Preeclampsia is a severe complication of human pregnancy that contributes significantly to maternal and perinatal mortality and morbidity (Burton et al. (2019)). This condition particularly affects first pregnancies and presents with different clinical features, but hypertension and proteinuria are usually seen. Notwithstanding several efforts, the pathogenesis of this disorder remains not fully understood, although many aspects of the physiopathology are known (Huppertz, 2018). We know that the presence of the placenta is necessary while the fetus is not (Redman et al. (2022)), that immunological alterations of the placental-maternal interface contribute to an abnormal placentation (Robillard et al. (2020)), and that maternal pre-pregnancy chronic diseases that lead to vascular damage or systemic inflammation increase the risk to develop the syndrome (Burton et al. (2019)). During early-onset preeclampsia (EOP), maternal clinical symptoms (hypertension, proteinuria, etc.) are related to an increase of antiangiogenic factors (i.e. sFlt-1) (Maynard et al., 2003, Rana et al., 2022) whereas this association was not demonstrated in most of the cases of late-onset preeclampsia (Chaiworapongsa et al., 2022, Chaiworapongsa et al., 2023, Huppertz, 2008). Maternal cardiovascular maladaptation to pregnancy contributes to the development of the syndrome and to several altered health conditions after pregnancy (Masini et al. (2022)).

Considering the systemic involvement of this pregnancy pathology, the maternal vascular endothelium represents the front line where main modifications occur and lead to maternal symptoms. Certainly, the placenta has a major role as the preeclamptic syndrome takes place only during pregnancy. Unfortunately, the lack of animal models that spontaneously develop preeclampsia during pregnancy limits our possibility to fully understand the pathogenesis of this disorder.

Inositol phosphoglycans are the cornerstone of cellular carbohydrate metabolism in prokaryote and eukaryote cells (Caro et al., 1997, Larner et al., 2003, Larner et al., 2010, Larner, 2013). In eukaryote mitochondria, inositol phosphoglycans regulate the non-oxidative pathways of glycogen synthesis that accounts for about 70% of the carbohydrate metabolism (Larner et al., 2010, McLean et al., 2008). The inositol phosphoglycan P-type (P-IPG) is a transmembrane second messenger at the cellular level, and as such, has a fugacious existence and effects on both sides of cellular membranes. During pregnancy, P-IPG is produced in great quantities at the fetoplacental side with minimal levels in maternal circulation under physiological conditions. It has been known for 23 years now (Kunjara et al. (2000)) that P-IPG is abundantly, and specifically, found in the urine of preeclamptic women 2-4 weeks before the clinical onset of the maternal syndrome (Scioscia et al., 2019a, Scioscia et al., 2019b). This review aims to show the possible role of placental metabolism adaptation to different conditions that may promote the maternal preeclamptic syndrome. We aim at understanding how P-IPG can enter the maternal circulation in preeclamptic women. Our hypothesis is that in preeclampsia there is a disruption of the syncytial glycocalyx, which constitutes a physical barrier for objects to move between maternal blood and the placenta. This disruption occurs first Moreover, we present the role of the glycocalyx disruption in the syncytiotrophoblast and subsequently in maternal endothelial cells, altering cell membrane exchange, inducing the leakage of P-IPG into the maternal circulation (and finally in urine), and prompting the release of soluble vasogenic factors during preeclampsia.