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Hypercholesterolemia is one of the main risk factors associated with atherosclerosis and cardiovascular disease, the leading cause of death worldwide. During pregnancy, maternal hypercholesterolemia develops, and it can occur in a physiological (MPH) or supraphysiological (MSPH) manner, where MSPH is associated with endothelial dysfunction and early atherosclerotic lesions in the fetoplacental vasculature. In the pathogenesis of atherosclerosis, endothelial activation and endothelial dysfunction, characterized by an imbalance in the bioavailability of nitric oxide, contribute to the early stages of this disease. Macrophages conversion to foam cells, cholesterol efflux from these cells and its differentiation into a pro- or anti-inflammatory phenotype are also important processes that contribute to atherosclerosis. In adults it has been reported that native and modified HDL and LDL play an important role in endothelial and macrophage function. In this review it is proposed that fetal lipoproteins could be also relevant factors involved in the detrimental vascular effects described in MSPH. Changes in the composition and function of neonatal lipoproteins compared to adults has been reported and, although in MSPH pregnancies the fetal lipid profile does not differ from MPH, differences in the lipidomic profiles of umbilical venous blood have been reported, which could have implications in the vascular function. In this review we summarize the available information regarding the effects of lipoproteins on endothelial and macrophage function, emphasizing its possible implications on fetal adverse outcomes associated to maternal hypercholesterolemia during pregnancy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

During pregnancy, there is a progressive increase in the levels of maternal cholesterol, a lipid that is essential for foetal growth and development. This increase can occur in a physiological (MPH) or supraphysiological (MSPH) manner, where MSPH is associated with detrimental effects on the mother and foetus, including endothelial dysfunction, oxidative stress, and atherosclerosis. Cholesterol is transported from the maternal to the foetal circulation through the placenta by a process that encompasses two main events: cholesterol uptake and efflux. The main receptors and transporters that participate in cholesterol transport are expressed in the human placenta, and their regulation in normal and pathological pregnancies has been evaluated. However, whether elevated levels of cholesterol induce these detrimental changes and whether their expression and function changes in the MSPH condition is still under study, along with the cell types involved in placental cholesterol traffic. Moreover, aside from cholesterol levels, the composition and function of lipoproteins have recently become important to study as these factors may also contribute to the atherogenic process. There is information regarding the maternal and neonatal lipoproteins profile and their changes during pregnancy. However, there are no reports that evaluate the changes of these lipoproteins in MSPH pregnancies. The latter could be relevant considering the consequences that MSPH has on the foetal vasculature. In this review, we summarize the available information regarding cholesterol transport through the placenta and the metabolism of maternal and neonatal lipoproteins in MPH and MSPH conditions, suggesting the importance of increasing our knowledge about these conditions and the monitoring of maternal cholesterol levels during pregnancy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Maternal physiological (MPH) or supraphysiological hypercholesterolaemia (MSPH) occurs during pregnancy. Cholesterol trafficking from maternal to foetal circulation requires the uptake of maternal LDL and HDL by syncytiotrophoblast and cholesterol efflux from this multinucleated tissue to ApoA-I and HDL. We aimed to determine the effects of MSPH on placental cholesterol trafficking. Placental tissue and primary human trophoblast (PHT) were isolated from pregnant women with total cholesterol <280 md/dL (MPH, n = 27) or ≥280 md/dL (MSPH, n = 28). The lipid profile in umbilical cord blood from MPH and MSPH neonates was similar. The abundance of LDL receptor (LDLR) and HDL receptor (SR-BI) was comparable between MSPH and MPH placentas. However, LDLR was localized mainly in the syncytiotrophoblast surface and was associated with reduced placental levels of its ligand ApoB. In PHT from MSPH, the uptake of LDL and HDL was lower compared to MPH, without changes in LDLR and reduced levels of SR-BI. Regarding cholesterol efflux, in MSPH placentas, the abundance of cholesterol transporter ABCA1 was increased, while ABCG1 and SR-BI were reduced. In PHT from MSPH, the cholesterol efflux to ApoA-I was increased and to HDL was reduced, along with reduced levels of ABCG1, compared to MPH. Inhibition of SR-BI did not change cholesterol efflux in PHT. The TC content in PHT was comparable in MPH and MSPH cells. However, free cholesterol was increased in MSPH cells. We conclude that MSPH alters the trafficking and content of cholesterol in placental trophoblasts, which could be associated with changes in the placenta-mediated maternal-to-foetal cholesterol trafficking.