Placental aberrant inflammation and spatial-specific lipid metabolism contribute to hypertensive disorder of pregnancy susceptibility in preeclampsia offspring.

Epidemiological studies have demonstrated that daughters of preeclamptic mothers have an increased risk of hypertensive disorders of pregnancy (HDP), but the underlying mechanisms remain unclear. To investigate the molecular changes underlying this HDP intergenerational transmission, we established an L-NAME-induced PE model in pregnant mice (F0) and examined female offspring (F1) during their pregnancies. F1 females developed gestational hypertension in late pregnancy, accompanied by enlarged placental labyrinthine areas and elevated VGFR1 expression, despite normal circulating sFlt1 levels. Across gestation, F2 placentas exhibited sustained impairment of apolipoprotein-mediated lipid transport beginning at mid-gestation, while inflammatory and HIF1α pathways were mainly activated at late gestation. Spatial transcriptomic data further showed that apolipoproteins were predominantly localized to yolk sac regions, whereas inflammatory factors exhibited widespread distribution. Importantly, F1 maternal lipid profiles remained normal before conception but manifested elevated serum triglyceride levels during pregnancy, concurrent with placental lipid accumulation. This pregnancy-specific dyslipidemia suggests that placental lipid metabolism dysfunction may contribute to maternal lipid dysregulation. Clinical validation in 28,117 women further confirmed that elevated mid-gestation triglyceride levels were strongly associated with HDP risk, consistent with the dyslipidemia observed in our mouse model. Together, these findings demonstrate that pregnancy-specific lipid dysregulation represents a conserved mechanism linking placental dysfunction to HDP susceptibility. Our study provides mechanistic insights into the intergenerational transmission of PE and identifies mid-gestation maternal lipid profiles as potential predictive biomarkers, offering a basis for early risk assessment and future therapeutic targeting.