Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia

Abstract

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. During the progress of human pregnancy, the concentrations of total cholesterol (TC) and low-(LDL) rises in a physiological (maternal physiological hypercholesterolemia, MPH) 1,2 or supraphysiological (maternal supraphysiological hypercholesterolemia, MSPH) 3,4 way. MSPH is determined in women with TC levels above a cutoff value of 280-300 mg/dL at term of pregnancy or above the 75th percentile for the different trimesters of pregnancy 1-6. Endothelial dysfunction of the macro-and the microvascular vessels of the placenta 4,7-9 as well as development of atherosclerosis in the foetal aorta 1,2,6 has been described in pregnancies with MSPH and increased LDL levels. This information suggest that MSPH could be related to the development of cardiovascular disease in the offspring later in life 2,6,10,11. Despite the increased maternal TC and LDL concentrations, the levels of TC and triglycerides (Tg) of neonates from MSPH pregnancies are comparable to those from MPH pregnancies, suggesting a possible regulation of placental maternal-to-foetal cholesterol trafficking across the placenta 7,12 .

Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage

“…However, our results showed significant reduction in ABCG1 expression in EMC both on the transcript and protein level. Involvement of ABCG1 in maternal-to-fetal cholesterol transport was confirmed in a recent study on maternal supraphysiological hypercholesterolemia [ 76 ], and its decreased expression was associated with decreased efflux [ 24 ]. Thus, the diminished expression of ABCG1 may contribute to reduced export of cholesterol to the growing fetus in EMC, and such a reduction in maternal–fetal cholesterol transport during early in pregnancy could compromise fetal development [ 77 ].…”

Trophoblast Differentiation Affects Crucial Nutritive Functions of Placental Membrane Transporters

“…The efflux of [ 3 H]-cholesterol from trophoblast cells to ApoA-I or HDL was determined with minor modifications as described ( Kallol et al, 2018a ; Fuenzalida et al, 2020 ). In brief, cells were seeded at a density of 0.3 × 10 6 cells/cm 2 in 24-well plates and allowed to attach for 8 h for CTB and 48 h for STB.…”

Evaluation of the PLAC8 Gene in Mexican Women With and Without Preeclampsia and Obesity

“…Primary human cytotrophoblast (PHCT) was isolated from fresh placental villus tissue obtained at term from normal ( n = 6) and preeclampsia ( n = 6) pregnancies, as we previously described ( 20 ). After the serial enzymatic digestion steps of the tissue, PHCT was isolated from gradient fractions between 35 and 55% in a Percoll gradient (10–70%) (GE Healthcare, USA).…”

“…The purified PHCT was washed three times with PBS and immediately homogenized to obtain RNA extracts. The purity of the PHCT preparation was determined to be 93–99% by staining the cells with the specific markers anti-cytokeratin 7 (CK7), anti-vimentin, anti-E-cadherin, and anti-von Willebrand factor (vWF) (Novus Biologicals, USA), followed by flow cytometry analysis in FACSDiva (BD Biosciences, USA), as previously described ( 20 ).…”