Lipid-endoglin interactions in preeclampsia

Preeclampsia has increased circulating levels of a short form of the auxillary TGF-beta (TGFB) receptor endoglin (sENG). However, its processing, release and functionality in preeclampsia remains poorly understood. Objective: To elucidate whether ENG is attracted to syncytial sphingomyelin-enriched apical membrane subdomains that facilitate ENG cleavage and subsequent shedding of sENG into the maternal circulation in preeclampsia. Results: We show that ENG interacts with specific sphingomyelin(SM)s which promote its clustering with particular metalloproteinases (MMP) in SM-enriched lipid rafts of the apical syncytial membranes from preeclamptic placenta where ENG is cleaved by MMP into sENG. The SM-enriched lipid rafts also contain TGFB receptors (TGFBR1 and TGFBR2), but not soluble fms-like tyrosine kinase 1 (sFLT1), another protein secreted in excess in the circulation of women with preeclampsia. The truncated ENG is then released into the maternal circulation via PLAP/CD63-positive and SM-enriched exosomes together with TGFBR1 and 2. Conclusion: Hypoxia-induced SMs facilitate ENG cleavage in the apical syncytial membrane via MMP and subsequent exosomal release of sENG with TGFBR1 and 2 into the maternal circulation. This TGFB receptor complex could block the vascular effects of TGFB in the circulation of preeclamptic women.