NEST-Scoring, a Novel miRNA Target Gene Profile Network Analysis of Placenta-Derived Extracellular Vesicles in a Transgenic Rat Model of Preeclampsia

Preeclampsia is a multisystem hypertensive disorder of pregnancy and a leading cause of maternal morbidity and mortality. Despite its increasing incidence and the debilitating nature of its cerebrovascular complications, the underlying mechanisms remain incompletely understood. The goals of this study were to 1) determine whether middle cerebral artery (MCA) hemodynamics are altered in late gestation (LG) or two months postpartum in transgenic rats with preeclampsia compared to normal pregnant Sprague-Dawley (SD) rats, and 2) evaluate the microRNA (miRNA) profiles of circulating placental-derived extracellular vesicles (EV ^PD ) using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway framework using NEST-Scoring [Node, Edge, System, Topology], a novel target gene profile network analysis. Our data showed elevated blood pressure in transgenic preeclampsia rats at both LG and two months post-partum (PP-2M) compared to normal pregnant SD rats in the setting of hypertension. The heart rate was also significantly higher in preeclampsia rats at LG. No differences were observed in left MCA (LMCA) velocities between strains or time points. However, LMCA resistance and pulsatility indexes were lower at PP-2M in transgenic preeclampsia rats compared to SD rats. Exposure to preeclampsia differentially altered the miRNA profiles of circulating EV ^PD in transgenic preeclampsia rats at both LG and PP-2M. The identified miRNA targets were associated with key vascular and cellular regulatory pathways, suggesting a mechanistic link between placental dysfunction and postpartum vascular alterations in this preeclampsia model. Overall, this study suggests that the TGA-PE rat model could be a valuable platform to study the mechanistic link between preeclampsia and cerebrovascular disease.