BTN3A2 interacted with MFGE8 to alleviate preeclampsia by promoting ferroptosis and inhibiting angiogenesis

Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality and is characterized by placental ischemia. Angiogenic disorders and ferroptosis are key mechanisms in PE; however, their relationship remains unclear. The butyrophilin 3A (BTN3A) family member BTN3A2 is involved in the progression of many cancers; however, its role in PE angiogenesis and ferroptosis is unclear. In this study, we investigated the role of BTN3A2 in PE angiogenesis and ferroptosis.

Placental tissues were collected from healthy individuals and PE patients to explore the correlation between ferroptosis and angiogenesis. Human umbilical vein endothelial cells (HUVECs) were subjected to hypoxia, ferrostatin-1, Erastin, and gene manipulations (oe-BTN3A2, si-BTN3A2, and si-milk factor-globule-EFG factor 8 (MFGE8)) to elucidate the underlying mechanisms. Finally, a rat model of PE was established by intraperitoneal injection of Nomega-nitro-L-arginine methyl ester to verify the effects of BTN3A2 on angiogenesis.

Placental ferroptosis was negatively correlated with angiogenesis in PE. Clone number, migration, and tube number decreased in HUVECs after hypoxic exposure, and these effects were reversed by ferrostatin-1. BTN3A2 was increased in PE placentae and inhibited the viability of hypoxic HUVECs by inducing ferroptosis. Mechanistically, BTN3A2 interacted with MFGE8, and BTN3A2 promoted hypoxia-induced ferroptosis in HUVECs by downregulating MFGE8. Additionally, BTN3A2 knockdown promoted placental angiogenesis and improved the prognosis in PE rats.

BTN3A2 interacted with MFGE8 to alleviate PE by promoting ferroptosis and inhibiting angiogenesis. Therefore, it may serve as a potential therapeutic target for the diagnosis and treatment of PE.