Soluble endoglin contributes to the pathogenesis of preeclampsia

Shivalingappa Venkatesha^1, 6, Mourad Toporsian^2, 6, Chun Lam^1, 6, Jun-ichi Hanai¹, Tadanori Mammoto¹, Yeon M Kim³, Yuval Bdolah¹, Kee-Hak Lim¹, Hai-Tao Yuan¹, Towia A Libermann¹, Isaac E Stillman¹, Drucilla Roberts⁴, Patricia A D'Amore⁵, Franklin H Epstein¹, Frank W Sellke¹, Roberto Romero³, Vikas P Sukhatme¹, Michelle Letarte² & S Ananth Karumanchi¹

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

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, Ontario M5G 1X8, Canada.

³  Perinatology Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, and Wayne State University School of Medicine, 3980 John R, Detroit, Michigan 48201, USA.

⁴  Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.

⁵  Schepens Eye Research Institute and Harvard Medical School, 20 Staniford Steet, Boston, Massachusetts 02114, USA.

⁶  These authors contributed equally to this work.

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- 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-1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF- signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.

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