Maternal-offspring brain and tissue cross-talk in preeclampsia: insights from a rat model

This study aimed to investigate the differential metabolic profiles across maternal and offspring brains, serum, and placental tissues in preeclampsia (PE), with a particular focus on elucidating the maternal-offspring brain and tissue cross-talk that may contribute to the complex pathophysiology of PE. PE was induced in rats using the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) to simulate both early-onset PE (EOPE) and late-onset PE (LOPE). We utilized non-targeted proton nuclear magnetic resonance (NMR) metabolomics to characterize the metabolic profiles of serum, placental tissue extracts, and brain tissues from both mothers and offspring. Multivariate analysis, Spearman correlation, Density-Based Spatial Clustering of Applications with Noise algorithm, Data-Driven Statistical Predictive Correlation network analysis and Tissue heterogeneity analysis were employed to explore tissue-specific metabolic signatures and their interactions. Following L-NAME induction, both EOPE and LOPE presented significant metabolic differences and shared traits across tissues, with distinct tissue-specific responses characterizing the metabolic profile of PE. Serum from both PE groups showed a decrease in tryptophan, isobutyrate, and lactate, with an increase in betaine. Lactate was upregulated in placental tissues, highlighting its metabolic role. Extensive intra-tissue metabolic correlations and inter-tissue metabolite exchanges were detected among the maternal brain, serum, placenta, and offspring brain across all three experimental groups. EOPE and LOPE exhibited distinctly different metabolic characteristics and trajectories of differential metabolites, along with diverse interaction patterns between the maternal/offspring brain and the placenta. This study uncovers the multi-tissue metabolic remodeling in response to preeclampsia, implying that addressing pathophysiological stress is crucial and may have potential implications for neurological outcomes. The comprehensive analysis highlights the pivotal role of the brain-placenta axis in preeclampsia, advocating for a classified diagnostic and management approach.