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Soluble endoglin contributes to the pathogenesis of preeclampsia

Nature Medicine volume 12, pages 642–649 (2006)Cite this article

A Corrigendum to this article was published on 01 July 2006

Abstract

Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-β coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-β1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-β signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.

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Figure 1: Expression of ENG mRNA and Eng in placentae of normal and preeclamptic pregnancies.
Figure 2: Increased sEng levels in sera from individuals with preeclampsia.
Figure 3: sEng inhibits capillary formation and increases vascular permeability.
Figure 4: Renal, placental and hepatic histological changes and peripheral blood smears in pregnant rats after sEng and sFlt1 treatment.
Figure 5: Recombinant sEng attenuates TGF-β1 binding and has effects on vasodilation through activation of eNOS.

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Acknowledgements

We thank all the staff in the Department of Obstetrics at the Beth Israel Deaconess Medical Center for help with patient identification and recruitment. We thank B. Furie's laboratory for help with measurement of platelet counts in rats, J. Min and the Physiology Core laboratory for help with blood pressure measurements, J. Li for vascular reactivity experiments, R. Mulligan for help with the production of sFlt1 adenoviruses, L. Zhang for technical assistance with mass spectrometry, B. Sachs, R. Levine, R. Thadhani, J. Flier, W. Aird and S. Pennathur for discussions. This work was funded by US National Institutes of Health grants DK064255 and HL079594 to S.A.K., Department of Medicine, Obstetrics and Gynecology seed funds to S.A.K. and V.P.S., and Heart and Stroke Foundation of Ontario grant T5016 to M.L.

Author information

Author notes

  1. Shivalingappa Venkatesha, Mourad Toporsian and Chun Lam: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Medicine, Center for Vascular Biology, Obstetrics and Gynecology, Surgery, and Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Shivalingappa Venkatesha, Chun Lam, Jun-ichi Hanai, Tadanori Mammoto, Yuval Bdolah, Kee-Hak Lim, Hai-Tao Yuan, Towia A Libermann, Isaac E Stillman, Franklin H Epstein, Frank W Sellke, Vikas P Sukhatme & S Ananth Karumanchi

  2. Cancer Research Program, Hospital for Sick Children, and The Heart and Stroke Foundation Richard Lewar Centre of Excellence, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Mourad Toporsian & Michelle Letarte

  3. Department of Health and Human Services, Perinatology Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

    Yeon M Kim & Roberto Romero

  4. Wayne State University School of Medicine, 3980 John R, Detroit, 48201, Michigan, USA

    Yeon M Kim & Roberto Romero

  5. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Drucilla Roberts

  6. Schepens Eye Research Institute and Harvard Medical School, 20 Staniford Steet, Boston, 02114, Massachusetts, USA

    Patricia A D'Amore

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Contributions

S.V.: mRNA and protein expression studies of Eng/sEng, generation and expression of sEng adenoviruses, all animal studies; substantial contribution to writing, editing and generation of figures. M.T.: biochemical characterization of sEng, TGF-β effects on eNOS dephosphorylation, studies of sEng on TGF-β effects; substantial contribution to writing and editing of manuscript and generation of figures. C.L.: enrollment and collection of all human material, ELISA studies on human samples, in vitro angiogenesis assays and biochemical studies of urine and plasma obtained from animals. J.H.: TGF-β–Smad promoter studies. T.M.: vascular permeability studies. Y.M.K.: immunohistochemistry of human placental samples. Y.B.: animal studies. K.H.L.: enrollment and collection of all human material, expertise in clinical preeclampsia. H.Y.: in vitro angiogenesis assays. T.A.L.: Affymetrix microarray experiments. I.E.S.: all rat histological studies, including electron microscopy. D.R.: rat placental histological studies. P.A.D.: provided expertise in vascular biology and TGF-β signaling. F.H.E.: provided expertise in clinical preeclampsia. F.W.S.: all microvascular reactivity experiments. R.R.: immunohistochemistry of human placental samples; provided expertise in preeclampsia. V.P.S.: interpretation of microarray experiments, microvascular permeability studies; provided overall expertise in vascular biology and preeclampsia; final editing of the manuscript. M.L.: provided expertise on Eng, analysis and interpretation of studies involving biochemical characterization of sEng, TGF-β effects on eNOS dephosphorylation, studies of sEng on TGF-β effects; substantially contributed to writing and editing of manuscript. S.A.K: principal investigator of the study; overall design and concept, analysis and interpretation of all data, drafting and final editing of the manuscript.

Corresponding author

Correspondence to S Ananth Karumanchi.

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Competing interests

S. Ananth Karumanchi and Vikas P. Sukhatme are listed as co-inventors on multiple patents filed by the Beth Israel Deaconness Medical Center for the diagnosis and therapy of preeclampsia. These patents have been licensed to multiple diagnostic and therapeutic companies.

S. Ananth Karumanchi and Vikas P. Sukhatme serve as consultants to Abbott, Beckman Coulter and Johnson & Johnson.

Supplementary information

Supplementary Fig. 1

Electron microscopy documents glomerular endotheliosis in pregnant rats. (PDF 330 kb)

Supplementary Fig. 2

sEng inhibits TGF-β1–mediated vascular reactivity in mesenteric vessels. (PDF 208 kb)

Supplementary Fig. 3

Western blots of rat plasma demonstrating expression of the recombinant sFlt1 and sEng. (PDF 572 kb)

Supplementary Table 1

Clinical characteristics in the pregnant patient groups. (PDF 91 kb)

Supplementary Methods (PDF 88 kb)

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Venkatesha, S., Toporsian, M., Lam, C. et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12, 642–649 (2006). https://doi.org/10.1038/nm1429

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