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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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) doi:10.1038/nm1429
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