Placental Gene Expression in a Rat 'Model' of Placental Insufficiency

Objective: Placental insufficiency is a major factor associated with pregnancy complications such as miscarriages, intrauterine growth restriction and pre-eclampsia. Recent studies have identified the Brown Norway (BN) rat as a natural 'model' of placental insufficiency associated with decreased trophoblast remodeling of maternal uterine arteries. Hypothesis: Genetic pathways involved in angiogenesis and immune cell regulation are dysregulated in the placenta of BN rats. Methods: Global gene expression in placentas from BN rats were compared with that from Sprague-Dawley (SD) controls at 17.5 days of gestation using the Affimetrix Rat 1.0 microarray chip, and results confirmed with real-time PCR and immunoblotting. Results: We found significant differences in 272 genes with 108 being up-regulated and 164 down-regulated in BN placentas compared to SD placentas. BN placentas overexpressed genes involved in the renin-angiotensin system (RAS) such as Ace, Ace2, Agtr1a, Nox4, and Ephx2, while key genes involved in angiogenesis, such as Mmp1, Mmp10, Fgfbp1, Esr1, Itga2, Rgs5, and Ccnb1 were down-regulated. We also observed increased expression of Timd2, Itm2a, Irak3, and Csf1r, and decreased expression of Slpi, Ncam1, and Igsf3 in BN placentas. In addition, we observed lower placental weights in BN males compared to BN females, together with increased expression of Cyp1a1 in BN males, as compared to BN females. Conclusions: The present study demonstrates differential expression of genes involved in blood pressure, angiogenesis and immune cell regulation in BN placenta, and suggests that the RAS may be involved in the pathogenesis of placental dysfunction observed in BN rats.