decreased in the FGR group (7.9 ± 0.9 × 105 EPC) compared with the normal group (11.8 ± 1.6 × 105 EPC) (p < 0.001). Additionally, the FGR group’s telomerase activity was noticeably lower than that of the normal group (70.3 ± 6.5% vs. 100.0 ± 9.4%; p < 0.001).
In summary, circulating fetal EPCs in FGR are more senescent, have a lower differentiation capacity, and are fewer in number. These findings imply that the functional and numerical impairment of fetal EPCs in idiopathic FGR offers a likely explanation and could point to a practical intrauterine growth restriction treatment approach. Additionally, a number of studies found that during an FGR pregnancy, the concentrations of several known inflammatory, hypoxic, and antiangiogenic markers were higher in the cord blood [115,116]. These findings could help to explain why fetal EPCs in FGR pregnancies have lower numbers, decreased functional ability, and higher senescence.

5. Conclusions

In this review, we address the importance of fetal EPCs in the pathophysiology of fetal growth restriction (FGR), gestational diabetes (GDM), and preeclampsia (PE) (Figure 1). First, we proposed that preeclamptic patients had a considerably higher rate of fetal EPC senescence than controls did. Furthermore, in comparison with the normally derived EPCs, the preeclampsia-derived EPCs showed lower angiogenic activity, delayed differentiation periods, and a significant decrease in the number of produced OECs colonies. Second, we concluded that prenatal exposure to GDM reduces the angiogenic potential of EPCs and causes a marked increase in fetal EPC senescence in the GDM group. Nonetheless, there was no difference in the number of fetal EPCs obtained from cord blood or in the differentiation activity of EPCs during GDM pregnancy. Third, we postulated that there are less circulating fetal EPCs in FGR, and they have lower angiogenic activity and differentiation potential and are more senescent. As a result, this study offers a thorough explanation for the role that cord blood fetal EPC plays in pregnancy problems and suggests that EPC may play a role in the elevated lifetime cardiovascular risk that the offspring of pregnancy disorders may face. Therefore, it is suggested that restoration of EPC function through correction of genes related to the decline in angiogenic function of EPCs in woman with gestational disease can be a way to suppress the development of diseases caused by vascular dysfunction. In addition, we suggest that it can be used as a predictive diagnostic marker for the development of gestational vascular disease by discovering specific genes abnormally expressed in the EPCs of pregnant woman.

Author Contributions

J.-Y.K. and Y.-S.M. have contributed to the writing of the manuscript. Y.-S.M. conceptualized the review. Y.-S.M. drew the images. J.-Y.K. edited language. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2019R1I1A1A01059738, NRF-2021R1A2C2014591, and NRF-2022R1I1A1A01064011).

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Asahara, T.; Murohara, T.; Sullivan, A.; Silver, M.; van der Zee, R.; Li, T.; Witzenbichler, B.; Schatteman, G.; Isner, J.M. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997, 275, 964–967. [Google Scholar] [CrossRef]
  2. Chong, M.S.; Ng, W.K.; Chan, J.K. Concise Review: Endothelial Progenitor Cells in Regenerative Medicine: Applications and Challenges. Stem Cells Transl. Med. 2016, 5, 530–538. [Google Scholar] [CrossRef]
  3. Ng, C.Y.; Cheung, C. Origins and functional differences of blood endothelial cells. Semin. Cell Dev. Biol. 2024, 155 Pt C, 23–29. [Google Scholar] [CrossRef]
  4. Yang, J.X.; Pan, Y.Y.; Wang, X.X.; Qiu, Y.G.; Mao, W. Endothelial progenitor cells in age-related vascular remodeling. Cell Transplant. 2018, 27, 786–795. [Google Scholar] [CrossRef]
  5. Jing, J.; Ma, B.; Zhao, X. Fetal endothelial colony-forming cells: Possible targets for prevention of the fetal origins of adult diseases. Placenta 2024, 145, 80–88. [Google Scholar] [CrossRef]
  6. Emontzpohl, C.; Simons, D.; Kraemer, S.; Goetzenich, A.; Marx, G.; Bernhagen, J.; Stoppe, C. Isolation of Endothelial Progenitor Cells from Healthy Volunteers and Their Migratory Potential Influenced by Serum Samples after Cardiac Surgery. J. Vis. Exp. 2017, 120, 55192. [Google Scholar]
  7. Asahara, T.; Kawamoto, A.; Masuda, H. Concise review: Circulating endothelial progenitor cells for vascular medicine. Stem Cells 2011, 29, 1650–1655. [Google Scholar] [CrossRef]
  8. Haider, K.H.; Aziz, S.; Al-Reshidi, M.A. Endothelial progenitor cells for cellular angiogenesis and repair: Lessons learned from experimental animal models. Regen. Med. 2017, 12, 969–982. [Google Scholar] [CrossRef]
  9. Liew, A.; Barry, F.; O’Brien, T. Endothelial progenitor cells: Diagnostic and therapeutic considerations. Bioessays 2006, 28, 261–270. [Google Scholar] [CrossRef]
  10. Yan, F.; Li, J.; Zhang, W. Transplantation of Endothelial Progenitor Cells: Summary and prospect. Acta Histochem. 2023, 125, 151990. [Google Scholar] [CrossRef]
  11. Li, Y.F.; Ren, L.N.; Guo, G.; Cannella, L.A.; Chernaya, V.; Samuel, S.; Liu, S.X.; Wang, H.; Yang, X.F. Endothelial progenitor cells in ischemic stroke: An exploration from hypothesis to therapy. J. Hematol. Oncol. 2015, 8, 33. [Google Scholar] [CrossRef]
  12. Maeng, Y.S.; Choi, H.J.; Kwon, J.Y.; Park, Y.W.; Choi, K.S.; Min, J.K.; Kim, Y.H.; Suh, P.G.; Kang, K.S.; Won, M.H.; et al. Endothelial progenitor cell homing: Prominent role of the IGF2-IGF2R-PLCbeta2 axis. Blood 2009, 113, 233–243. [Google Scholar] [CrossRef]
  13. Orimo, A.; Gupta, P.B.; Sgroi, D.C.; Arenzana-Seisdedos, F.; Delaunay, T.; Naeem, R.; Carey, V.J.; Richardson, A.L.; Weinberg, R.A. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005, 121, 335–348. [Google Scholar] [CrossRef]
  14. Li, J.H.; Li, Y.; Huang, D.; Yao, M. Role of Stromal Cell-Derived Factor-1 in Endothelial Progenitor Cell-Mediated Vascular Repair and Regeneration. Tissue Eng. Regen. Med. 2021, 18, 747–758. [Google Scholar] [CrossRef]
  15. Vasa, M.; Fichtlscherer, S.; Aicher, A.; Adler, K.; Urbich, C.; Martin, H.; Zeiher, A.M.; Dimmeler, S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ. Res. 2001, 89, E1–E7. [Google Scholar] [CrossRef]
  16. Tepper, O.M.; Galiano, R.D.; Capla, J.M.; Kalka, C.; Gagne, P.J.; Jacobowitz, G.R.; Levine, J.P.; Gurtner, G.C. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 2002, 106, 2781–2786. [Google Scholar] [CrossRef]
  17. Benitez-Camacho, J.; Ballesteros, A.; Beltran-Camacho, L.; Rojas-Torres, M.; Rosal-Vela, A.; Jimenez-Palomares, M.; Sanchez-Gomar, I.; Duran-Ruiz, M.C. Endothelial progenitor cells as biomarkers of diabetes-related cardiovascular complications. Stem Cell Res. Ther. 2023, 14, 324. [Google Scholar] [CrossRef]
  18. Jain, R.; Awal, H.; Sen, S. Using adult stem cells to monitor endothelial dysfunction in diabetes mellitus. J. Diabetes Complicat. 2020, 34, 107588. [Google Scholar] [CrossRef]
  19. Schmidt-Lucke, C.; Rossig, L.; Fichtlscherer, S.; Vasa, M.; Britten, M.; Kamper, U.; Dimmeler, S.; Zeiher, A.M. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: Proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005, 111, 2981–2987. [Google Scholar] [CrossRef]
  20. Assmus, B.; Urbich, C.; Aicher, A.; Hofmann, W.K.; Haendeler, J.; Rossig, L.; Spyridopoulos, I.; Zeiher, A.M.; Dimmeler, S. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ. Res. 2003, 92, 1049–1055. [Google Scholar] [CrossRef]
  21. Imanishi, T.; Hano, T.; Sawamura, T.; Nishio, I. Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction. Clin. Exp. Pharmacol. Physiol. 2004, 31, 407–413. [Google Scholar] [CrossRef]
  22. Shimizu, S.; Iba, T.; Naito, H.; Rahmawati, F.N.; Konishi, H.; Jia, W.; Muramatsu, F.; Takakura, N. Aging impairs the ability of vascular endothelial stem cells to generate endothelial cells in mice. Angiogenesis 2023, 26, 567–580. [Google Scholar] [CrossRef]
  23. Park, Y.; Lee, H.J.; Jung, Y.J.; Kwon, H.Y.; Kim, H.; Lee, J.; Kim, Y.H.; Kim, H.O.; Maeng, Y.S.; Kwon, J.Y. CD133+/C-kit+Lin(-) endothelial progenitor cells in fetal circulation demonstrate impaired differentiation potency in severe preeclampsia. Pregnancy Hypertens. 2019, 15, 146–153. [Google Scholar] [CrossRef]
  24. Monga, R.; Buck, S.; Sharma, P.; Thomas, R.; Chouthai, N.S. Effect of preeclampsia and intrauterine growth restriction on endothelial progenitor cells in human umbilical cord blood. J. Matern. Fetal Neonatal Med. 2012, 25, 2385–2389. [Google Scholar] [CrossRef]
  25. Chen, Y.; Wan, G.; Li, Z.; Liu, X.; Zhao, Y.; Zou, L.; Liu, W. Endothelial progenitor cells in pregnancy-related diseases. Clin Sci. 2023, 137, 1699–1719. [Google Scholar] [CrossRef]
  26. Mayhew, T.M.; Wijesekara, J.; Baker, P.N.; Ong, S.S. Morphometric evidence that villous development and fetoplacental angiogenesis are compromised by intrauterine growth restriction but not by pre-eclampsia. Placenta 2004, 25, 829–833. [Google Scholar] [CrossRef]
  27. Kwon, J.Y.; Maeng, Y.S.; Kwon, Y.G.; Kim, Y.H.; Kang, M.H.; Park, Y.W. Decreased endothelial progenitor cells in umbilical cord blood in severe preeclampsia. Gynecol. Obstet. Investig. 2007, 64, 103–108. [Google Scholar] [CrossRef]
  28. Blue, E.K.; Sheehan, B.M.; Nuss, Z.V.; Boyle, F.A.; Hocutt, C.M.; Gohn, C.R.; Varberg, K.M.; McClintick, J.N.; Haneline, L.S. Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus. Diabetes 2015, 64, 2664–2675. [Google Scholar] [CrossRef]
  29. Ingram, D.A.; Lien, I.Z.; Mead, L.E.; Estes, M.; Prater, D.N.; Derr-Yellin, E.; DiMeglio, L.A.; Haneline, L.S. In vitro hyperglycemia or a diabetic intrauterine environment reduces neonatal endothelial colony-forming cell numbers and function. Diabetes 2008, 57, 724–731. [Google Scholar] [CrossRef]
  30. Buemi, M.; Allegra, A.; D’Anna, R.; Coppolino, G.; Crasci, E.; Giordano, D.; Loddo, S.; Cucinotta, M.; Musolino, C.; Teti, D. Concentration of circulating endothelial progenitor cells (EPC) in normal pregnancy and in pregnant women with diabetes and hypertension. Am. J. Obstet. Gynecol. 2007, 196, 68.e1–68.e6. [Google Scholar] [CrossRef]
  31. Schreiber, V.; Hurst, C.; da Silva Costa, F.; Stoke, R.; Turner, J.; Kumar, S. Definitions matter: Detection rates and perinatal outcome for infants classified prenatally as having late fetal growth restriction using SMFM biometric vs ISUOG/Delphi consensus criteria. Ultrasound Obstet. Gynecol. 2023, 61, 377–385. [Google Scholar] [CrossRef]
  32. Hwang, H.S.; Kwon, Y.G.; Kwon, J.Y.; Won Park, Y.; Maeng, Y.S.; Kim, Y.H. Senescence of fetal endothelial progenitor cell in pregnancy with idiopathic fetal growth restriction. J. Matern. Fetal Neonatal Med. 2012, 25, 1769–1773. [Google Scholar] [CrossRef]
  33. Singh, A.; Jaiswar, S.P.; Priyadarshini, A.; Deo, S. Reduced Endothelial Progenitor Cells: A Possible Biomarker for Idiopathic Fetal Growth Restriction in Human Pregnancies. J. Mother. Child. 2023, 27, 182–189. [Google Scholar]
  34. Wright, C.S.; Rifas-Shiman, S.L.; Rich-Edwards, J.W.; Taveras, E.M.; Gillman, M.W.; Oken, E. Intrauterine exposure to gestational diabetes, child adiposity, and blood pressure. Am. J. Hypertens. 2009, 22, 215–220. [Google Scholar] [CrossRef]
  35. Boney, C.M.; Verma, A.; Tucker, R.; Vohr, B.R. Metabolic syndrome in childhood: Association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 2005, 115, e290–e296. [Google Scholar] [CrossRef]
  36. Bianco, M.E.; Josefson, J.L. Hyperglycemia During Pregnancy and Long-Term Offspring Outcomes. Curr. Diab. Rep. 2019, 19, 143. [Google Scholar] [CrossRef]
  37. Low, J.A.; Handley-Derry, M.H.; Burke, S.O.; Peters, R.D.; Pater, E.A.; Killen, H.L.; Derrick, E.J. Association of intrauterine fetal growth retardation and learning deficits at age 9 to 11 years. Am. J. Obstet. Gynecol. 1992, 167, 1499–1505. [Google Scholar] [CrossRef]
  38. Godfrey, K.M.; Barker, D.J. Fetal nutrition and adult disease. Am. J. Clin. Nutr. 2000, 71 (Suppl. S5), 1344s–1352s. [Google Scholar] [CrossRef]
  39. National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am. J. Obstet. Gynecol. 1990, 163 Pt 1, 1691–1712. [CrossRef]
  40. Shen, X.; Wang, C.; Yue, X.; Wang, Q.; Xie, L.; Huang, Z.; Huang, X.; Li, J.; Xu, Y.; Chen, L.; et al. Preeclampsia associated changes in volume density of fetoplacental vessels in Chinese women and mouse model of preeclampsia. Placenta 2022, 121, 116–125. [Google Scholar] [CrossRef]
  41. Mayhew, T.M.; Charnock-Jones, D.S.; Kaufmann, P. Aspects of human fetoplacental vasculogenesis and angiogenesis. III. Changes in complicated pregnancies. Placenta 2004, 25, 127–139. [Google Scholar] [CrossRef]
  42. Resta, L.; Capobianco, C.; Marzullo, A.; Piscitelli, D.; Sanguedolce, F.; Schena, F.P.; Gesualdo, L. Confocal laser scanning microscope study of terminal villi vessels in normal term and pre-eclamptic placentas. Placenta 2006, 27, 735–739. [Google Scholar] [CrossRef]
  43. Fadini, G.P.; Schiavon, M.; Cantini, M.; Baesso, I.; Facco, M.; Miorin, M.; Tassinato, M.; de Kreutzenberg, S.V.; Avogaro, A.; Agostini, C. Circulating progenitor cells are reduced in patients with severe lung disease. Stem Cells 2006, 24, 1806–1813. [Google Scholar] [CrossRef]
  44. Hill, J.M.; Zalos, G.; Halcox, J.P.; Schenke, W.H.; Waclawiw, M.A.; Quyyumi, A.A.; Finkel, T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N. Engl. J. Med. 2003, 348, 593–600. [Google Scholar] [CrossRef]
  45. Kalka, C.; Masuda, H.; Takahashi, T.; Kalka-Moll, W.M.; Silver, M.; Kearney, M.; Li, T.; Isner, J.M.; Asahara, T. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc. Natl. Acad. Sci. USA 2000, 97, 3422–3427. [Google Scholar] [CrossRef]
  46. Takahashi, T.; Kalka, C.; Masuda, H.; Chen, D.; Silver, M.; Kearney, M.; Magner, M.; Isner, J.M.; Asahara, T. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med. 1999, 5, 434–438. [Google Scholar] [CrossRef]
  47. Stamm, C.; Westphal, B.; Kleine, H.D.; Petzsch, M.; Kittner, C.; Klinge, H.; Schümichen, C.; Nienaber, C.A.; Freund, M.; Steinhoff, G. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003, 361, 45–46. [Google Scholar] [CrossRef]
  48. Tateishi-Yuyama, E.; Matsubara, H.; Murohara, T.; Ikeda, U.; Shintani, S.; Masaki, H.; Amano, K.; Kishimoto, Y.; Yoshimoto, K.; Akashi, H.; et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: A pilot study and a randomised controlled trial. Lancet 2002, 360, 427–435. [Google Scholar] [CrossRef]
  49. Hwang, H.S.; Maeng, Y.S.; Park, Y.W.; Koos, B.J.; Kwon, Y.G.; Kim, Y.H. Increased senescence and reduced functional ability of fetal endothelial progenitor cells in pregnancies complicated by preeclampsia without intrauterine growth restriction. Am. J. Obstet. Gynecol. 2008, 199, 259.e1–259.e7. [Google Scholar] [CrossRef]
  50. Brodowski, L.; Schroder-Heurich, B.; von Hardenberg, S.; Richter, K.; von Kaisenberg, C.S.; Dittrich-Breiholz, O.; Meyer, N.; Dork, T.; von Versen-Hoynck, F. MicroRNA Profiles of Maternal and Neonatal Endothelial Progenitor Cells in Preeclampsia. Int. J. Mol. Sci. 2021, 22, 5320. [Google Scholar] [CrossRef]
  51. Xia, L.; Zhou, X.P.; Zhu, J.H.; Xie, X.D.; Zhang, H.; Wang, X.X.; Chen, J.Z.; Jian, S. Decrease and dysfunction of endothelial progenitor cells in umbilical cord blood with maternal pre-eclampsia. J. Obstet. Gynaecol. Res. 2007, 33, 465–474. [Google Scholar] [CrossRef] [PubMed]
  52. Tchkonia, T.; Morbeck, D.E.; Von Zglinicki, T.; Van Deursen, J.; Lustgarten, J.; Scrable, H.; Khosla, S.; Jensen, M.D.; Kirkland, J.L. Fat tissue, aging, and cellular senescence. Aging Cell 2010, 9, 667–684. [Google Scholar] [CrossRef] [PubMed]
  53. Melk, A.; Schmidt, B.M.; Vongwiwatana, A.; Rayner, D.C.; Halloran, P.F. Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney. Am. J. Transplant. 2005, 5, 1375–1382. [Google Scholar] [CrossRef] [PubMed]
  54. Waaijer, M.E.; Parish, W.E.; Strongitharm, B.H.; van Heemst, D.; Slagboom, P.E.; de Craen, A.J.; Sedivy, J.M.; Westendorp, R.G.; Gunn, D.A.; Maier, A.B. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell 2012, 11, 722–725. [Google Scholar] [CrossRef] [PubMed]
  55. Minamino, T.; Orimo, M.; Shimizu, I.; Kunieda, T.; Yokoyama, M.; Ito, T.; Nojima, A.; Nabetani, A.; Oike, Y.; Matsubara, H.; et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 2009, 15, 1082–1087. [Google Scholar] [CrossRef] [PubMed]
  56. Minamino, T.; Komuro, I. Vascular cell senescence: Contribution to atherosclerosis. Circ. Res. 2007, 100, 15–26. [Google Scholar] [CrossRef] [PubMed]
  57. Westhoff, J.H.; Hilgers, K.F.; Steinbach, M.P.; Hartner, A.; Klanke, B.; Amann, K.; Melk, A. Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hypertension 2008, 52, 123–129. [Google Scholar] [CrossRef] [PubMed]
  58. Roberts, J.M.; Lain, K.Y. Recent Insights into the pathogenesis of pre-eclampsia. Placenta 2002, 23, 359–372. [Google Scholar] [CrossRef]
  59. Frusca, T.; Morassi, L.; Pecorelli, S.; Grigolato, P.; Gastaldi, A. Histological features of uteroplacental vessels in normal and hypertensive patients in relation to birthweight. Br. J. Obstet. Gynaecol. 1989, 96, 835–839. [Google Scholar] [CrossRef]
  60. Minamino, T.; Miyauchi, H.; Yoshida, T.; Ishida, Y.; Yoshida, H.; Komuro, I. Endothelial cell senescence in human atherosclerosis: Role of telomere in endothelial dysfunction. Circulation 2002, 105, 1541–1544. [Google Scholar] [CrossRef]
  61. Donato, A.J.; Morgan, R.G.; Walker, A.E.; Lesniewski, L.A. Cellular and molecular biology of aging endothelial cells. J. Mol. Cell Cardiol. 2015, 89 Pt B, 122–135. [Google Scholar] [CrossRef] [PubMed]
  62. Tian, X.L.; Li, Y. Endothelial cell senescence and age-related vascular diseases. J. Genet. Genom. 2014, 41, 485–495. [Google Scholar] [CrossRef] [PubMed]
  63. Regina, C.; Panatta, E.; Candi, E.; Melino, G.; Amelio, I.; Balistreri, C.R.; Annicchiarico-Petruzzelli, M.; Di Daniele, N.; Ruvolo, G. Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases. Mech. Ageing Dev. 2016, 159, 14–21. [Google Scholar] [CrossRef] [PubMed]
  64. Sugawara, J.; Mitsui-Saito, M.; Hayashi, C.; Hoshiai, T.; Senoo, M.; Chisaka, H.; Yaegashi, N.; Okamura, K. Decrease and senescence of endothelial progenitor cells in patients with preeclampsia. J. Clin. Endocrinol. Metab. 2005, 90, 5329–5332. [Google Scholar] [CrossRef] [PubMed]
  65. Gumina, D.L.; Su, E.J. Endothelial Progenitor Cells of the Human Placenta and Fetoplacental Circulation: A Potential Link to Fetal, Neonatal, and Long-term Health. Front. Pediatr. 2017, 5, 41. [Google Scholar] [CrossRef] [PubMed]
  66. Kajantie, E.; Osmond, C.; Eriksson, J.G. Gestational hypertension is associated with increased risk of type 2 diabetes in adult offspring: The Helsinki Birth Cohort Study. Am. J. Obstet. Gynecol. 2017, 216, 281.e1–281.e7. [Google Scholar] [CrossRef] [PubMed]
  67. Kajantie, E.; Eriksson, J.G.; Osmond, C.; Thornburg, K.; Barker, D.J. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: The Helsinki birth cohort study. Stroke 2009, 40, 1176–1180. [Google Scholar] [CrossRef] [PubMed]
  68. Warshafsky, C.; Pudwell, J.; Walker, M.; Wen, S.W.; Smith, G.N. Prospective assessment of neurodevelopment in children following a pregnancy complicated by severe pre-eclampsia. BMJ Open 2016, 6, e010884. [Google Scholar] [CrossRef] [PubMed]
  69. Henley, D.; Brown, S.; Pennell, C.; Lye, S.; Torpy, D.J. Evidence for central hypercortisolism and elevated blood pressure in adolescent offspring of mothers with pre-eclampsia. Clin. Endocrinol. 2016, 85, 583–589. [Google Scholar] [CrossRef]
  70. Eguchi, M.; Masuda, H.; Asahara, T. Endothelial progenitor cells for postnatal vasculogenesis. Clin. Exp. Nephrol. 2007, 11, 18–25. [Google Scholar] [CrossRef]
  71. Kunz, G.A.; Liang, G.; Cuculi, F.; Gregg, D.; Vata, K.C.; Shaw, L.K.; Goldschmidt-Clermont, P.J.; Dong, C.; Taylor, D.A.; Peterson, E.D. Circulating endothelial progenitor cells predict coronary artery disease severity. Am. Heart J. 2006, 152, 190–195. [Google Scholar] [CrossRef]
  72. Fadini, G.P.; Sartore, S.; Albiero, M.; Baesso, I.; Murphy, E.; Menegolo, M.; Grego, F.; Vigili de Kreutzenberg, S.; Tiengo, A.; Agostini, C.; et al. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 2140–2146. [Google Scholar] [CrossRef]
  73. Fadini, G.P.; Coracina, A.; Baesso, I.; Agostini, C.; Tiengo, A.; Avogaro, A.; de Kreutzenberg, S.V. Peripheral blood CD34+KDR+ endothelial progenitor cells are determinants of subclinical atherosclerosis in a middle-aged general population. Stroke 2006, 37, 2277–2282. [Google Scholar] [CrossRef] [PubMed]
  74. Ebner, P.; Picard, F.; Richter, J.; Darrelmann, E.; Schneider, M.; Strauer, B.E.; Brehm, M. Accumulation of VEGFR-2+/CD133+ cells and decreased number and impaired functionality of CD34+/VEGFR-2+ cells in patients with SLE. Rheumatology 2010, 49, 63–72. [Google Scholar] [CrossRef] [PubMed]
  75. Jialal, I.; Devaraj, S.; Singh, U.; Huet, B.A. Decreased number and impaired functionality of endothelial progenitor cells in subjects with metabolic syndrome: Implications for increased cardiovascular risk. Atherosclerosis 2010, 211, 297–302. [Google Scholar] [CrossRef]
  76. Beasley, K.M.; Lovering, A.T.; Gilbert, J.S. Decreased endothelial progenitor cells in preeclampsia and consequences for developmental programming. Hypertension 2014, 64, 23–25. [Google Scholar] [CrossRef] [PubMed]
  77. Cardenas, C.; Kwon, J.Y.; Maeng, Y.S. Human Cord Blood-Derived CD133(+)/C-Kit(+)/Lin(-) Cells Have Bipotential Ability to Differentiate into Mesenchymal Stem Cells and Outgrowth Endothelial Cells. Stem Cells Int. 2016, 2016, 7162160. [Google Scholar] [CrossRef]
  78. Muñoz-Hernandez, R.; Miranda, M.L.; Stiefel, P.; Lin, R.Z.; Praena-Fernández, J.M.; Dominguez-Simeon, M.J.; Villar, J.; Moreno-Luna, R.; Melero-Martin, J.M. Decreased level of cord blood circulating endothelial colony-forming cells in preeclampsia. Hypertension 2014, 64, 165–171. [Google Scholar] [CrossRef]
  79. Gumina, D.L.; Black, C.P.; Balasubramaniam, V.; Winn, V.D.; Baker, C.D. Umbilical Cord Blood Circulating Progenitor Cells and Endothelial Colony-Forming Cells Are Decreased in Preeclampsia. Reprod. Sci. 2017, 24, 1088–1096. [Google Scholar] [CrossRef]
  80. Voigt, P.; Tee, W.W.; Reinberg, D. A double take on bivalent promoters. Genes. Dev. 2013, 27, 1318–1338. [Google Scholar] [CrossRef]
  81. Metzger, B.E.; Buchanan, T.A.; Coustan, D.R.; de Leiva, A.; Dunger, D.B.; Hadden, D.R.; Hod, M.; Kitzmiller, J.L.; Kjos, S.L.; Oats, J.N.; et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 2007, 30 (Suppl. S2), S251–S260. [Google Scholar] [CrossRef] [PubMed]
  82. Zhu, Y.; Zhang, C. Prevalence of Gestational Diabetes and Risk of Progression to Type 2 Diabetes: A Global Perspective. Curr. Diabetes Rep. 2016, 16, 7. [Google Scholar] [CrossRef] [PubMed]
  83. Penno, G.; Pucci, L.; Lucchesi, D.; Lencioni, C.; Iorio, M.C.; Vanacore, R.; Storti, E.; Resi, V.; Di Cianni, G.; Del Prato, S. Circulating endothelial progenitor cells in women with gestational alterations of glucose tolerance. Diabetes Vasc. Dis. Res. 2011, 8, 202–210. [Google Scholar] [CrossRef] [PubMed]
  84. Altabas, V. Diabetes, Endothelial Dysfunction, and Vascular Repair: What Should a Diabetologist Keep His Eye on? Int. J. Endocrinol. 2015, 2015, 848272. [Google Scholar] [CrossRef] [PubMed]
  85. Rigato, M.; Avogaro, A.; Fadini, G.P. Levels of Circulating Progenitor Cells, Cardiovascular Outcomes and Death: A Meta-Analysis of Prospective Observational Studies. Circ. Res. 2016, 118, 1930–1939. [Google Scholar] [CrossRef] [PubMed]
  86. Rigato, M.; Bittante, C.; Albiero, M.; Avogaro, A.; Fadini, G.P. Circulating Progenitor Cell Count Predicts Microvascular Outcomes in Type 2 Diabetic Patients. J. Clin. Endocrinol. Metab. 2015, 100, 2666–2672. [Google Scholar] [CrossRef] [PubMed]
  87. Mordwinkin, N.M.; Ouzounian, J.G.; Yedigarova, L.; Montoro, M.N.; Louie, S.G.; Rodgers, K.E. Alteration of endothelial function markers in women with gestational diabetes and their fetuses. J. Matern. Fetal Neonatal Med. 2013, 26, 507–512. [Google Scholar] [CrossRef] [PubMed]
  88. Gui, J.; Rohrbach, A.; Borns, K.; Hillemanns, P.; Feng, L.; Hubel, C.A.; von Versen-Hoynck, F. Vitamin D rescues dysfunction of fetal endothelial colony forming cells from individuals with gestational diabetes. Placenta 2015, 36, 410–418. [Google Scholar] [CrossRef] [PubMed]
  89. Blue, E.K.; DiGiuseppe, R.; Derr-Yellin, E.; Acosta, J.C.; Pay, S.L.; Hanenberg, H.; Schellinger, M.M.; Quinney, S.K.; Mund, J.A.; Case, J.; et al. Gestational diabetes induces alterations in the function of neonatal endothelial colony-forming cells. Pediatr. Res. 2014, 75, 266–272. [Google Scholar] [CrossRef]
  90. Wu, Y.; Fu, C.; Li, B.; Liu, C.; He, Z.; Li, X.E.; Wang, A.; Ma, G.; Yao, Y. Bradykinin Protects Human Endothelial Progenitor Cells from High-Glucose-Induced Senescence through B2 Receptor-Mediated Activation of the Akt/eNOS Signalling Pathway. J. Diabetes Res. 2021, 2021, 6626627. [Google Scholar] [CrossRef]
  91. Sahin, E.; Depinho, R.A. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 2010, 464, 520–528. [Google Scholar] [CrossRef] [PubMed]
  92. Egan, C.G.; Lavery, R.; Caporali, F.; Fondelli, C.; Laghi-Pasini, F.; Dotta, F.; Sorrentino, V. Generalised reduction of putative endothelial progenitors and CXCR4-positive peripheral blood cells in type 2 diabetes. Diabetologia 2008, 51, 1296–1305. [Google Scholar] [CrossRef] [PubMed]
  93. Loomans, C.J.; de Koning, E.J.; Staal, F.J.; Rookmaaker, M.B.; Verseyden, C.; de Boer, H.C.; Verhaar, M.C.; Braam, B.; Rabelink, T.J.; van Zonneveld, A.J. Endothelial progenitor cell dysfunction: A novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 2004, 53, 195–199. [Google Scholar] [CrossRef] [PubMed]
  94. Fadini, G.P.; Pucci, L.; Vanacore, R.; Baesso, I.; Penno, G.; Balbarini, A.; Di Stefano, R.; Miccoli, R.; de Kreutzenberg, S.; Coracina, A.; et al. Glucose tolerance is negatively associated with circulating progenitor cell levels. Diabetologia 2007, 50, 2156–2163. [Google Scholar] [CrossRef] [PubMed]
  95. Fadini, G.P.; Miorin, M.; Facco, M.; Bonamico, S.; Baesso, I.; Grego, F.; Menegolo, M.; de Kreutzenberg, S.V.; Tiengo, A.; Agostini, C.; et al. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J. Am. Coll. Cardiol. 2005, 45, 1449–1457. [Google Scholar] [CrossRef] [PubMed]
  96. Bunt, J.C.; Tataranni, P.A.; Salbe, A.D. Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children. J. Clin. Endocrinol. Metab. 2005, 90, 3225–3229. [Google Scholar] [CrossRef] [PubMed]
  97. Cho, N.H.; Silverman, B.L.; Rizzo, T.A.; Metzger, B.E. Correlations between the intrauterine metabolic environment and blood pressure in adolescent offspring of diabetic mothers. J. Pediatr. 2000, 136, 587–592. [Google Scholar] [CrossRef] [PubMed]
  98. Varberg, K.M.; Garretson, R.O.; Blue, E.K.; Chu, C.; Gohn, C.R.; Tu, W.; Haneline, L.S. Transgelin induces dysfunction of fetal endothelial colony-forming cells from gestational diabetic pregnancies. Am. J. Physiol. Cell Physiol. 2018, 315, C502–C515. [Google Scholar] [CrossRef] [PubMed]
  99. Gui, J.; Potthast, A.; Rohrbach, A.; Borns, K.; Das, A.M.; von Versen-Hoynck, F. Gestational diabetes induces alterations of sirtuins in fetal endothelial cells. Pediatr. Res. 2016, 79, 788–798. [Google Scholar] [CrossRef]
  100. Urbich, C.; Dimmeler, S. Endothelial progenitor cells functional characterization. Trends Cardiovasc. Med. 2004, 14, 318–322. [Google Scholar] [CrossRef]
  101. Robb, A.O.; Mills, N.L.; Newby, D.E.; Denison, F.C. Endothelial progenitor cells in pregnancy. Reproduction 2007, 133, 1–9. [Google Scholar] [CrossRef] [PubMed]
  102. Houde, A.A.; Guay, S.P.; Desgagne, V.; Hivert, M.F.; Baillargeon, J.P.; St-Pierre, J.; Perron, P.; Gaudet, D.; Brisson, D.; Bouchard, L. Adaptations of placental and cord blood ABCA1 DNA methylation profile to maternal metabolic status. Epigenetics 2013, 8, 1289–1302. [Google Scholar] [CrossRef] [PubMed]
  103. Dilli, D.; Dogan, N.N.; Ipek, M.S.; Cavus, Y.; Ceylaner, S.; Dogan, H.; Dursun, A.; Kucukozkan, T.; Zenciroglu, A. MaFOS-GDM trial: Maternal fish oil supplementation in women with gestational diabetes and cord blood DNA methylation at insulin like growth factor-1 (IGF-1) gene. Clin. Nutr. ESPEN 2018, 23, 73–78. [Google Scholar] [CrossRef] [PubMed]
  104. Pauwels, S.; Ghosh, M.; Duca, R.C.; Bekaert, B.; Freson, K.; Huybrechts, I.; Langie, S.A.S.; Koppen, G.; Devlieger, R.; Godderis, L. Maternal intake of methyl-group donors affects DNA methylation of metabolic genes in infants. Clin. Epigenetics 2017, 9, 16. [Google Scholar] [CrossRef] [PubMed]
  105. Ott, R.; Melchior, K.; Stupin, J.H.; Ziska, T.; Schellong, K.; Henrich, W.; Rancourt, R.C.; Plagemann, A. Reduced Insulin Receptor Expression and Altered DNA Methylation in Fat Tissues and Blood of Women With GDM and Offspring. J. Clin. Endocrinol. Metab. 2019, 104, 137–149. [Google Scholar] [CrossRef] [PubMed]
  106. Awamleh, Z.; Butcher, D.T.; Hanley, A.; Retnakaran, R.; Haertle, L.; Haaf, T.; Hamilton, J.; Weksberg, R. Exposure to Gestational Diabetes Mellitus (GDM) alters DNA methylation in placenta and fetal cord blood. Diabetes Res. Clin. Pract. 2021, 174, 108690. [Google Scholar] [CrossRef] [PubMed]
  107. Kwon, H.; Jung, Y.J.; Lee, Y.; Son, G.H.; Kim, H.O.; Maeng, Y.S.; Kwon, J.Y. Impaired Angiogenic Function of Fetal Endothelial Progenitor Cells via PCDH10 in Gestational Diabetes Mellitus. Int. J. Mol. Sci. 2023, 24, 6082. [Google Scholar] [CrossRef] [PubMed]
  108. Karlberg, J.; Albertsson-Wikland, K. Growth in full-term small-for-gestational-age infants: From birth to final height. Pediatr. Res. 1995, 38, 733–739. [Google Scholar] [CrossRef] [PubMed]
  109. Illanes, S.; Soothill, P. Management of fetal growth restriction. Semin. Fetal Neonatal Med. 2004, 9, 395–401. [Google Scholar] [CrossRef]
  110. Burton, G.J.; Jauniaux, E. Pathophysiology of placental-derived fetal growth restriction. Am. J. Obstet. Gynecol. 2018, 218, S745–S761. [Google Scholar] [CrossRef]
  111. Resnik, R. Intrauterine growth restriction. Obstet. Gynecol. 2002, 99, 490–496. [Google Scholar] [PubMed]
  112. Rosso, I.M.; Cannon, T.D.; Huttunen, T.; Huttunen, M.O.; Lönnqvist, J.; Gasperoni, T.L. Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort. Am. J. Psychiatry 2000, 157, 801–807. [Google Scholar] [CrossRef] [PubMed]
  113. Gale, C.R.; Martyn, C.N. Birth weight and later risk of depression in a national birth cohort. Br. J. Psychiatry 2004, 184, 28–33. [Google Scholar] [CrossRef] [PubMed]
  114. Frisk, V.; Amsel, R.; Whyte, H.E. The importance of head growth patterns in predicting the cognitive abilities and literacy skills of small-for-gestational-age children. Dev. Neuropsychol. 2002, 22, 565–593. [Google Scholar] [CrossRef]
  115. Amarilyo, G.; Oren, A.; Mimouni, F.B.; Ochshorn, Y.; Deutsch, V.; Mandel, D. Increased cord serum inflammatory markers in small-for-gestational-age neonates. J. Perinatol. 2011, 31, 30–32. [Google Scholar] [CrossRef]
  116. Wallner, W.; Sengenberger, R.; Strick, R.; Strissel, P.L.; Meurer, B.; Beckmann, M.W.; Schlembach, D. Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction. Clin. Sci. 2007, 112, 51–57. [Google Scholar] [CrossRef]
Ijms 25 04444 g001
Figure 1. Proposed model describing the vessel formation of EPCs in the pathophysiology of preeclampsia (PE), gestational diabetes (GDM), fetal growth restriction (FGR), and normal pregnancy conditions. The fetal EPCs of pregnancy complications displayed decreased blood vessel formation activity.
Figure 1. Proposed model describing the vessel formation of EPCs in the pathophysiology of preeclampsia (PE), gestational diabetes (GDM), fetal growth restriction (FGR), and normal pregnancy conditions. The fetal EPCs of pregnancy complications displayed decreased blood vessel formation activity.
Ijms 25 04444 g001
Table 1. Patient characteristics.
Table 1. Patient characteristics.
Normal Pregnancy
(n = 30)		Preeclampsia
(n = 30)		p-Value
Maternal age (years)33.7 ± 5.332.75 ± 3.10.549
Gestational age at delivery (weeks)38.65 ± 0.836.35 ± 2.10.386
Gravida2.5 ± 1.41.55 ± 1.00.05
Pre-pregnancy body mass index (BMI) (kg/m2)21.75 ± 4.722.1 ± 3.80.387
Blood pressure (mmHg)
Systolic blood pressure115.1 ±7151.05 ±15<0.015
Diastolic blood pressure74.25 ±1595.7 ±18<0.015
Birth weight (g)3301.0 ± 3652303.1 ± 536 <0.001
Small gestational age (n)0210.03
Free VEGF, mean (SD)22.66 (12.88)12.84 (1.56)0.04
sVEGFR-1, median (range)1.11 (1.66)1.25 (27.81)0.24
EPC count (×106/50 mL)8.612.650.009
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Kwon, J.-Y.; Maeng, Y.-S. Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction). Int. J. Mol. Sci. 2024, 25, 4444. https://doi.org/10.3390/ijms25084444

AMA Style

Kwon J-Y, Maeng Y-S. Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction). International Journal of Molecular Sciences. 2024; 25(8):4444. https://doi.org/10.3390/ijms25084444

Chicago/Turabian Style

Kwon, Ja-Young, and Yong-Sun Maeng. 2024. "Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction)" International Journal of Molecular Sciences 25, no. 8: 4444. https://doi.org/10.3390/ijms25084444

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