Review: The enigmatic role of endoglin in the placenta☆
Introduction
There are now close to 1300 papers on endoglin listed on PubMed, thirty years after its discovery. Its constant versus transient expression pattern on a restricted number of cell types, the ability of membrane endoglin to interact with multiple ligands of the TGF-β superfamily, the exact sequence of the soluble protein (sEng), its mechanism of production from the placenta and its ligand specificity, are all fascinating but remain controversial aspects of endoglin biology. We will review endoglin distribution, structure, ligand specificity, and role in the vascular endothelium, particularly in the context of normal pregnancy and preeclampsia.
Section snippets
Vascular endothelium
We first identified endoglin with the monoclonal antibody 44G4, raised against cell surface proteins prepared from a childhood leukemia cell line [1]. It soon became apparent that this glycoprotein was found in blood vessels and it was later classified as the endothelial marker CD105 [2]. Activation of endothelial cells leads to increased expression of endoglin, in response to an angiogenic or inflammatory stimulus [3], [4]. Endoglin is in fact widely used as a marker of tumor angiogenesis [3],
Membrane endoglin
Human endoglin is an integral membrane glycoprotein, composed of an N-terminal signal peptide, an orphan domain, a zona pellucida (ZP) domain, a juxtamembrane region, a transmembrane region and a short cytoplasmic domain [18], [24] as shown in Fig. 1. The protein is highly glycosylated with five potential N-linked sites within the orphan domain and O-glycan sites mostly in the ZP domain. Enzymatic removal of all the sugars leads to an observed reduction of about 25 kDa in molecular mass [25].
Ligands interacting with membrane endoglin
Membrane endoglin bound to radioactive TGF-β was first identified by chemical cross-linking in human umbilical vein endothelial cells, in complex with the types I and II serine kinase receptors [34]. Membrane endoglin interacts with TGF-β1 and TGF-β3 but not TGF-β2 isoforms [34]. In most cell types, responses to TGF-β are mediated via the type II receptor (TβRII) and the type I receptor ALK5 [35] (Fig. 2). This pathway is known to inhibit cellular proliferation, mediate fibronectin and collagen
eNOS and membrane endoglin
We demonstrated previously that membrane endoglin, through its short cytoplasmic domain, associates with endothelial NO synthase (eNOS) and Hsp90 in caveolae [9]. ALK1 also associates with eNOS, implying a multimeric complex at the cell surface [43]. The importance of endoglin and ALK1 in eNOS activation is seen in endothelial cells from patients with HHT and in animal models of the disease, which show uncoupling of eNOS, reduced NO production and increased eNOS-derived superoxide production
Conclusions
The enigmatic distribution of endoglin in terms of its persistent expression on vascular endothelium and the syncytiotrophoblast versus its transient expression in mesenchymal cells and the extravillous trophoblast likely will reveal cues as to the functions exerted in these different cell types during development. The sequence and 3D-structure of sEng produced by the placenta and elevated in preeclampsia remains to be established and its ligand specificity determined before its mode of action
Conflict of interest statement
The authors confirm that there is no conflict of interest in the above paper.
Acknowledgments
We wish to thank Zhijie Li and Dr James Rini of the Department of Biochemistry, University of Toronto, for their help and guidance with the surface Plasmon resonance experiments.
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Present address: Center Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, China.