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ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice

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Science  18 Aug 2017:
Vol. 357, Issue 6352, pp. 707-713
DOI: 10.1126/science.aam6607

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  • The relevance of ELABELA in pre-eclampsia
    • D. Stephen Charnock-Jones, Professor of Reproductive Biology, University of Cambridge, UK
    • Other Contributors:
      • Natasha Pritchard, University of Melbourne, Australia
      • Tu’uhevaha Kaitu’u-Lino, University of Melbourne, Australia
      • Sungsam Gong, Bioinformatician, University of Cambridge, UK
      • Justyna Dopierala, University of Cambridge, UK
      • Gordon C. S. Smith, Professor of Obstetrics and Gynaecology, University of Cambridge, UK
      • Stephen Tong, Professor of Obstetrics, University of Melbourne, Australia

    Ho et al demonstrated that ablation of ELABELA in pregnant mice induced preeclampsia-like changes and speculated it may have a role in the etiology of this condition in women. While they show it is present in human placenta, they did not show levels are perturbed in human disease. Therefore, we measured circulating levels and placental ELABELA mRNA in women with preeclampsia and compared them to healthy women. We draw readers attention our recent study: “ELABELA/APELA levels are not decreased in the maternal circulation or placenta among women with preeclampsia”. American Journal of Pathology 2018. doi: 10.1016/j.ajpath.2018.04.008, PMID:29803833.

    In brief, we used samples from the Pregnancy Outcome Prediction study which is a prospective cohort of 4512 pregnant women. From this pool, we performed RNA-Seq on mRNA from 82 placentas obtained from women with preeclampsia and 82 controls (matched for laboring status, gestational age, fetal sex, caesarean section, smoking, maternal body mass index and age). There were no differences in the placental mRNAs encoding ELABELA: mean difference 0.53 %; 95% CI, -25.9 to 27.0, P = 0.78. In contrast, FLT1 mRNA was 1.31-fold higher (P=0.00098) in women with preeclampsia.

    Using an independent set of samples, we measured plasma ELABELA by immunoassay in 32 women with preterm preeclampsia and 32 controls delivered without complications at full term (matched for gestation at blood collection (29 weeks gestation), matern...

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    Competing Interests: None declared.
  • RE: ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice
    • Kun Sun, Pediatric Cardiologist, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
    • Other Contributors:
      • Jian Wang, Pediatric Cardiologist, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Sun Chen, Pediatric Cardiologist, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Jun Zhang, Epidemiologist, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Qingjie Wang, Principle Investigator, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Liping Feng, Parttime Principle Investigator, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Yurong Wu, Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    We were very interested in the work by Lena Ho et al(1) that the deficiency of plasma ELA in pregnant mouse model would lead to cardiovascular malformation in the offspring. Their previous study in zebrafish(2) also suggested that embryos with the loss of ELA would lead to a rudimentary heart. Therefore we performed a pilot study with 20 cases of normotensive pregnant women prenatally diagnosed with fetal congenital heart disease (CHD), and 20 controls matched with time of enrollment, gestational age (24.45±0.81 weeks) and blood pressure status. The ELA concentrations in EDTA anticoagulated plasma were measured in duplicates by human ELA Elisa Kit (Peninsula Laboratories International, Inc. USA).
    We found that plasma ELA concentration in pregnant women with fetal CHD was significantly lower (median: 12.65ng/ml, range: 12.0-17.43ng/ml) than the controls (median: 17.32ng/ml, 14.54-19.23ng/ml), with a p-value of 0.026. This result is in accordance with the results by Ho et al (1), and is the first validation of ELA concentration in pregnant human samples with fetal CHD(3).
    Hereby, we raised a hypothesis that maternal plasma ELA level could be a potential early biomarker for fetal CHD? There are several questions need be explored. 1) Will this significant correlation be the same during first trimester when the cardiovascular system is establishing? This question might be answered by a large birth cohort study. 2) Are there any differences in the regulation or funct...

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    Competing Interests: None declared.
  • RE: Greater caution should be exercised with respect to the extrapolation that ELA might enhance spiral artery remodeling to prevent the development of PE
    • Lionel Carbillon, Professor, Obstetrics & Gynecology, Assistance Publique - Hopitaux de Paris, Université Paris 13

    aI read with great interest the study published by Ho et al (1), who observed a preeclampsia(PE)-like syndrome in pregnant ELABELA (ELA) knockout mice that normalized after infusion with recombinant ELA or after parturition. These findings suggested that in mice, ELA acts as an essential systemic hormone during physiologic gestation. However, much greater caution should be exercised with respect to the extrapolation that based on its expression in trophoblasts of the mouse and in human villous trophoblasts during the first trimester, ELA might enhance subsequent spiral artery remodeling to prevent the development of PE during human pregnancy.
    In particular, in the mouse placenta, trophoblast invasion affects only a few spiral arteries and is mainly perivascular (2, 3, 4); this model is usually considered to be unsuitable for studying this particular aspect of the pathophysiology of PE (3). In contrast, human cytotrophoblasts migrate deeply into the lumen of spiral arteries (5) and invade their media in an extremely specific process involving vascular smooth muscle breakdown with replacement of the endothelium (6, 7). This incorporation of human invasive trophoblasts into spiral artery walls and the process of angiogenesis in the placental bed of Old World monkeys, great apes and humans are crucial to physiological changes in the spiral arteries, for which remodeling to form wide, low-resistance vessels is essential to the development of an adequate blood supply to t...

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    Competing Interests: None declared.
  • RE: ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice
    • Jun Zhang, Professor, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
    • Other Contributors:
      • Rong Huang, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Jing Zhu, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Lin Zhang, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Xiaolin Hua, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Liping Feng, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Weiping Ye, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Weiye Wang, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
      • Kun Sun, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    While the etiology of preeclampsia is largely unknown, Ho et al. published a report article in Science, which found that deficiency of ELABELA (ELA) might lead to the development of preeclampsia in mice[1]. However, little is known whether this is true in human.

    The Early Life Plan is an ongoing prospective cohort study where pregnant women are recruited in early pregnancy at the Xinhua Hospital in Shanghai, China, and followed prospectively until delivery[2]. As a pilot study, we identified 20 cases and 20 normotensive controls among primipara with similar gestational week at enrollment between cases ( mean±SD: 13.2±0.55 weeks) and controls (13.1±0.55 weeks). We used human ELA Elisa Kit (Peninsula Laboratories International, Inc. USA) to measure ELA concentration in duplicates in plasma samples collected at enrollment.

    We found that preeclamptic women had significantly higher concentration of plasma ELA (median: 182 ng/ml, range: 31-988 ng/ml) than the controls (114 ng/ml, 5.4-1006 ng/ml), p= 0.01) . Significant differences mainly came from severe preeclampsia or preeclampsia superimposed on chronic hypertension. This is in direct contrast to the results reported by Ho et al.[1]. If ELA plays an important role in the placental angiogenesis, preeclampsia should be associated with lower, not higher concentration of ELA in early human pregnancy.

    One possibility might be that there are potential differences between mice and humans in regulation and fun...

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    Competing Interests: None declared.
  • RE: Letter in response to “ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice.” (Ho L et al., Science 2017, June 29)
    • Romain ARRESTIER, Nephrologist, French National Institute of Health and Medical (INSERM), UMR_S1155, Tenon Hospital, F-75020, Paris, France
    • Other Contributors:
      • Alexandre HERTIG, Nephrologist, French National Institute of Health and Medical (INSERM), UMR_S1155, Tenon Hospital, F-75020, Paris, France

    The work by Lena Ho and collaborators (1) is a potential breakthrough: similar to the Vascular Endothelial Growth Factor [VEGF] system, where epithelial production of VEGF maintains the integrity of the adjacent endothelium through its cognate receptor Flt-1, epithelial (i.e. by syncytiotrophoblasts) secretion of ELA appears critical, via endothelial receptor APLR, for placental angiogenesis and endothelial tipping. ELA deficiency induces a convincing mouse model of placental insufficiency of vascular origin (in contrast to the increase in sFlt-1, the soluble form of Flt-1, characteristic of human preeclampsia(2), yet probably sFlt-1 does not cause the placental defect: sFlt1 was elegantly shown to control placental angiogenesis(3), but it acts downstream and the primum movens remains unknown). Three hallmarks of preeclampsia – hypertension, proteinuria, and glomerular endotheliosis – are present in gravid mice carrying ELA-deficient embryos. However, the level of current evidence linking the maternal preeclamptic phenotype with an increase in sFlt1 in maternal blood is so high(2,4), and the hypoxic RNA signal in ELA-deficient placentas so strong (placental hypoxia induces Flt1(5)), that the absence of increase of sFlt1 in maternal preeclamptic blood is puzzling. While it would be of interest to know whether ELA is decreased in blood from women about to develop preeclampsia (information not provided in the paper, which reports on the human production of ELA by syncytiotro...

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    Competing Interests: None declared.

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