Immune and Apoptosis Mechanisms Regulating Placental Development and Vascularization in Preeclampsia

Abstract

Preeclampsia is the most severe type of hypertensive disorder of pregnancy, affecting one in 10 pregnancies worldwide and increasing significantly maternal and neonatal morbidity and mortality. Women developing preeclampsia display an array of symptoms encompassing uncontrolled hypertension and proteinuria, with neurological symptoms including seizures at the end of pregnancy. The main causes of preeclampsia are still unknown. However, abnormal placentation and placenta vascularization seem to be common features in preeclampsia, also leading to fetal growth restriction mainly due to reduced placental blood flow and chronic hypoxia. An over activation of maternal immunity cells against the trophoblasts, the main cells forming the placenta, has been recently shown as an important mechanism triggering trophoblast apoptosis and death. This response will further disrupt the remodeling of maternal uterine arteries, in a first stage, and the formation of new placental vessels in a later stage. A consequent chronic hypoxia stress will further contribute to increase placental stress and exacerbate systemic circulatory changes in the mother. The molecular mechanisms driving these processes of apoptosis and anti-angiogenesis are also not well-understood. In this review, we group main evidences suggesting potential targets and molecules that should be better investigated in preeclampsia. This knowledge will contribute to improve therapies targeting a better placenta formation, having a positive impact on maternal disease prevention and on fetal development.

circCRAMP1L is a novel biomarker of preeclampsia risk and may play a role in preeclampsia pathogenesis via regulation of the MSP/RON axis in trophoblasts

“…The theory holds that obstruction of the trophoblast differentiation phenotype during placenta formation leads to inadequate invasion and poor spiral artery remodelling, resulting in vascular endothelial cell damage, hypertension, and urinary protein in patients [ 6 , 7 ]. The main pathological manifestation of the placenta in patients with PE is that trophoblasts invade the endometrium too shallowly and only reach the decidual layer, providing experimental evidence for this theory [ 8 ].…”

Serum levels of soluble Fas and Fas ligand in pregnant women who smoke

“…9 In addition, preeclampsia is associated with increased trophoblast apoptosis where the Fas and Fas ligand (FasL) system plays a key role. 10 The objective of our study was to investigate maternal serum levels of sFlt1, sEng, PlGF and cytokines IFN-γ, TNF-α, IL-6,10 and 1β in normotensive pregnant women, who smoked and compare them to normotensive non-smoking pregnant women. We also investigated levels of soluble Fas (sFas) and soluble FasL (sFasL) in the two groups.…”

Cyclosporin A protects JEG-3 cells against oxidative stress-induced apoptosis by inhibiting the p53 and JNK/p38 signaling pathways

“…OS can induce apoptosis via extrinsic and intrinsic signals. The former is mediated by the FAS receptor on the cell surface upon binding of its FAS ligand, which results in the activation of the caspase-8 signal; the latter is activated during intracellular stress, such as ischemia and DNA damage, and is induced from signals transmitted by mitochondria-mediated caspase-9 pathways [29]. The tumor suppressor p53 is an important sensor of OS, and the induction of oxidative stress is generally accompanied by the activation of p53.…”