The downregulation of B2R inhibits spiral artery remodeling by reducing the autophagy of trophoblast cells

Preeclampsia (PE) is a severe pregnancy complication characterized by hypertension and proteinuria after 20 weeks of gestation, posing significant risks to maternal and fetal health. Although its exact etiology remains unclear, inadequate trophoblast invasion and impaired remodeling of uterine spiral arteries are recognized as key contributors. The Bradykinin B2 receptor (B2R), a G protein-coupled receptor, was found to be downregulated in the placenta of early pregnancies that subsequently progress to PE. Our previous study has also shown that B2R can suppress the proliferation and migration of extravillous trophoblasts (EVT). However, the underlying mechanism remains elusive. By analyzing the transcriptome of HTR8 cells (an EVT cell line) with B2R knockdown, we found that B2R downregulation impairs Autophagy in EVTs. Subsequently, we confirmed that Autophagy is downregulated in EVTs from the placentas of patients with PE. In vitro experiments further demonstrated that B2R knockdown leads to defective Autophagy in HTR8 cells, resulting in decreased cell proliferation, migration, and invasion capabilities. Activating Autophagy can alleviate the functional abnormalities of EVT cells caused by B2R downregulation. Mechanistic exploration revealed that B2R knockdown inhibits Autophagy through the activation of the Wnt signaling pathway. Furthermore, we generated trophoblast-specific B2R knockout mice and found that the placentas of these mice exhibited reduced Autophagy, insufficient EVT invasion, and abnormal spiral artery remodeling. These findings suggest that B2R-regulated Autophagy is crucial for proper trophoblast function and spiral artery remodeling. Our study highlights the potential of targeting Autophagy as a therapeutic strategy for PE, providing new insights into the molecular mechanisms underlying this complex disorder.

Autophagy; Bradykinin B2 receptor; Preeclampsia; Spiral artery remodeling; Trophoblast.