taVNS alleviates preeclampsia-induced vascular endothelial dysfunction via α7nAChR- IP3R1/GRP75/VDAC1 signal pathway.

Background: Endothelial dysfunction is considered to play a pivotal role in the pathogenesis of preeclampsia (PE). Transcutaneous auricular vagus nerve stimulation (taVNS) is a potential non-pharmaceutical alternative treatment for PE. This study aimed to explore the mechanisms of taVNS on endothelial dysfunction.

Methods: We used the reduced uterine perfusion pressure method to establish PE model and TNF-α to establish endothelial dysfunction model in HUVECs. In vivo, we detected blood pressure, vascular proteomics and morphology, ACh and receptor α7nAChR, and inflammatory factors (IL-6, IL-1β, and TNF-α). In vitro, we checked cell viability, mitochondrial membrane potential, apoptosis rate, calcium levels, HUVECs morphology, and Endoplasmic reticulum (ER) and mitochondria (MITO) interaction.

Results: taVNS promoted the release of ACh, which decreased Ca²⁺ inflow from ER to MITO through the IP3R1/GRP75/VDAC1 complex, presumably through α7nAChR. This reduced the release of pro-apoptotic proteins (cleaved caspase-3, HSC70, and cytochrome C) and helped preserve the morphological and functional integrity of mitochondria, thus reducing the apoptosis of HUVECs, improving endothelial function, and relieving PE.

Conclusion: taVNS may exert an anti-PE effect through ER-MITO interaction. These findings offer preliminary insights into PE pathogenesis, and suggest that the ACh/α7nAChR axis and IP3R1/GRP75/VDAC1 complex could be promising targets for future therapeutic investigation.