Journal Article

Role of soluble endoglin in BMP9 signaling

Dijke, Peter ten, Redgrave, Rachael E., Tong, Zhen, Cai, Jie, van Dinther, Maarten, Li, Wei, Thorikay, Midory, Morrell, Nicholas W., Arthur, Helen M., Lawera, Aleksandra, Charnock-Jones, D. Stephen, Afink, Gijs B.

2019

Overview

Endoglin (ENG) is a coreceptor of the transforming growth factor-β (TGFβ) family signaling complex, which is highly expressed on endothelial cells and plays a key role in angiogenesis. Its extracellular domain can be cleaved and released into the circulation as soluble ENG (sENG). High circulating levels of sENG contribute to the pathogenesis of preeclampsia (PE). Circulating bone morphogenetic protein 9 (BMP9), a vascular quiescence and endothelial-protective factor, binds sENG with high affinity, but how sENG participates in BMP9 signaling complexes is not fully resolved. sENG was thought to be a ligand trap for BMP9, preventing type II receptor binding and BMP9 signaling. Here we show that, despite cell-surface ENG being a dimer linked by disulfide bonds, sENG purified from human placenta and plasma from PE patients is primarily in a monomeric form. Incubating monomeric sENG with the circulating form of BMP9 (prodomain-bound form) in solution leads to the release of the prodomain and formation of a sENG:BMP9 complex. Furthermore, we demonstrate that binding of sENG to BMP9 does not inhibit BMP9 signaling. Indeed, the sENG:BMP9 complex signals with comparable potency and specificity to BMP9 on human primary endothelial cells. The full signaling activity of the sENG:BMP9 complex required transmembrane ENG. This study confirms that rather than being an inhibitory ligand trap, increased circulating sENG might preferentially direct BMP9 signaling via cell-surface ENG at the endothelium. This is important for understanding the role of sENG in the pathobiology of PE and other cardiovascular diseases.

• Publisher: National Academy of Sciences
• Subject: Angiogenesis / Binding / Biochemistry / Biological Sciences / Bone morphogenetic protein 9 / Cardiovascular diseases / Cell surface / Dimers / Disulfide bonds / Endoglin / Endoglin - metabolism / Endothelial cells / Endothelial Cells - metabolism / Endothelial Cells - pathology / Endothelium / Female / Growth Differentiation Factor 2 - metabolism / Growth factors / Humans / Ligands / Pathogenesis / Placenta / Placenta - metabolism / Placenta - pathology / PNAS Plus / Pre-eclampsia / Pre-Eclampsia - metabolism / Pre-Eclampsia - pathology / Pregnancy / Pregnancy Proteins - metabolism / Signal Transduction / Signaling / Transforming growth factor-b