Proteomic Epithelial‐To‐Mesenchymal Transition Signature in Fetoplacental Small Extracellular Vesicles of Early‐Onset Preeclampsia

ABSTRACT Preeclampsia (PE), a hypertensive disorder in pregnancy, is linked to placental vascular remodelling, increasing risks of foetal growth restriction and long‐term offspring health problems. The role of fetoplacental endothelial cell‐derived extracellular vesicles (EVs) in PE remains underexplored. This study investigates whether EV composition in Early‐Onset PE (EO‐PE) is altered, potentially contributing to impaired foetal development. Small EVs (sEVs) were isolated from primary fetoplacental endothelial cells (fpECs) of term (T), preterm (PT) and EO‐PE pregnancies. sEVs were characterised using transmission electron microscopy, nanoparticle tracking analysis and Western blotting, confirming spherical morphology, size (<200 nm) and expression of canonical EV and endothelial markers. Proteomic profiling via nano‐LC MS/MS and gene set enrichment analysis revealed a cohesive proteomic profile in fpEC‐derived T‐ and PT‐sEVs, but EO‐PE‐derived sEVs showed heterogeneity and functional alterations compared to T‐ and PT‐derived sEVs. Notably, EO‐PE‐sEVs were enriched in proteins affiliated to epithelial‐to‐mesenchymal transition and myogenesis, processes tied to tissue remodelling and vascular homeostasis, all hallmarks in PE. This signature may represent a molecular signal associated with endothelial dysfunction. In contrast, T‐sEVs were enriched in cell cycle and DNA repair pathways. These findings underscore the role of fetoplacental‐derived EVs in placental‐foetal communication under pathophysiological conditions.