Extracellular vesicles derived from M1 macrophages deliver miR-515-5p to suppress trophoblast migration and invasion by targeting YAP in preeclampsia.

Trophoblast migration and invasion are critical processes in the pathogenesis of preeclampsia (PE), with maternal-fetal cellular communication playing a key role in their regulation. Among the immune components at the maternal-fetal interface, M1-like macrophages are known to influence trophoblast behavior, however, the specific underlying mechanisms remain unclear. Here, we reveal a novel pathway through which M1-like macrophages regulate trophoblast function through extracellular vesicle (EV)-mediated communication. We demonstrated that M1-derived extracellular vesicles (M1-EVs) inhibit trophoblast migration and invasion in vitro. miRNA sequencing and validation revealed that miR-515-5p as one of the most significantly upregulated miRNAs in recipient trophoblast cells following M1-EVs treatment. Mechanistically, miR-515-5p is delivered into trophoblasts via M1-EVs, where it directly targets and downregulates Yes-associated protein (YAP), a central regulator of cellular motility. In vivo, the administration of M1-EVs to pregnant mice induced hallmark PE phenotypes, including hypertension and proteinuria. Importantly, mechanistic studies demonstrating the role of miR-515-5p in targeting YAP were conducted in human trophoblast cells, as miR-515-5p is primate specific and not endogenously expressed in mice. Clinically, miR-515-5p expression was significantly upregulated in human PE placental tissues and inversely correlated with YAP levels. Collectively, the results of our study reveal that M1-EVs deliver miR-515-5p to trophoblasts, leading to YAP downregulation and suppression of migration and invasion, thereby providing new insights into immune-mediated regulation of trophoblast function in preeclampsia.