Preeclampsia (PE) is a placenta-origin pregnancy complication. Although its development has long been divided into two stages: abnormal placentation (stage I) and the release of factors from the hypoperfused placenta into circulation, triggering PE due to endothelial dysfunction (stage II), the placenta-derived substances coupling the two stages remain unclear.Excessive NEP in PEPL-EVs is transported into the endothelial cells of uterine and placental arteries to cleave and degrade CNP, resulting in compromised CNP paracrine activity and NPR-B-mediated cGMP production in adjacent VSMCs and triggering the hypertensive manifestation of PE.