**1. Introduction**

PE a ffects ~2–5% of the pregnancies. This disease, characterized in the classical definition by hypertension and proteinuria, surging from the mid-gestation at the earliest, is often seen as a two-stage disease, where a placental dysfunction occurs, first without observable symptoms and is followed later by a symptomatic phase from the 20th week of gestation at the earliest. The placenta is central to the disease development [1]. During pregnancy, the cytotrophoblasts (CTs) invade and remodel the structure of the spiral arteries of the myometrium [2]. These changes cause a significant increase in blood flow to the placenta. In a classical vision of the disease etiology, it is said that deep invasion is deficient in preeclampsia [3]. It is generally acknowledged that in preeclamptic pregnancies, placentation is disrupted because the CTs fail to properly invade the myometrium and transform the spiral arteries [4]. This decreases the blood flow and alters the oxygenation of the placenta (causing hypoxia and hyperoxia events), triggering oxidative stress, necrosis and inflammation [5]. In a very stimulating paper, B. Huppertz challenges this classical understanding of PE etiology, by dissociating the defect of deep trophoblast invasion from preeclampsia but rather associating this defect with the Fetal Growth Restriction (FGR) phenotype [6]. In this vision, preeclampsia would rather be caused by a combination of *villous* trophoblast defects (which are not involved in invasion, contrary to *extravillous* trophoblast) and maternal susceptibility. He based his reasoning on the fact that invasion defects are actually not histologically visible in many cases of preeclampsia. This may be connected to mouse models of preeclampsia where no obvious fetal growth restriction occurs, consistently with the fact that invasion is not important in rodent [7]. More accepted than this vision, the same paper strengthens the idea that hyperoxia rather than hypoxia is a major actor of the disease [6,8].

The preeclamptic placenta releases vasoactive molecules, pro-inflammatory cytokines, microparticles and syncytial fragments into the maternal circulation which ultimately cause a systemic endothelial dysfunction [9]. Epigenetics plays an important role in the regulation of the development and physiology of the placenta [10]. Besides, substantial epigenetic alterations, in the preeclamptic placenta and other affected tissues have been described and are likely playing a substantial role in the evolution of the disease [11–14].

### **2. Epigenetics and Normal Placental Development**

#### *2.1. Description of the Placenta and Placental Cells*

The placenta is a temporary organ connecting the developing fetus to the uterine wall through the umbilical cord, to allow for nutrient absorption, thermal regulation, waste disposal and gas exchange via the mother's blood supply. In addition, the placenta produces hormones that support pregnancy and it acts as a barrier to fight against internal infection [15].

The human placenta at term has a discoid shape, an average diameter of 15–20 cm, a thickness of 2.5 cm in the center and a weight of about 500 g. Its surfaces are the chorionic plate on the fetus side and to which the umbilical cord is attached and the basal plate facing the maternal endometrium. Between the endometrium and the basal plate there is a cavity filled with maternal blood, the intervillous space, into which branched chorionic villi project. The chorionic villi are the structural and functional unit of the placenta. Their core is made of fibroblasts, mesenchymal cells, endothelial cells, immune cells such as Hofbauer cells (supposed to be macrophage-like) and fetal-placental vessels. The villi are covered by two layers of trophoblasts. The inner layer is composed of villous cytotrophoblasts (vCTs), which are highly proliferative and can di fferentiate into either outer layer villous syncytiotrophoblasts (SCT), which are in direct contact with the maternal blood or extravillous trophoblasts (EVTs), as shown in Figure 1.
