Endothelial microparticles in high glucose environment: molecular pathways of GDM-associated placental dysfunction...

Gestational diabetes mellitus (GDM) is frequently linked to placental overgrowth and hypertrophy, while maternal hyperglycaemic environment consistently induces systemic vascular endothelial cell injury. Damaged endothelial cells stimulate the release of endothelial microparticles (EMPs), but their impact on placental function has not been fully characterized. In this study, we clinically observed that the levels of EMPs in the peripheral blood of GDM patients are significantly higher than those in healthy pregnant women. Furthermore, we identified that EMPs from GDM patients promote excessive trophoblast migration and invasion. Mechanistically, hyperglycemia activates KLF9 in endothelial cells, leading to transcriptional upregulation of NGF. When encapsulated within EMPs, NGF binds to NGFR on placental trophoblast membranes and promotes NGFR interaction with CYLD, which inhibited NGFR ubiquitination and degradation. This interaction activated the downstream MAPK/ERK signalling pathway, facilitating excessive trophoblast migration and invasion and ultimately resulting in placental overgrowth. Notably, by screening natural molecules safe for gestational intake, we identified coenzyme Q10, which directly targets and binds to NGFR to eliminate the interaction between NGFR and CYLD, thereby promoting NGFR degradation via the ubiquitin‒proteasome pathway and reducing pathological NGFR accumulation caused by G-EMPs exposure. Our findings illuminate the intricate relationship between vascular endothelial cell injury and placental developmental abnormalities and identifying potential therapeutic targets and drugs to improve outcomes for affected patients.