Computational analysis identified accelerated senescence as a significant contribution to preeclampsia pathophysiology.

Abstract

Preeclampsia is a heterogenous disorder of pregnancy that has distinct subtypes based on the phenotype of the placenta. In all pregnancies, there is a progressive loss of placental function throughout gestation due to increasing placental senescence. The aim of our study was to determine, through bioinformatic analyses, if accelerated or abnormal placental senescence underlies the development of the different subtypes of preeclampsia. Gene expression datasets were processed in R using the limma package for quantification and differential expression and the camera function for gene set enrichment. The pro- and anti-senescence gene sets were obtained from CellAge (https://genomics.senescence.info/cells/). We demonstrate an overall downregulation of anti-senescence genes across healthy and preeclamptic placentas as a function of gestation that is accelerated in certain subtypes of preeclampsia. We also discovered that while senescence-related signatures are common to preeclampsia, they represented unique biological pathways to different subtypes of the disease. Overall, our results support the role of senescence as a mediator in the pathophysiology of preeclampsia. We describe possible mechanistic differences between the role of senescence in different subtypes of preeclampsia that could provide a basis for identifying drug targets.