Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2774
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2831-2834
Copyright © 2007 by The Endocrine Society
Maternal Plasma Concentrations of Soluble Endoglin in Pregnancies with Intrauterine Growth Restriction
Holger Stepan,
Thomas Krämer and
Renaldo Faber
Department of Obstetrics and Gynecology, University of Leipzig, 04103 Leipzig, Germany
Address all correspondence and requests for reprints to: Holger Stepan, M.D., Department of Obstetrics and Gynecology, Philipp-Rosenthalstr. 55, 04103 Leipzig, Germany. E-mail: holger.stepan{at}medizin.uni-leipzig.de.
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Abstract
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Context: Soluble endoglin (sEng), a coreceptor for TGF with antiangiogenic properties, acts synergistically with soluble fms-like tyrosine kinase 1 (sFlt1) to induce symptoms of HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in animal models and to promote a preeclamptic phenotype. Pregnant women with preeclampsia show increased sEng concentrations in circulation, whereas the sEng increase is detectable months before the clinical onset of the disease.
Objective: The aim of the study was to determine whether maternal sEng is altered in pregnancies with normotensive intrauterine growth restriction (IUGR).
Design: sEng and sFlt1 were retrospectively determined by a commercial ELISA.
Patients: The study included 11 normotensive pregnancies with IUGR, 18 pregnancies with manifest preeclampsia, and 15 gestational-age-matched controls.
Results: Patients with preeclampsia showed significantly higher sEng concentrations compared with controls (57.0 ng/ml vs. 5.3 ng/ml; P < 0.001). Also IUGR pregnancies showed significantly elevated sEng concentrations (25.9 ng/ml; P < 0.001), but the levels were lower compared with the preeclamptic patients. There was a strong positive correlation between the sEng and sFlt1 concentration (Pearson 0.552; P < 0.01). Similar to sEng, the maternal sFlt1 concentration is highest in the preeclamptic patients (8388 vs. 2602 pg/ml; P < 0.01) but also significantly elevated in the IUGR patients (6952 pg/ml; P < 0.01).
Conclusions: Pregnancy with IUGR, but without maternal symptoms, was characterized by elevated sEng concentrations in circulation. Although this finding is less pronounced when compared with preeclampsia, sEng seems to be involved in different clinical manifestations of placental pathology.
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Introduction
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THERE IS GROWING evidence that an imbalance between factors that promote or antagonize angiogenesis has a crucial role in the pathogenesis of preeclampsia (1, 2, 3, 4). For example, a number of studies have shown consistently that an excess of soluble fms-like tyrosine kinase 1 (sFlt1) is associated with preeclampsia. However, there are data also supporting the concept that intrauterine growth restriction (IUGR), another placenta-related pregnancy disorder, is associated with increased levels of circulatory sFlt1 (5, 6, 7).
A recent study could show that a novel antiangiogenic protein, soluble endoglin (sEng), contributes to the pathogenesis of preeclampsia (8). In rats, coadministration of sEng and sFlt1 induces a phenotype of HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Similar to sFlt1, sEng is up-regulated in the preeclamptic placenta, and elevated levels of sEng are detectable in maternal circulation weeks before the clinical manifestation of preeclampsia (9). The question whether circulatory sEng is also altered in IUGR pregnancies has not been clearly answered yet. Levine et al. (9) could demonstrate that normotensive pregnancies with small for gestational age (SGA) infants have increasing sEng levels beginning in the second trimester with a large increase after wk 37 leading to equally high concentrations like term preeclampsia. However, the classification SGA with fetuses below the 10th percentile, although adjusted for gestational age and gender, covers a rather heterogeneous group of fetuses with widely different reasons for their low birth weight. In contrast, IUGR means that a fetus does not reach its own theoretical normal growth potential as a result of a disturbed placental function. IUGR is used to denote a pathological process resulting in restriction of fetal growth, whereas SGA refers to a statistical grouping of fetuses below a percentile. There is certainly a considerable overlap of these groups, and the percentile reflects biological diversity as well as IUGR because statistically, 10% of infants should fall below the 10th percentile. This implies that not all fetuses below the 10th percentile are growth-restricted and some fetuses above the 10th percentile may be growth-restricted. Consequently, we aimed at answering the question how is sEng altered in pregnancies with "real" IUGR?
Therefore, the purpose of this study was to compare sEng in pregnancies with IUGR characterized by abnormal uteroplacental perfusion to pregnancies with manifest preeclampsia and healthy, gestational-age-matched controls.
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Subjects and Methods
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The study was designed as a retrospective cohort study and includes 11 normotensive pregnancies with IUGR, 18 pregnancies with manifest preeclampsia, and 15 controls. Approval of the local ethics committee has been provided. All women gave informed consent. All investigated pregnancies were singleton. IUGR was defined as an estimated birth weight below the 5th percentile of a reference group. Women with IUGR pregnancies were normotensive and had no proteinuria. All IUGR pregnancies were characterized by an abnormal perfusion of the uterine arteries. The uterine perfusion was defined as abnormal if there was bilateral notching and/or if the mean pulsatility index of both arteries was greater than the 90th percentile. Additionally, all IUGR pregnancies were characterized by at least one sign of disturbed placental function such as oligohydramnios and/or a pulsatility index of the umbilical artery greater than the 90th percentile (data not shown). Preeclampsia was defined as gestational proteinuric hypertension, which was developed antenatally, for the first time in labor or for the first time in the puerperium according to the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy (10). Under this classification, gestational hypertension is defined as a blood pressure greater than 140 mm Hg systolic or greater than 90 mm Hg diastolic in a woman who was normotensive before 20 wk gestation. Significant proteinuria is defined as at least 300 mg total protein in a 24-h urine collection or at least 1+ proteinuria by dipstick in a random urine determination with no evidence of urinary tract infection. All patients with preeclampsia in this study had appropriate-for-gestational age fetuses. Controls were chosen from a group with preterm labor but not premature rupture of the membranes. All patients in this group were normotensive, had appropriate-for-gestational-age fetuses, and had no signs of placental dysfunction.
From each patient, one venous blood sample (10 ml) was drawn from each woman into tubes containing EDTA. Immediately after sampling, plasma was separated by centrifugation at 4000 x g for 10 min and frozen at –80 C. Maternal plasma sEng and sFlt1 were measured using commercial enzyme-linked immunosorbent assays (R&D Systems, Minneapolis, MN) that measure total (bound and unbound) protein concentrations.
Group summaries are expressed as median value with interquartile ranges (25–75%). Statistical analysis was performed via one-way ANOVA, Tukey HSD test and Pearson’s correlation coefficients where appropriate using the program Statistical Package for Social Sciences (SPSS, Chicago, IL). In all tests, the criterion for statistical significance is P < 0.05.
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Results
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Clinical characteristics of the patients are given in Table 1
. As expected, patients with preeclampsia showed significantly higher sEng concentrations compared with controls [57.09 (32.6–81.7) ng/ml vs. 5.3 (4.1–7.1) ng/ml; P < 0.001; Fig. 1A]. IUGR pregnancies also showed significantly elevated sEng concentration [25.9 (18.0–42.0) ng/ml; P < 0.001] but did not reach the levels of the preeclamptic patients (P < 0.05; Fig. 1A). In the study group, we found a strong positive correlation between the sEng and sFlt1 concentration (Pearson 0.552; P < 0.01; Fig. 2). This positive correlation between sEng and sFlt1 also reaches statistical significance in the subgroup with IUGR (Pearson 0.653; P < 0.05) and in the controls (Pearson 0.91; P < 0.01). Similar to sEng, the maternal sFlt1 concentration is highest in the preeclamptic patients [8,388 (6,747–15,392) vs. 2,602 (2,218–3,332) pg/ml; P < 0.01; Fig. 1B] but also significantly elevated in the IUGR patients [6,952 (1,697–10,095) pg/ml; P < 0.01].
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FIG. 1. A, Maternal plasma concentration of sEng in pregnancies with IUGR, preeclampsia (PE), and gestational-age-matched controls. Data are present as median ± SD. B, Maternal plasma concentration of sFlt1 in pregnancies with IUGR, preeclampsia, and gestational-age-matched controls. Data are presented as median ± SD. **, P < 0.001 vs. controls; *, P < 0.01 vs. controls; #, P < 0.05 vs. preeclampsia.
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FIG. 2. Scatter plot and correlation between maternal sEng plasma concentration (ng/ml) and maternal sFlt1 plasma concentration (pg/ml).
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Discussion
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This study is the first to show maternal sEng concentrations in pregnant women with IUGR. Endoglin is a cell-surface coreceptor for TGF-ß1 and TGF-ß3 isoforms, and it is highly expressed in endothelial cells and the trophoblast. It could be demonstrated that endoglin plays a crucial role in blood cell-mediated vascular repair (11). A placenta-derived soluble form of endoglin (sEng) shows antiangiogenic effects in vitro and is elevated in the circulation of preeclamptic patients (9). Thus, the question whether sEng is also altered in IUGR pregnancies was a logical consequence. Both pregnancy complications, preeclampsia and IUGR, result from a disturbed placental function, share important pathophysiological phenomena such as shallow trophoblast invasion, and often occur combined with an overlap in the clinical presentation. To answer this question properly, IUGR has to be clearly defined. Usually, IUGR is defined as a fetus below a certain weight percentile and mixed with SGA fetuses. As mentioned above, this definition is common and also includes healthy fetuses with a low genetic growth potential. These pregnancies do not have a placental problem and presumably have an unaltered angiogenic balance. IUGR in a narrow and precise meaning includes only fetuses that do not reach their growth potential due to placental insufficiency. The IUGR pregnancies enrolled in this study are all characterized by increased placental impedance as a consequence of an inadequate trophoblast invasion. Our study also shows that pregnancies with "isolated" IUGR have significantly increased sEng concentrations in maternal circulation. However, the measured levels are lower in comparison to patients with manifest preeclampsia at the same gestational age. This finding allows two interpretations: 1) the up-regulation and release of sEng is mainly a phenomenon of preeclampsia and sEng is to a lesser extent involved in the pathogenesis of IUGR. This would be in conformance with the observation that sEng induces in vivo vascular permeability and hypertension, typical features of preeclampsia. 2) IUGR and preeclampsia share a common pathobiological pathway, but IUGR pregnancies may have a different sequence of the symptoms with a delayed maternal reaction and attenuated sEng action in IUGR. Thus, IUGR, although without hypertension, can be considered as a related clinical manifestation in which sEng does not reach the threshold for the full maternal syndrome. Our data also confirm previous studies that report increased sFlt1 level in IUGR pregnancies (5, 6, 7). However, it has to be mentioned that other studies did not find increased sFlt1 concentrations in IUGR pregnancies (12, 13). The reason for this contradiction could be the above-mentioned difficulties to define IUGR. We cannot exclude that some of the IUGR patients in our study would have developed preeclampsia later on. The tendency of elevated blood pressure values in IUGR patients when compared with the controls indicates that some of the IUGR pregnancies were possibly close to the threshold of preeclamptic symptoms and criteria. This has to be considered in the interpretation of the data and would be in line with the above-mentioned hypothesis of a different sequence of the clinical symptoms and a retarded sEng increase in those patients.
In our study, both antiangiogenic markers, sEng and sFlt1, correlate strongly, and the figures that show the differences between the groups look almost identical. This implies that both factors indeed act in concert to induce the pathological alterations in these placenta-related diseases. One can speculate that the analog elevations of both factors result from a common trigger mechanism for the placental production and liberation of sEng and sFlt1. Further studies have to test diagnostic and predictive potential of sEng and other angiogenic factors.
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Acknowledgments
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We thank Andrea Rothe for the excellent laboratory work.
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Footnotes
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Disclosure Statement: The authors have nothing to disclose.
First Published Online April 10, 2007
Abbreviations: IUGR, Intrauterine growth restriction; sEng, soluble endoglin; sFlt1, soluble fms-like tyrosine kinase 1; SGA, small for gestational age.
Received December 14, 2006.
Accepted April 3, 2007.
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References
|
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- Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA 2003 Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658[CrossRef][Medline]
- Lam C, Lim KH, Karumanchi SA 2005 Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 46:1077–1085[Abstract/Free Full Text]
- Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA 2004 Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683[Abstract/Free Full Text]
- Tjoa ML, Levine RJ, Karumanchi SA 2007 Angiogenic factors and preeclampsia. Front Biosci 12:2395–2402[CrossRef][Medline]
- Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A, Schaaps JP, Cabrol D, Frankenne F, Foidart JM 2003 Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 88:5555–5563[Abstract/Free Full Text]
- Wallner W, Sengenberger R, Strick R, Strissel PL, Meurer B, Beckmann MW, Schlembach D 2007 Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction. Clin Sci (Lond) 112:51–57[Medline]
- Stepan H, Geide A, Faber R 2004 Soluble fms-like tyrosine kinase 1. N Engl J Med 351:2241–2242[Free Full Text]
- Venkatesha S, Toporsian M, Lam C, Hanai JI, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D’Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA 2006 Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12:642–649[CrossRef][Medline]
- Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA; CPEP Study Group 2006 Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005[Abstract/Free Full Text]
- National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy 2000. Am J Obstet Gynecol 183:1–22
- van Laake LW, van den Driesche S, Post S, Feijen A, Jansen MA, Driessens MH, Mager JJ, Snijder RJ, Westermann CJ, Doevendans PA, van Echteld CJ, ten Dijke P, Arthur HM, Goumans MJ, Lebrin F, Mummery CL 2006 Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation 114:2288–2297[Abstract/Free Full Text]
- Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar LM, Crombleholme WR, Ness RB, Roberts JM, Hubel CA 2005 Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor. J Clin Endocrinol Metab 90:4895–4903[Abstract/Free Full Text]
- Wathen KA, Tuutti E, Stenman UH, Alfthan H, Halmesmaki E, Finne P, Ylikorkala O, Vuorela P 2006 Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation. J Clin Endocrinol Metab 91:180–184[Abstract/Free Full Text]
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Abstract
Introduction
