Transcutaneous Auricular Vagus Nerve Stimulation Ameliorates Preeclampsia-Induced Apoptosis of Placental Trophoblastic Cells Via Inhibiting the Mitochondrial Unfolded Protein Response

 Jing Zhao1,2 · Yanan Yang3  · Jiayi Qin4  · Siyu Tao1  · Chunmei Jiang4  · Huixuan Huang4  · Qiunan Wan1  · Yuqi Chen4  · Shouzhu Xu3  · Haifa Qiao1,2
1 College of Acupuncture and Tuina, Shaanxi University of Chinese Medicine, Xixian New Area, Xianyang 712046, China 
2 Shaanxi Key Laboratory of Acupuncture and Medicine, Xixian New Area, Xianyang 712046, China 
3 Department of Public Health, Shaanxi University of Chinese Medicine, Xixian New Area, Xianyang 712046, China 
4 College of Medical Technology, Shaanxi University of Chinese Medicine, Xixian New Area, Xianyang 712046, China

Abstract
Preeclampsia is a serious obstetric complication. Currently, there is a lack of effective preventive approaches for this disease. Recent studies have identified transcutaneous auricular vagus nerve stimulation (taVNS) as a potential novel non-pharmaceutical therapeutic modality for preeclampsia. In this study, we investigated whether taVNS inhibits apoptosis of placental trophoblastic cells through ROS-induced UPRmt. Our results showed that taVNS promoted the release of acetylcholine (ACh). ACh decreased the expression of UPRmt by inhibiting the formation of mitochondrial ROS (mtROS), presumably through M3AChR. This reduced the release of pro-apoptotic proteins (cleaved caspase-3, NF-κB-p65, and cytochrome C) and helped preserve the morphological and functional integrity of mitochondria, thus reducing the apoptosis of placental trophoblasts, improving placental function, and relieving preeclampsia. Our study unravels the potential pathophysiological mechanism of preeclampsia. In-depth characterization of the UPRmt is essential for developing more effective therapeutic strategies for preeclampsia targeting mitochondrial function.

Keywords
Preeclampsia; Transcutaneous auricular vagus nerve stimulation; Acetylcholine; Reactive oxygen species; Mitochondrial unfolded protein response; Placental trophoblastic cells