Topological dependent modifications of gene expression in the preeclamptic placenta under aspirin treatment.

Abstract

Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction and placental inflammatory activation. Low dose aspirin reduces preeclampsia incidence when initiated early, yet its molecular effects on the diseased human placenta remain poorly defined. We performed a topologically resolved transcriptomic analysis of placentas from two independent cohorts of preeclamptic women treated or not with aspirin. Placental samples were obtained either from the villous surface (syncytiotrophoblast rich) or from deep parenchymal regions (stromal and endothelial rich). In villous samples, microarray profiling identified 1,836 differentially expressed genes, predominantly down regulated. Gene set enrichment demonstrated marked suppression of pathways central to hypertensive placental pathology, including TNF/NF {kappa}B signaling, hypoxia responsive programs, glycolysis, and estrogen response cascades. RNA seq analysis of parenchymal samples identified 645 differentially expressed genes, again dominated by down regulation of cell cycle progression, mTORC1 signaling, inflammatory pathways, and metabolic stress responses. Across cohorts, 116 genes were consistently down regulated by aspirin and enriched for hypoxia, NF {kappa}B, estrogen response, and inflammatory signatures. Promoter analysis implicated transcription factors central to vascular inflammation and stress signaling, including NF {kappa}B1, RELA, HIF1A, PPARG, and PARP1. Functional validation in BeWo trophoblasts confirmed aspirin dependent modulation of key placental transcripts and altered secretion of MMP9, ANGPT2, and soluble endoglin (sENG) molecules directly implicated in endothelial dysfunction and hypertensive disease. These findings demonstrate that aspirin attenuates core inflammatory, hypoxic, and metabolic pathways across multiple placental lineages in preeclampsia, providing a mechanistic framework linking early aspirin administration to improved vascular and placental adaptation in hypertensive pregnancy. The action of aspirin upon differentiation of trophoblasts contribute to explain why aspirin protects only when administered early in pregnancy, before the end of the first trimester.