taVNS alleviates preeclampsia-induced placental trophoblast dysfunction by attenuating endoplasmic reticulum Ca²⁺...

Preeclampsia (PE) is a major cause of maternal and perinatal morbidity, driven by placental dysfunction, oxidative stress, and trophoblast apoptosis. This study investigates the therapeutic potential of transcutaneous auricular vagus nerve stimulation (taVNS) in mitigating PE-induced placental injury via modulation of endoplasmic reticulum (ER) stress and calcium homeostasis. Using a reduced uterine perfusion pressure (RUPP) rat model and HTR-8/SVneo trophoblast cells, we assessed taVNS effects on hypertension, placental proteome, apoptosis, and molecular pathways. taVNS treatment was associated with significant reductions in mean arterial pressure, placental apoptosis, and ER ultrastructural damage in PE rats, while proteomic analysis revealed downregulation of calcium/calmodulin-dependent protein kinase II (CAMK II). In vitro, TNFα induced ROS accumulation, ER stress (via PERK activation), IP3R1-associated calcium dysregulation, and apoptosis, which were attenuated by taVNS-enhanced acetylcholine (ACh) through M3AChR signaling. Genetic silencing of PERK or IP3R1, or treatment with the ROS scavenger N-acetylcysteine or ER stress inhibitor 4-phenylbutyric acid, attenuated this injury cascade, providing functional support for a ROS-ER stress-calcium dysregulation-apoptosis axis in trophoblast dysfunction. These findings provide preliminary mechanistic and proof-of-concept evidence supporting further preclinical investigation of taVNS as a potential non-pharmacological approach in PE, offering mechanistic insights that may inform the design of future preclinical safety and translational feasibility studies.