Gene expression changes in uteroplacental development associated with superimposed preeclampsia in the Dahl salt‐sensitive rat model
Authors: Johnson Ashley C , Garrett Michael R , Sasser Jennifer M 
Published: November 2023

Preeclampsia is a leading cause of maternal and fetal morbidity and mortality; however, the initiating factors responsible for the development of preeclampsia remain unknown. Previous work suggests that impaired placentation precedes the maternal syndrome of preeclampsia; therefore, our goal is to identify specific factors that contribute to altered vascular remodeling at the maternal‐fetal interface using the Dahl salt‐sensitive (S) rat, a spontaneous model of superimposed preeclampsia that exhibits impaired placental vasculogenesis. To identify genes or pathways that could explain abnormal placental development in the Dahl S, whole transcriptome analysis was performed using the Affymetrix microarray platform. Sprague Dawley (SD) rats were utilized as a model of healthy pregnancy and normal placentation. Uterine samples were collected from virgin Dahl S and SD rats at gestational day 0 (GD0)] to identify the extent of gene expression differences in uterus between rat models. Additional groups of female S and SD rats strains were each mated, and uterine samples were collected from implantation sites on GD 7 and 10 (n=4–5/group). On GD14, placentas from multiple regions of the uterus were collected from both S and SD rats (n=5 rats, each sample pool of n=3 placentas). RNA was isolated, checked for quality, and whole transcriptome analysis was performed using Rat 2.0ST Arrays. Subsequently, data was normalized, differential expression determined, and pathway analysis performed using GeneSifter and Ingenuity Pathway Analysis (IPA) software. Using a fold‐change (FC) >1.5 and p<0.05 criteria, several hundred genes were observed to be differentially expressed at GD0 (466 genes), 7 (714), and 10 (679) in uterine samples. At GD0‐10, only a few genes [e.g., fibronectin type III domain containing 7 and Cd86 (involved in T‐cell activation and proliferation)] were significantly different using more stringent FDR (P<0.05), suggesting that small/relatively subtle changes in the S rat (compared to SD) lead to the preeclampsia phenotype. Using a 2‐way ANOVA to identify changes that occur between groups and over time (strain × time), 419 genes were found to be differentially expressed (FC >1.5 and FDR<0.05). Based on IPA, inflammatory response (p=4.11E‐03 ‐ 3.27E‐10) and cellular movement/lipid metabolism (p=4.65E‐03 ‐ 1.77E‐07) were identified as the top disease and molecular functions, respectively. At GD14 using a FC>1.5and p<0.05 criteria, 329 genes were observed to be differentially expressed in the placenta. These genes were found associated with the canonical pathway FXR/RXR activation (5.78E‐18) containing a number of apolipoproteins [APOA2,4, APOB, APOC2, APOE, APOH (FC=2–11)]. However, using more stringent statistical criteria (FDR<0.05), a relatively small number of genes (n=22) were differentially expressed. In summary, the current study identified new gene/gene pathways that could provide insight into abnormal utero‐placental development exhibited by the Dahl S rat model. Future studies will investigate several identified genes and their role as novel biomarkers and/or targets for new treatments of preeclampsia.