Review: the enigmatic role of endoglin in the placenta

The cellular expression, structure and function of endoglin, and its implication in several vascular disorders remain enigmatic, even 30 years after its discovery. Endoglin (CD105) is a homodimeric glycoprotein (180 kDa) constitutively expressed in the vascular endothelium. It is essential for cardiovascular development and mutations in the ENG gene lead to Hereditary Hemorrhagic Telangiectasia, a disorder characterized by arteriovenous malformations. Endoglin is also expressed in the syncytiotrophoblast throughout pregnancy, but transiently upregulated in the extravillous trophoblast of anchoring villi. Endoglin modulates responses to several TGF-β superfamily ligands and is essential for the negative regulation by TGF-β isoforms 1 and 3 of extravillous trophoblast differentiation. Membrane endoglin binds endothelial NO synthase and regulates its activation and vasomotor tone. There is also a circulating soluble form of endoglin (sEng; 65 kDa); its levels in the serum of women with preeclampsia are increased and correlated with disease severity. The exact sequence of sEng is still unresolved and the proposed mechanism of release from the syncytium by metalloproteases would not yield the expected size protein. The nature of the ligand sequestered by sEng is also an enigma. sEng is said to block the effects of TGF-β on NO-mediated vasorelaxation. However, sEng alone cannot scavenge these ligands for which it has very low affinity. sEng binds with high affinity to BMP9, which stimulates secretion from endothelial cells of the vascoconstrictor endothelin-1, also implicated in endothelial cell stabilization. It remains to be determined if scavenging of circulating BMP9 by sEng is important in preeclampsia and regulation of hypertension.