**1. Introduction**

Placental development is complex and is spatio-temporally regulated by an array of factors including placentally- and maternally-derived growth factors, hormones, and cytokines [1]. Uterine spiral arteries are remodeled into highly dilated vessels by the invasion of the extravillous trophoblasts (EVT). Invaded EVTs disrupt the vascular smooth cell layer and replace the endothelium, converting muscular wall arteries into wide bore low-resistance vessels ensuring a local increase in blood supply, which allows for sufficient maternal blood flow into the intervillous space for the nutritional requirements of the fetus [2]. These cellular and physiological homeostatic processes are critical steps in the establishment of a successful pregnancy and occurs in association with an increase in blood volume over the course of pregnancy [3]. Concomitant to the normal physiological adaptation, vascular resistance is also reduced via decreased vascular tone that takes place as the placenta is being

formed [4]. An abnormality in the physiological adaptation to normal pregnancy occurs in the common pregnancy-related disorder that endangers the proper development of the embryo/fetus, as well as the health of the mother is preeclampsia (PE). PE is a complex pathophysiological condition where vascular resistance is abnormally increased and contributes to maternal hypertension (Figure 1). Concurrent maladaptation of the maternal cardiovascular system along with abnormal placentation predisposes an individual to PE [5]. There are no cures for PE and removal of the placenta leads to resolution of symptoms of PE, and thus its managemen<sup>t</sup> mainly relies on delivery, often preterm. Despite the importance of the placenta and the maternal cardiovascular maladaptation in the development of PE, exploring the key molecular pathways is critical for the maintenance of homeostasis in pregnancy and also for identifying novel targets for the prevention and managemen<sup>t</sup> of PE. This review thereby highlights the importance of inflammasomes as potential molecular links of the key inflammatory pathways underlying the development of PE.

**Figure 1.** Depicts the complex gestation and stage specific pathophysiological processes associated with preeclampsia. Genetic factors, maternal factors, and immunological factors may cause placental dysfunction (stage I), which in turn leads to the release of anti-angiogenic and other inflammatory mediators that induce preeclampsia (PE) (stage II). AT1: Angiotensin II type I receptor; dNK: Decidual natural killer; HELLP: Haemolysis, elevated liver enzymes and low platelet count; SNP: Single-nucleotide polymorphism; Treg: Regulatory T-cell.

#### *1.1. Human Trophoblast Di*ff*erentiation Establishes the Maternal–Fetal Interface*

In a normal pregnancy, the complex architecture at the boundary of the maternal uterus and the fetally-derived placental tissue is governed largely by the differentiation of immunocompetent cytotrophoblasts. Cytotrophoblasts readily undergo differentiation by emigrating from the anchoring villi and joining the cell columns as extravillous cytotrophoblasts (EVTs), serving as conduits to the uterine wall [2,6]. Briefly, the process of invasion of the EVTs in the maternal decidua and inner third of the myometrium occurs via two spatial routes. Firstly, migration and invasion through the decidual layer gives rise to interstitial EVTs that interact with specialized populations of maternal immune cells present within the decidua. Secondly, the EVTs that move up and target the lumen of the spiral arteries become endovascular EVT, adopt an endothelial-like phenotype, and intercalate within the smooth muscle cells of the tunica media. The remodeling of the spiral arterial wall involves loss of normal musculoelastic structure and replacement of the vascular media with fibrinoid material. This results in converting the originally low capacitance/high resistance uterine arteries into high capacitance low resistance channels that perfuse the surface of the placenta, which is enveloped by multinucleated transport epithelium, namely syncytiotrophoblast (STB) [1]. The invading EVTs exhibit a major transformation at both the cellular and molecular levels. Cytotrophoblasts attached to the chorionic villi initially express adhesion molecules characteristic of epithelial cells such as integrins α6/β1, αv/β5. As cytotrophoblasts enter the cell columns and adopt the invasive pathway, the expression of epithelial cell-like adhesion molecules decrease, whilst the expression of endothelial cell adhesion markers such as integrins α1/β1, αv/β3, and VE-cadherin is upregulated to promote vascular mimicry [2,7].
