Maternal cause of early-onset preeclampsia: excessive endometrial gland-derived apolipoprotein D induces placental ferroptosis and developmental abnormalities

Early-onset pre-eclampsia (ePE) is a severe pregnancy complication affecting millions of pregnancies worldwide, resulting in significant maternal and fetal morbidity. The etiology of ePE is associated with defective trophoblast functions, leading to abnormal placental development. Regulatory factors released by endometrial glands are crucial for proper placental development. While circumstantial evidence indicates that defective endometrial gland development or function may lead to defective placental development and ePE in humans, direct evidence has been lacking. This study explored the role of endometrial gland-derived factors both in vitro and in vivo and correlated the findings with the clinical phenotypes of ePE. Our findings revealed that the secretome of organoids derived from the endometrial tissues of ePE patients impeded spiral artery remodeling and thus disrupted proper placental perfusion. Transcriptomic and proteomic analyses identified an increased apolipoprotein D (APOD) production in ePE organoids and decidual tissues compared to their normotensive (NT) counterparts. Overexpression of endometrial APOD impaired the vascular remodeling functions of extravillous trophoblasts (EVT) and endothelial cells in vitro. These findings were corroborated using an endometrial-specific APOD knock-in mouse model. APOD-induced ferroptosis through the PI3K/Akt pathway in both human ePE placentas and the mouse model. Moreover, elevated APOD levels were detected in the first-trimester serum of pregnant women who subsequently developed ePE. These results provide the first direct evidence that dysregulated endometrial gland secretome is a maternal cause of defective placental development and ePE. Clinically, APOD could serve as a biomarker for early detection of ePE, enabling early intervention with the potential to improve outcomes for both mothers and their babies.