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The relationship between circulating tissue transglutaminase, soluble fms-like tyrosine kinase-1, soluble endoglin and vascular endothelial growth factor in pre-eclampsia

Abstract

Preeclampsia (PE) is a pregnancy-specific syndrome that causes substantial maternal and fetal morbidity and mortality. Increased production of antiangiogenic factors, soluble fms-like tyrosine kinase receptor-1 (sFlt-1) and soluble endoglin (sEng), as well as decreased circulating levels of free vascular endothelial growth factor (VEGF), contribute to the pathophysiology of PE. Our objective was to evaluate a novel placenta-related factor, tissue transglutaminase (tTG), in PE and to investigate the correlation among tTG and sFlt-1, sEng and VEGF levels in both normotensive pregnant patients and PE patients. A total of 205 pregnant primigravid women were recruited and divided into a normotensive group (n=100), a mild PE group (n=45) and a severe PE group (n=60). Circulating serum tTG, sFlt-1, sEng and free VEGF levels were determined using an enzyme-linked immunosorbent assay. The severe PE group showed higher levels of tTG, sFlt-1 and sEng than the mild PE and normotensive groups. Free VEGF levels were lower in the severe PE group than in the mild PE and normotensive groups. tTG correlated significantly with sFlt-1, sEng and VEGF in the PE groups, whereas this correlation was not observed in the normotensive group. The tTG, sFlt-1, sEng and VEGF levels showed a significant correlation with mean arterial pressure in the PE groups but not in the normotensive group. The tTG, sFlt-1, sEng and VEGF levels correlated with the degree of proteinuria. Our results reveal that tTG is associated with sFlt-1, sEng and VEGF in the maternal circulation of PE patients, suggesting that tTG may have a role in the pathogenesis of PE.

Introduction

Preeclampsia (PE) is not a single disorder but a complex syndrome that is induced by various pathophysiological triggers and mechanisms. PE complicates 5% of obstetric patients worldwide and is a leading cause of premature delivery and maternal and fetal morbidity and mortality. This condition is characterised by the onset of hypertension and proteinuria after 20 weeks of gestation and affects nearly every organ system.1 Severe PE can induce the appearance of HELLP syndrome, seizures (eclampsia) and/or restriction of fetal growth.1, 2 The exact cause of PE remains unknown; however, many theories suggest that abnormal placental development in early pregnancy triggers systemic inflammation, oxidative stress and endothelial dysfunction, all of which lead to the clinical manifestations of PE.3 In recent years, accumulating evidence suggests that an imbalance between pro-angiogenic (for example, vascular endothelial growth factor (VEGF) and placental growth factor and antiangiogenic factors (soluble VEGF receptor-1, also referred to as soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and soluble endoglin (sEng)) is involved in the pathophysiology of PE.4, 5, 6 Liu et al.7 revealed that enzyme activity and the expression level of tissue transglutaminase (tTG) are significantly elevated in preeclamptic placentas. Therefore, this study evaluated a novel placenta-related factor, tTG, in the circulating serum of PE patients and investigated the relationship between tTG and other factors.

tTG or TG2 belongs to a family of enzymes that catalyse the Ca2+-dependent posttranslational modification of proteins. This process results from an acyl-transfer reaction between the γ-carboxamide group of glutamine residues on one peptide and the ɛ-amino group of lysine residues on another peptide.8, 9 In addition to its acyltransferase activity, tTG can alter proteins by deamidation and hydrolysing isopeptides.10 tTG is widely expressed in human cells and tissues.11 Notably, tTG is enriched in the placental syncytiotrophoblast layer,12, 13 from which it is shed into the maternal circulation.14 tTG gene expression can be induced by transforming growth factor-β (TGFβ), tumor necrosis factor-α and interleukin-6,15, 16, 17 inflammatory cytokines that are highly elevated in PE.18, 19, 20, 21

sFlt-1, a splice variant of the VEGF receptor-1 (Flt-1) that lacks the trans-membrane and cytoplasmic domains, acts as a potent VEGF and placental growth factor antagonist.22, 23 sFlt-1 is produced by a number of tissues, including the placenta,24, 25 and its levels are elevated in the blood of patients with PE.26, 27 Overexpression of sFlt-1 in rats leads to hypertension, proteinuria and glomerular endotheliosis, which are classical manifestations of PE, suggesting that excess circulating sFlt-1 has a causal role in PE.28 sEng, which is a truncated form of endoglin, impairs the binding of TGFβ1 to its receptor on the cell surface, thus leading to dysregulation of TGFβ1 signalling with effects on the activation of endothelial nitric oxide synthase and vasodilation. Zhou et al.29 found a fourfold greater concentration of sEng in women with PE than in women with normotensive pregnancy. Infusion of a recombinant adenovirus encoding sFlt-1 and sEng can induce the development of hypertension, proteinuria and histological lesions, which are characteristic of PE, in various organs of pregnant rats.28, 30

VEGF is a well-known promoter of angiogenesis; it can induce nitric oxide and vasodilatory prostacyclins in endothelial cells, suggesting an important role in decreasing blood pressure.31, 32 A high concentration of circulating sFlt-1 and sEng along with decreased free VEGF levels have been confirmed in women with PE.28, 33, 34, 35 In this study, we show that circulating serum tTG levels are significantly elevated in women with PE and are increased with disease severity. We also identified the relationship between tTG and sFlt-1, sEng and VEGF and discovered a strong correlation between elevated tTG and both sFlt-1 and sEng in the maternal circulation of PE patients.

Patients and methods

A total of 205 pregnant women were enrolled in this case–control study from the Clinics and Antenatal Wards of the Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, China. This study was approved by the Institutional Ethical Review Board of Guangzhou Women and Children’s Hospital. We assigned these pregnant women into a normotensive group (n=100), a mild PE group (n=45) and a severe PE group (n=60). According to Xie Xing, editor in chief of the eighth edition of Obstetrics and Gynecology, PE was defined by maternal systolic blood pressure 140 mm Hg and/or diastolic pressure 90 mm Hg on two occasions separated by at least 4 h and new-onset proteinuria >300 mg in a 24-h urine collection or on a dipstick with 3+ after 20 weeks of gestation in previously normotensive pregnant women. PE was considered severe if 1 of the following criteria was present: maternal blood pressure 160/110 mm Hg on two separate readings at least 4 h apart; proteinuria >3+ by dipstick or >5 g per 24 h; persistent headache or visual disturbances; epigastric or right upper quadrant pain; impaired liver function; pulmonary oedema; abnormal renal function; thrombocytopenia; or fetal growth restriction. Patients with baseline hypertension, proteinuria, diabetes, kidney disease, twin pregnancy or infection were excluded.

After obtaining informed consent, blood samples were collected from women with PE before the administration of any medication and from normotensive pregnant women. Serum was separated by centrifugation and stored at −80 °C before use. tTG, sFlt-1, sEng and free VEGF levels were determined in duplicate using a specific enzyme-linked immunosorbent assay according to the manufacturer’s instructions (ELISA kits, BlueGene Biotech, Shanghai, China). The detection range of tTG was from 0 to 50 ng ml−1, and the intra-assay and inter-assay variations were 5.8% and 5.5%, respectively. The detection range of sFlt-1 was from 0 to 10 ng ml−1, and the intra-assay and inter-assay variations were 5.6% and 5.3%, respectively. The detection range of sEng was from 0 to 10 ng ml−1, and the intra-assay and inter-assay variation was 5.7% and 5.9%, respectively. The detection range of free VEGF was from 0 to 2500 pg ml−1, and the intra-assay and inter-assay variations were 5.5% and 4.9%, respectively.

All values are expressed as the means±s.e.m. and were analysed using the SPSS 13.0 software (Three students, Stanford, CA, USA). Comparisons among multiple groups were made using analysis of variance. Correlations between two variables were ascertained using Spearman’s rank correlation coefficient or Pearson’s correlation coefficient. A probability level of P<0.05 was considered significant.

Results

There were no significant differences in the age of the patients, body mass index, gestational age at blood sampling or gestational age at delivery. According to the grouping criteria, the systolic blood pressure, diastolic blood pressure and mean arterial blood pressure were significantly higher in the severe PE group than in both the mild PE and normotensive groups. Proteinuria (g per 24 h) was significantly higher in the severe PE group than in the mild PE group (Table 1).

Table 1 Clinical characteristics of study subjects

The circulating tTG, sFlt-1, sEng and free VEGF values for the three study groups are shown in Figure 1. The serum levels of tTG were significantly increased in both the mild PE and severe PE groups compared with the normotensive pregnant women (8.73±0.63 vs 11.79±1.09 vs 7.18±0.65 ng ml−1, respectively, P<0.001). Additionally, the serum tTG levels in the severe PE group were elevated compared with the mild PE group (11.79±1.09 vs 8.73±0.63 ng ml−1, P<0.001). The serum levels of sFlt-1 were significantly elevated in both the mild PE and severe PE groups compared with normotensive pregnant women (2.58±0.61 vs 5.58±0.60 vs 1.15±0.40 ng ml−1, respectively, P<0.001). Additionally, the serum sFlt-1 levels in the severe PE group were elevated compared with the mild PE group (5.58±0.60 vs 2.58±0.61 ng ml−1, P<0.001). The serum levels of sEng were significantly higher in both the mild PE and severe PE groups than in the normotensive pregnant women (5.21±0.70 vs 7.27±0.64 vs 1.52±0.56 ng ml−1, respectively, P<0.001). Additionally, the serum sEng levels in the severe PE group were significantly elevated compared with the mild PE group (7.27±0.64 vs 5.21±0.70 ng ml−1, P<0.001). By contrast, the serum levels of free VEGF were significantly decreased in both the mild PE and severe PE groups compared with the normotensive pregnant women (214.51±27.09 vs 123.24±23.73 vs 311.02±38.48 pg ml−1, respectively, P<0.001). Furthermore, the serum free VEGF levels in the severe PE group were lower than in the mild PE group (123.24±23.73 vs 214.51±27.09 pg ml−1, respectively, P<0.001).

Figure 1
figure1

Circulating serum (a) tTG, (b) sFlt-1, (c) sEng and (d) VEGF levels in normotensive pregnant women, women with mild PE and women with severe PE. Serum tTG, sFlt-1 and sEng levels are increased, but VEGF levels are decreased in the mild PE and severe PE compared with normotensive pregnant women. ##P<0.001, severe PE and mild PE vs NT. **P<0.001, severe PE vs mild PE. A full colour version of this figure is available at the Journal of Human Hypertension journal online.

We examined the correlation among sFlt-1, sEng and VEGF levels in both the normotensive and the PE groups. There was no significant correlation among sEng and VEGF, sFlt-1 and VEGF or sFlt-1 and sEng in the normotensive group (r=−0.033, P=0.674; r=−0.024, P=0.873; and r=0.076, P=0.451, respectively). As shown in Figure 2 in the PE group, a strong positive correlation was observed between the sFlt-1 and sEng levels (r=0.819, P<0.001). By contrast, a strong negative correlation was observed between sEng and VEGF levels, and this correlation was similar to that between sFlt-1 and VEGF (r=−0.760, P<0.001; and r=−0.830, P<0.001, respectively).

Figure 2
figure2

Correlation between sFlt-1 and sEng (a), sEng and VEGF (b) and sFlt-1 and VEGF (c) in the PE group.

Figure 3 shows the correlation between tTG and sFlt-1, between tTG and sEng and between tTG and VEGF in PE patients. tTG showed a significant positive correlation with sFlt-1 and sEng in PE patients (r=0.819, P<0.001; and r=0.734, P<0.001, respectively) and a negative correlation with VEGF (r=−0.767, P<0.001), whereas there were no associations with other factors in normotensive patients. Additionally, we found that the serum tTG levels correlated with disease severity in the PE groups (r=0.863, P<0.001).

Figure 3
figure3

Correlation between tTG and sFlt-1 (a), sEng (b) and VEGF (c) in the PE group.

Serum tTG, sFlt-1 and sEng levels showed a significant positive association with mean arterial pressure in the PE groups. However, VEGF levels showed a negative association. In the normotensive group, tTG, sFlt-1, sEng and VEGF levels showed no association with mean arterial pressure (Table 2).

Table 2 Association of tTG, sFlt-1, sEng and VEGF levels with mean arterial pressure in the PE and NT groups

Moreover, tTG, sFlt-1, sEng and VEGF levels displayed a significant correlation with the degree of proteinuria. The positive correlations of proteinuria with tTG, sFlt-1 and sEng levels were significant in the PE groups (r=0.428, P=0.033; r=0.636, P=0.001; and r=0.478, P=0.016, respectively). The serum VEGF levels showed a negative correlation with proteinuria (r=−0.526, P=0.007).

Discussion

The circulating factor secreted by the placenta and the pathogenesis of PE have not yet been identified. Here we report that a novel tTG that is present in the serum of pregnant women is elevated in preeclamptic patients and correlates with disease severity. This study is the first to show a relationship between circulating tTG levels and sFlt-1, sEng and VEGF levels in women with PE. Consistent with other studies, we confirmed the changes in circulating sFlt-1, sEng and VEGF in Chinese individuals with PE.

Significant advances have recently been made in our understanding of the pathogenesis of PE. Maynard et al.28 and Venkatesha et al.30 demonstrated the abnormally elevated production of sFlt-1 and sEng, two powerful antiangiogenic factors that are secreted by preeclamptic placentae, and further identified the significance of these findings in animal models. Subsequent studies have validated these findings in a cohort of pregnant women; sFlt-1 and sEng levels correlated with disease severity and were elevated prior to the clinical manifestations.33, 34 sFlt-1 and sEng exert their pathogenic effects by antagonising the biological effect of VEGF and TGFβ. As shown in Figures 1b–d, the severe PE group showed higher levels of sFlt-1 (5.58±0.60 vs 2.58±0.61 vs 1.15±0.40 ng ml−1, P<0.001) and sEng (7.27±0.64 vs 5.21±0.70 vs 1.52±0.56 ng ml−1, P<0.001) and lower levels of free VEGF (123.24±23.73 vs 214.51±27.09 vs 311.02±38.48 pg ml−1, P<0.001) than the mild PE and normotensive groups. Our findings suggest that sFlt-1 and sEng may have important diagnostic implications.

tTG has an extensive role in the human body and has been implicated in many physiological and pathological processes. tTG is associated with Alzheimer's disease, neurodegenerative diseases (such as Huntington's disease), liver fibrosis, the degree of tumor malignancy, peritoneal immune disease (celiac disease) and diabetes. These findings show that tTG has wide-ranging effects in the body.

Recent studies13, 36, 37 have found that tTG has an important role in the maternal–fetal interface and placental development. Liu et al.7 reported a significant increase in plasma TG activity in patients with PE. The increase in plasma TG activity may result from the increased circulating tTG shed from PE placental syncytiotrophoblasts.14 Here we examined the circulating serum tTG levels in PE patients and normotensive pregnant women. The serum tTG levels were significantly elevated in the severe PE group compared with both the mild PE and normotensive groups. The strong positive correlation between tTG levels and disease severity suggests that serum tTG levels may act as a novel biomarker of PE.

We showed a significant correlation among sFlt-1, sEng and free VEGF levels in the PE groups but not in the normotensive group. The increased sFlt-1 and sEng likely occur through a direct effect on the reduction of VEGF levels and contribute to the pathogenesis of PE. We also reported that tTG was positively correlated with sFlt-1 and sEng and negatively correlated with VEGF in the PE groups. These results further reveal the probable role of tTG in PE. We analysed the relationship between tTG and both mean arterial pressure and the degree of proteinuria. tTG positively correlated with both of these symptoms. We speculate that tTG contributes to endothelial dysfunction, hypertension and proteinuria in PE, although the exact mechanism remains unclear.

However, this study has some limitations. Although we demonstrated a statistical correlation between tTG and other antiangiogenic and pro-angiogenic factors, causality remains unclear. A larger sample of prospective studies is required to establish the temporal profile of elevated tTG and other factors. To determine the role of elevated tTG originating from the placenta, serum at 48 h after delivery should be collected and used to examine tTG levels.

In summary, we show a relationship between tTG, which is a potential PE pathogenic factor, with the antiangiogenic factors sFlt-1 and sEng and the pro-angiogenic factor VEGF, revealing a possible link between these factors in PE pathogenesis. This interaction may lead to the development of PE. Our results also suggest that tTG acts as a new serological marker in screening for PE and offer a new target for the effective prediction and treatment of PE. This study is only a small case–control study of China patients with PE. Therefore, we will examine a larger sample size with the classification of gestational hypertensive disorder, which will improve the precision of our findings.

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We thank Guangzhou Medical College and Guangzhou Women and Children’s Medical Center for providing support and guidance.

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Cheng, M., He, P. & Fu, J. The relationship between circulating tissue transglutaminase, soluble fms-like tyrosine kinase-1, soluble endoglin and vascular endothelial growth factor in pre-eclampsia. J Hum Hypertens 30, 788–793 (2016). https://doi.org/10.1038/jhh.2016.32

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