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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NOTE: Due to an editing error, some reference citations in the text are incorrect. In particular, the second citation of ref. 22 (on p. 644) should be ref. 23 and refs. 23–49 should be refs. 24–50. This has been corrected in the HTML and PDF versions of the article.
Sibai, B., Dekker, G. & Kupferminc, M. Pre-eclampsia. Lancet 365, 785–799 (2005).
Weinstein, L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am. J. Obstet. Gynecol. 142, 159–167 (1982).
Roberts, J.M. et al. Preeclampsia: an endothelial cell disorder. Am. J. Obstet. Gynecol. 161, 1200–1204 (1989).
Maynard, S.E. et al. 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 (2003).
Zhou, Y. et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am. J. Pathol. 160, 1405–1423 (2002).
Ahmad, S. & Ahmed, A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ. Res. 95, 884–891 (2004).
Chaiworapongsa, T. et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am. J. Obstet. Gynecol. 190, 1541–1547; discussion 1547–1550 (2004).
Taylor, R.N. et al. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am. J. Obstet. Gynecol. 188, 177–182 (2003).
Levine, R.J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683 (2004).
Chaiworapongsa, T. et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J. Matern. Fetal Neonatal Med. 17, 3–18 (2005).
Hertig, A. et al. Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin. Chem. 50, 1702–1703 (2004).
Romero, R. et al. Clinical significance, prevalence, and natural history of thrombocytopenia in pregnancy-induced hypertension. Am. J. Perinatol. 6, 32–38 (1989).
Cheifetz, S. et al. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J. Biol. Chem. 267, 19027–19030 (1992).
Gougos, A. et al. Identification of distinct epitopes of endoglin, an RGD-containing glycoprotein of endothelial cells, leukemic cells, and syncytiotrophoblasts. Int. Immunol. 4, 83–92 (1992).
St-Jacques, S., Forte, M., Lye, S.J. & Letarte, M. Localization of endoglin, a transforming growth factor-beta binding protein, and of CD44 and integrins in placenta during the first trimester of pregnancy. Biol. Reprod. 51, 405–413 (1994).
McAllister, K.A. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat. Genet. 8, 345–351 (1994).
Bourdeau, A., Dumont, D.J. & Letarte, M. A murine model of hereditary hemorrhagic telangiectasia. J. Clin. Invest. 104, 1343–1351 (1999).
Li, D.Y. et al. Defective angiogenesis in mice lacking endoglin. Science 284, 1534–1537 (1999).
Toporsian, M. et al. A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ. Res. 96, 684–692 (2005).
Dimmeler, S., Dernbach, E. & Zeiher, A.M. Phosphorylation of the endothelial nitric oxide synthase at ser-1177 is required for VEGF-induced endothelial cell migration. FEBS Lett. 477, 258–262 (2000).
Garcia-Cardena, G. et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 392, 821–824 (1998).
Fleming, I., Fisslthaler, B., Dimmeler, S., Kemp, B.E. & Busse, R. Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circ. Res. 88, E68–E75 (2001).
Brown, M.A., Zammit, V.C. & Lowe, S.A. Capillary permeability and extracellular fluid volumes in pregnancy-induced hypertension. Clin. Sci. (Lond.) 77, 599–604 (1989).
Inoue, N. et al. Molecular regulation of the bovine endothelial cell nitric oxide synthase by transforming growth factor-beta 1. Arterioscler. Thromb. Vasc. Biol. 15, 1255–1261 (1995).
Saura, M. et al. Smad2 mediates transforming growth factor-β induction of endothelial nitric oxide synthase expression. Circ. Res. 91, 806–813 (2002).
Bdolah, Y., Sukhatme, V.P. & Karumanchi, S.A. Angiogenic imbalance in the pathophysiology of preeclampsia: newer insights. Semin. Nephrol. 24, 548–556 (2004).
Redman, C.W. & Sargent, I.L. Latest advances in understanding preeclampsia. Science 308, 1592–1594 (2005).
Li, C. et al. Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer. Int. J. Cancer 89, 122–126 (2000).
Velasco-Loyden, G., Arribas, J. & Lopez-Casillas, F. The shedding of betaglycan is regulated by pervanadate and mediated by membrane type matrix metalloprotease-1. J. Biol. Chem. 279, 7721–7733 (2004).
Benian, A., Madazli, R., Aksu, F., Uzun, H. & Aydin, S. Plasma and placental levels of interleukin-10, transforming growth factor-β1, and epithelial-cadherin in preeclampsia. Obstet. Gynecol. 100, 327–331 (2002).
Muy-Rivera, M. et al. Transforming growth factor-β1 (TGF-β1) in plasma is associated with preeclampsia risk in Peruvian women with systemic inflammation. Am. J. Hypertens. 17, 334–338 (2004).
Hennessy, A. et al. Transforming growth factor-β 1 does not relate to hypertension in pre-eclampsia. Clin. Exp. Pharmacol. Physiol. 29, 968–971 (2002).
Barbara, N.P., Wrana, J.L. & Letarte, M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J. Biol. Chem. 274, 584–594 (1999).
Shesely, E.G. et al. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 93, 13176–13181 (1996).
Lowe, D.T. Nitric oxide dysfunction in the pathophysiology of preeclampsia. Nitric Oxide 4, 441–458 (2000).
Papapetropoulos, A., Garcia-Cardena, G., Madri, J.A. & Sessa, W.C. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J. Clin. Invest. 100, 3131–3139 (1997).
Predescu, D., Predescu, S., Shimizu, J., Miyawaki-Shimizu, K. & Malik, A.B. Constitutive eNOS-derived nitric oxide is a determinant of endothelial junctional integrity. Am. J. Physiol. Lung Cell. Mol. Physiol. 289, L371–L381 (2005).
Tatsumi, M., Kishi, Y., Miyata, T. & Numano, F. Transforming growth factor-beta(1) restores antiplatelet function of endothelial cells exposed to anoxia-reoxygenation injury. Thromb. Res. 98, 451–459 (2000).
Ristimaki, A., Ylikorkala, O. & Viinikka, L. Effect of growth factors on human vascular endothelial cell prostacyclin production. Arteriosclerosis 10, 653–657 (1990).
He, H. et al. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J. Biol. Chem. 274, 25130–25135 (1999).
Mills, J.L. et al. Prostacyclin and thromboxane changes predating clinical onset of preeclampsia: a multicenter prospective study. J. Am. Med. Assoc. 282, 356–362 (1999).
Darland, D.C. et al. Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev. Biol. 264, 275–288 (2003).
Zhou, Y. et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J. Clin. Invest. 99, 2139–2151 (1997).
Zhou, Y., Damsky, C.H. & Fisher, S.J. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J. Clin. Invest. 99, 2152–2164 (1997).
Caniggia, I., Taylor, C.V., Ritchie, J.W., Lye, S.J. & Letarte, M. Endoglin regulates trophoblast differentiation along the invasive pathway in human placental villous explants. Endocrinology 138, 4977–4988 (1997).
Fonsatti, E., Altomonte, M., Arslan, P. & Maio, M. Endoglin (CD105): a target for anti-angiogenetic cancer therapy. Curr. Drug Targets 4, 291–296 (2003).
Holash, J. et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl. Acad. Sci. USA 99, 11393–11398 (2002).
ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet. Gynecol. 99, 159–167 (2002).
Kuo, C.J. et al. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Proc. Natl. Acad. Sci. USA 98, 4605–4610 (2001).
Akiyoshi, S. et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J. Biol. Chem. 274, 35269–35277 (1999).
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.
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.
Electron microscopy documents glomerular endotheliosis in pregnant rats. (PDF 330 kb)
sEng inhibits TGF-β1–mediated vascular reactivity in mesenteric vessels. (PDF 208 kb)
Western blots of rat plasma demonstrating expression of the recombinant sFlt1 and sEng. (PDF 572 kb)
Clinical characteristics in the pregnant patient groups. (PDF 91 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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