Preeclampsia (PE), the leading cause of maternal and fetal morbidity and mortality, is associated with poor fetal growth, intrauterine growth restriction (IUGR) and low birth weight (LBW). Offspring of women who had PE are at increased risk for cardiovascular (CV) disease later in life. However, the exact etiology of PE is unknown. Moreover, there are no effective interventions to treat PE or alleviate IUGR and the developmental origins of chronic disease in the offspring. The placenta is critical to fetal growth and development. Epigenetic regulatory processes such as histone modifications, microRNAs and DNA methylation play an important role in placental development including contributions to the regulation of trophoblast invasion and remodeling of the spiral arteries. Epigenetic processes that lead to changes in placental gene expression in PE mediate downstream effects that contribute to the development of placenta dysfunction, a critical mediator in the onset of PE, impaired fetal growth and IUGR. Therefore, this review will focus on epigenetic processes that contribute to the pathogenesis of PE and IUGR. Understanding the epigenetic mechanisms that contribute to normal placental development and the initiating events in PE may lead to novel therapeutic targets in PE that improve fetal growth and mitigate increased CV risk in the offspring.

Placenta ischemia, the initiating event in preeclampsia (PE), is associated with fetal growth restriction. Inhibition of the agonistic autoantibody against the angiotensin type 1 receptor, AT1-AA, using an epitope-binding inhibitory peptide ('n7AAc') attenuates increased blood pressure at gestational day (G)19 in the clinically relevant reduced uterine perfusion pressure (RUPP) model of PE. Thus, we tested the hypothesis that maternal administration of 'n7aac' does not transfer to the fetus, improves uterine blood flow and fetal growth, and attenuates elevated placental expression of miRNAs implicated in PE and FGR. Sham or RUPP surgery was performed at G14 with vehicle or 'n7aac' (144µg/day) administered via osmotic pump from G14 to G20. Maternal plasma levels of the peptide on G20 were 16.28 ± 4.4 nM, and fetal plasma levels were significantly lower at 1.15 ± 1.7 nM (p=0.0007). Uterine artery resistance index was significantly elevated in RUPP (P<0.0001), but was not increased in 'n7aac'-RUPP or 'n7aac'-Sham versus Sham. The significant reduction in fetal weight at G20 in RUPP (P=0.003) was not observed in 'n7aac'-RUPP. Yet, percent survival was reduced in RUPP (P=0.0007) and 'n7aac-RUPP (P <0.0002). Correlation analysis indicated the reduction in percent survival during gestation was specific to the RUPP (r=0.5342, p=0.043) and independent of 'n7aac'. Placental miR-155 (P=0.0091) and miR-181a (P=0.0384) expression were upregulated in RUPP at G20 but were not elevated in 'n7aac'-RUPP. Collectively, our results suggest that maternal administration of 'n7aac' does not alter fetal growth in the RUPP implicating its potential as a therapeutic for the treatment of PE.