Integrated multi-omics analysis reveals immunovascular mechanisms of the placenta-maternal brain axis and lifespan neurobehavior changes in a mouse model of preeclampsia.

Abstract

Preeclampsia (PE) is a hypertensive disorder of pregnancy, among the leading global drivers of maternal morbidity. PE can precipitate neuropsychiatric risk, including for peripartum anxiety, depression, and cognitive problems. To investigate mechanisms underlying psycho-obstetric risk in PE, we examined maternal metabolic, placental, brain, and behavioral changes in our chronic vasopressin (AVP) infusion PE mouse model (C57Bl6/J). Elevated maternal AVP secretion predicts PE in humans, and chronic AVP administration is sufficient to phenocopy immune, obstetric, and renal phenotypes of PE in pregnant mice. Late-pregnancy metabolomics (N = 4-6/condition/tissue) revealed no significant disruptions in plasma, but 33 changed metabolites were changed in AVP mouse placenta, implicating altered protein, energy, and nutrient functions. Placental RNA sequencing (RNA-seq; N = 3/condition) revealed 140 differentially expressed genes (DEGs), with pathway analyses highlighting changes in structural and metabolic remodeling. Placental multi-omic integration (RNA-seq and metabolomics) identified altered purine metabolism. Analysis of RNA-seq-predicted placental secretome suggested altered immunovascular factors (e.g., C2cd4, Klk1b1). In late-gestation maternal brain, RNA-seq (N = 3/condition) revealed extensive gene suppression in the hypothalamic paraventricular nucleus (PVN, 329 DEGs; 322 down-regulated) and frontal cortex (114 DEGs; 113 down-regulated), implicating altered signaling and immune-vascular pathways, respectively. AVP increased antepartum exploratory behavior without changing depressive-like or hedonic behaviors. Spatial memory deficits in aged postpartum AVP dams were also significant and associated with molecular changes in the hippocampus. Overall, the AVP model of PE induces placental and maternal brain changes, invoking immune and vascular mechanisms. This work identifies potential mechanisms underlying PE impacts on maternal brain, with implications for associated mental health challenges.