**6. MBG in Relation to Sex and Gender Medicine with a Special Focus on Pre-Eclampsia**

In the last few years, the concept of gender medicine emerged in relation to the presence of significant and underestimated effects of gender-based differences on clinical evolution and therapeutic outcomes of many diseases [135–137]. Despite CTS, such as MBG, playing a role in human physiopathology, regardless of sex- and gender-related aspects, there is evidence regarding specific actions occurring in sex-specific diseases, such as pregnancy diseases [68], which can be considered a valid example of gender medicine. MBG was identified as a biomarker of angiogenic imbalance in the pathogenesis of PE [47], a relatively common and potentially devastating complication of pregnancy.

PE is a progressive multisystem syndrome that is characterized by the onset, after the 20th week of gestation, of hypertension and proteinuria or by the onset of hypertension with severe organ dysfunction, with or without proteinuria [138–140]. A systematic review stated that 4.6% of pregnancies worldwide were complicated by PE [141], which represents the second leading cause of fetal and maternal morbidity and mortality [142–145]. PE is caused by both maternal and fetal/placental factors. Placental vessels develop abnormally early in pregnancy and result in a placental hypoperfusion with the release of antiangiogenic factors into the maternal circulation. These factors promote endothelial dysfunction, which leads to the development of a vascular leak that enhances the volume expansion. MBG causes endothelial hyperpermeability, activating MAPKs with the disruption of the tight junction. This feature triggers apoptotic mechanisms, resulting in further endothelial dysfunction and leading to edema and the release of angiogenic factors [47,146].

An important element that could make MBG a potential biomarker for the early detection of PE was shown in an animal study, in which circulating MBG was shown to rise earlier than the onset of proteinuria and hypertension [13]. Thus, MBG can represent a predictive marker of PE, opening up new perspectives for its prevention, as well as halting its progression to the severe clinical state of eclampsia. Moreover, the administration of MBG in pregnant rats mimics this syndrome with proteinuria, hypertension and intrauterine growth restriction (IUGR) [12,147].

As well as MBG being involved in the pathophysiology and progression of PE, its antagonist RBG was seen to have a role in the prevention and possible treatment of this disorder [148,149]. The administration of RBG in a rat model of PE leads to the resolution of hypertension and, if given early in pregnancy, it prevents all symptoms of PE, including IUGR [112]. Recently, a relationship between MBG and leptin in a pregnancy model of Sprague Dawley rats was investigated, showing that RBG administration can reverse the leptin-induced increase in systolic blood pressure, proteinuria and endothelial activation and suggesting a link between MBG and leptin signaling during pregnancy [150]. The RBG and, consequently, MBG molecular actions were also related to oxidative stress pathways [151], further amplifying the network of the interactions of CTS.

Similar to the action of RBG, Fedorova at al. investigated the role of antibodies against MBG in reversing the placenta-induced fibrosis of umbilical arteries in PE [152]. Monoclonal anti-MBG antibodies ex vivo reversed the placenta-induced fibrosis of umbilical arteries, indicating an active role of MBG in placental pathology. This represents the starting point on the possible development and use of RBG or monoclonal antibody Fab fragments to MBG [113] for the prevention and/or treatment of this complex syndrome.

Likewise, mineralocorticoid antagonists have been demonstrated to block the development of the fibrosis of umbilical arteries in PE, which is likely related to elevated MGB plasma levels [153].

Increased MBG production in women with PE, compared with physiological pregnancies, has also been demonstrated in humans [14,26]. Indeed, in healthy pregnant women, MBG levels are twice as high as in non-pregnant controls [26], with an increase in up to eight times in patients with PE [27], which leads to an increase in blood pressure values, due to direct vasoconstriction and profibrotic changes that occur at the umbilical and placental level. MBG also alters cytotrophoblast differentiation in the first trimester of gestation [16], suggesting its involvement in the early pathological events leading to PE. Human cytotrophoblast cells cultured in the first trimester and stimulated by MBG have been shown to undergo alterations of proliferation, migration and invasion, caused by the activation of JNKs, p38 and SRC and leading to increased cell apoptosis [15].

The complete and definite role of MBG in the pathogenesis of PE is not yet fully known. In addition, the mechanisms and sites of synthesis of this molecule in mammals are also not completely understood, although it is already known that the placenta is a site for its production.

Beyond sex and gender differences, it was seen that racial differences may contribute to different clinical parameters involving endogenous CTS, such as sodium sensitivity [154], suggesting that these molecules are affected not only by sex- and gender-related factors but also by genetically related ones; further research is needed to define the set of MBG expression-regulating factors. A study by Kantaria et al. showed that salt-sensitivity of blood pressure values, in which CTS are implicated, may vary within the same population [155], suggesting a relevant impact of inter-individual variability on CTS activity.
