Maternal Hypercholesterolemia Research Articles

Natural cocoa inhibits maternal hypercholesterolaemia-induced atherogenesis in rabbit pups.

Atherosclerosis begins during foetal development and is enhanced by maternal hypercholesterolaemia during pregnancy. This study assessed the effect of natural cocoa on atherosclerosis in offspring conceived in maternal hypercholesterolaemia. Female rabbits were fed a cholesterol-enriched diet for two weeks and hypercholesterolaemia was confirmed, after which they were crossed with normocholesterolaemic males. One group of hypercholesterolaemic mothers (HCC) received natural cocoa powder (NCP) in their drinking water, whereas the other group (HC) received only water. Histological analysis of three segments of the aorta (arch, thoracic and abdominal) from offspring of both groups was compared with a control group (NC). Intima-media thickness of the aortic arch in offspring born to hypercholesterolaemic rabbits (HC: 146 µm) was higher compared to HCC (99 µm) and control rabbits (58.5 µm). All the sections from the aortic arch of the HC group had atherosclerotic lesions while none of the sections of the aortic arch from the NC and HCC groups had lesions present. Inferentially, regular and voluntary consumption of NCP during pregnancy may inhibit aortic atherogenesis in offspring of hypercholesterolaemic mothers.

Gestational hypercholesterolemia alters fetal hepatic lipid metabolism and microRNA expression in Apo-E-deficient mice.

Maternal hypercholesterolemia (MHC) is a pathological condition characterized by an exaggerated rise in maternal serum cholesterol during gestation, which can alter offspring hepatic lipid metabolism. However, the extent that these maladaptations occur during gestation and the molecular mechanisms involved remain unknown. MicoRNAs (miRNA) are small, noncoding RNAs that contribute to the development and progression of nonalcoholic fatty liver disease. Therefore, we sought to determine the degree to which in utero exposure to excessive cholesterol affects fetal hepatic lipid metabolism and miRNA expression. Twelve female apoE-/- mice were randomly assigned to two different chow-based diets throughout gestation: control (CON) or the CON diet with cholesterol (0.15%). MHC reduced maternal fecundity and reduced litter size and weight. On gestational day 18, fetuses from MHC dams possessed increased placental cholesterol and hepatic triglycerides (TG), which were accompanied by a downregulation in the expression of hepatic lipogenic and TG synthesis and transport genes. Furthermore, fetal livers from MHC mothers showed increased miRNA-27a and reduced miRNA-200c expression. In summary, in utero exposure to MHC alters fetal lipid metabolism and lends mechanistic insight that implicates early changes in miRNA expression that may link to later-life programming of disease risk.

Supraphysiological Maternal Hypercholesterolemia Associates With Increased Maternal Levels Of Pcsk9 And With Changes In The Maternal And Neonatal Ldl And Hdl Profile

Background and Aims: Physiological maternal hypercholesterolemia (MPH; total cholesterol (TC)≤280 mg/dL) occurs during pregnancy. However, some women develop supraphysiological maternal hypercholesterolemia (MSPH; TC>280 mg/dL) which associates with increased levels of LDL and leads to fetal endothelial dysfunction and atherosclerosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL levels. It is unknown whether (1) PCSK9 is modulated in MSPH and (2) if MSPH associates with changes in maternal and neonatal lipoproteins functions, favoring a pro-atherogenic profile.

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

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

Supraphysiological maternal hypercholesterolemia modulates the composition and antiatherogenic functions of maternal and neonatal lipoproteins, beyond cholesterol levels during pregnancy

Supraphysiological maternal hypercholesterolemia modulates the composition and antiatherogenic functions of maternal and neonatal lipoproteins, beyond cholesterol levels during pregnancy

Epigenetic Hallmarks of Fetal Early Atherosclerotic Lesions in Humans

Although increasingly strong evidence suggests a role of maternal total cholesterol and low-density lipoprotein cholesterol (LDLC) levels during pregnancy as a risk factor for atherosclerotic disease in the offspring, the underlying mechanisms need to be clarified for future clinical applications. To test whether epigenetic signatures characterize early fetal atherogenesis associated with maternal hypercholesterolemia and to provide a quantitative estimate of the contribution of maternal cholesterol level to fetal lesion size. This autopsy study analyzed 78 human fetal aorta autopsy samples from the Division of Human Pathology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. Maternal levels of total cholesterol, LDLC, high-density lipoprotein cholesterol (HDLC), triglycerides, and glucose and body mass index (BMI) were determined during hospitalization owing to spontaneous fetal death. Data were collected and immediately processed and analyzed to prevent degradation from January 1, 2011, through November 30, 2016. Results of DNA methylation and messenger RNA levels of the following genes involved in cholesterol metabolism were assessed: superoxide dismutase 2 (SOD2), low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein 2 (SREBP2), liver X receptor α (LXRα), and adenosine triphosphate-binding cassette transporter 1 (ABCA1). Among the 78 fetal samples included in the analysis (59% male; mean [SD] fetal age, 25 [3] weeks), maternal cholesterol level explained a significant proportion of the fetal aortic lesion variance in multivariate analysis (61%; P = .001) independently by the effect of levels of HDLC, triglycerides, and glucose and BMI. Moreover, maternal total cholesterol and LDLC levels were positively associated with methylation of SREBP2 in fetal aortas (Pearson correlation, 0.488 and 0.503, respectively), whereas in univariate analysis, they were inversely correlated with SREBP2 messenger RNA levels in fetal aortas (Pearson correlation, -0.534 and -0.671, respectively). Epivariations of genes controlling cholesterol metabolism in cholesterol-treated human aortic endothelial cells were also observed. The present study provides a stringent quantitative estimate of the magnitude of the association of maternal cholesterol levels during pregnancy with fetal aortic lesions and reveals the epigenetic response of fetal aortic SREBP2 to maternal cholesterol level. The role of maternal cholesterol level during pregnancy and epigenetic signature in offspring in cardiovascular primary prevention warrants further long-term causal relationship studies.

Milk cholesterol concentration in mice is not affected by high cholesterol diet- or genetically-induced hypercholesterolaemia

Breast milk cholesterol content may imply to affect short- and long-term cholesterol homeostasis in the offspring. However, mechanisms of regulating milk cholesterol concentration are only partly understood. We used different mouse models to assess the impact of high cholesterol diet (HC)- or genetically-induced hypercholesterolaemia on milk cholesterol content. At day 14 postpartum we determined milk, plasma and tissue lipids in wild type (WT), LDL receptor knockout (Ldlr−/−), and ATP-binding cassette transporter G8 knockout (Abcg8−/−) mice fed either low- or 0.5% HC diet. In chow-fed mice, plasma cholesterol was higher in Ldlr−/− dams compared to WT. HC-feeding increased plasma cholesterol in all three models compared to chow diet. Despite the up to 5-fold change in plasma cholesterol concentration, the genetic and dietary conditions did not affect milk cholesterol levels. To detect possible compensatory changes, we quantified de novo cholesterol synthesis in mammary gland and liver, which was strongly reduced in the various hypercholesterolaemic conditions. Together, these data suggest that milk cholesterol concentration in mice is not affected by conditions of maternal hypercholesterolaemia and is maintained at stable levels via ABCG8- and LDLR-independent mechanisms. The robustness of milk cholesterol levels might indicate an important physiological function of cholesterol supply to the offspring.

Maternal supraphysiological hypercholesterolemia associates with endothelial dysfunction of the placental microvasculature

Maternal physiological or supraphysiological hypercholesterolemia (MPH, MSPH) occurs during pregnancy. MSPH is associated with foetal endothelial dysfunction and atherosclerosis. However, the potential effects of MSPH on placental microvasculature are unknown. The aim of this study was to determine whether MSPH alters endothelial function in the placental microvasculature both ex vivo in venules and arterioles from the placental villi and in vitro in primary cultures of placental microvascular endothelial cells (hPMEC). Total cholesterol < 280 mg/dL indicated MPH, and total cholesterol ≥280 mg/dL indicated MSPH. The maximal relaxation to histamine, calcitonin gene-related peptide and adenosine was reduced in MSPH venule and arteriole rings. In hPMEC from MSPH placentas, nitric oxide synthase (NOS) activity and L-arginine transport were reduced without changes in arginase activity or the protein levels of endothelial NOS (eNOS), human cationic amino acid 1 (hCAT-1), hCAT-2A/B or arginase II compared with hPMEC from MPH placentas. In addition, it was shown that adenosine acts as a vasodilator of the placental microvasculature and that NOS is active in hPMEC. We conclude that MSPH alters placental microvascular endothelial function via a NOS/L-arginine imbalance. This work also reinforces the concept that placental endothelial cells from the macro- and microvasculature respond differentially to the same pathological condition.

Maternal hypercholesterolemia enhances oxysterol concentration in mothers and newly weaned offspring but is attenuated by maternal phytosterol supplementation

In hypercholesterolemic pregnancies, the maternal environment is characterized by excessive levels of atherogenic lipids that may increase cardiovascular disease risk in mothers and their offspring. We examined the influence of maternal hypercholesterolemia and phytosterol (PS) intervention on the concentration and metabolism of oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, in mothers and their newly weaned offspring. Twenty-one female apoE−/− mice were randomly assigned to three different diets throughout gestation and lactation: (1) chow, (2) high cholesterol (CH; 0.15%) and (3) CH with added PS (2%, CH/PS). At the end of the lactation period, mothers and pups were euthanized for serum and hepatic oxysterol analyses, hepatic transcriptional profiling of hepatic sterol regulatory targets and atherosclerosis. Hypercholesterolemic dams and their pups demonstrated increased (P˂.05) serum oxysterols [including 24 hydroxycholesterol (HC), 25HC, 27HC, 7αHC, 7βHC and 7 ketocholesterol)] compared with the chow group that were normalized by maternal PS supplementation. Hepatic oxysterol concentrations followed a similar pattern of response in mothers but were not altered in newly weaned pups. Hepatic mRNA expression suggested a pattern of enhanced abca1/g1 high-density-lipoprotein-mediated efflux but a reduction in biliary abcg5/g8 export in both dams and their pups. Although arterial lesions were not apparent in newly weaned pups, CH dams demonstrated enhanced atherosclerosis that was reduced upon PS intervention. These results demonstrate that offspring from hypercholesterolemic pregnancies have enhanced circulating oxysterol concentrations and highlight the potential utility of PS as a lipid-lowering option during hypercholesterolemic pregnancies for which there are currently limited options.

Perinatal Hypercholesterolemia Exacerbates Atherosclerosis Lesions in Offspring by Altering Metabolism of Trimethylamine-N-Oxide and Bile Acids.

Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E-deficient mice and the underlying mechanism. Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E-deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and Fmo3 hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic Scarb1 and Cyp7a1 but higher Nr1h4 gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in Scarb1 and Ldlr gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower Cyp7a1 gene expression compared with female born to normocholesterolemic mothers. DNA methylation of Fmo3, Scarb1, and Ldlr promoter regions was slightly modified and may explain the mRNA expression modulation. Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.

Lipidomic analysis reveals the significant increase in diacylglycerophosphocholines in umbilical cord blood from pregnant women with gestational hypercholesterolemia

Gestational hypercholesterolemia has been recognized as a risk factor of some pregnancy complications. We supposed that maternal hypercholesterolemia modified the lipid profile of the fetus. Thirty pregnant women with hypercholesterolemia and matched controls were recruited and cord blood was sampled. Lipidomic analysis was used to evaluate the lipid profile change between the two groups. The results showed that the content of diacylglycerophosphocholines (PC) was significantly high in cord blood from hypercholesterolemic pregnant women. PC (16:0/20:4) and PC (18:0/20:4) were selected as the most important lipid species in cord plasma and their contents were positively related to the total cholesterol and high-density lipoprotein cholesterol levels in cord blood. The contents of these two PCs were significantly higher in the hypercholesterolemic group than in the control group. These results suggested that gestational hypercholesterolemia might program the phospholipid metabolism in offspring.

Maternal Hypercholesterolemia and Phytosterol Intervention on Oxysterol Concentrations in Newly‐Weaned ApoE Deficient Mice

During hypercholesterolemic pregnancies, the fetus is exposed to excessive cholesterol that is thought to increase cardiovascular disease risk in adults. We recently reported that newly‐weaned offspring from hypercholesterolemic apoE−/− mice have increased blood lipid concentrations that are normalized by maternal phytosterol (PS) supplementation throughout gestation and lactation. However, the influence of maternal hypercholesterolemia and PS supplementation on offspring oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, have yet to be addressed. Therefore, we tested the hypothesis that offspring born to hypercholesterolemic mothers would have increased circulating oxysterol concentrations and that pups from PS‐supplemented mothers would have a more favorable serum and hepatic oxysterol profile compared with pups from unsupplemented mothers. Twenty‐one female apoE−/− mice were randomly assigned to three different chow based diets throughout gestation and lactation: chow (chow; control), chow diet with high cholesterol (CH; 0.15% (w/w), and chow diet with 0.15% (w/w) cholesterol and 2% (w/w) phytosterol (CH/PS). On postnatal day 21, offspring were euthanized for serum and hepatic oxysterol profiling and transcriptional changes in hepatic sterol regulatory targets by HPLC and RT‐PCR, respectively. Pups born to hypercholesterolemic mothers had increased (p&lt;0.05) serum cholesterol, 25‐hydroxycholesterol (HC), 7αHC, 7βHC, and 7‐ketocholesterol that were normalized by maternal PS‐supplementation. Hepatic mRNA expression of 7α‐hydroxylase (CYP7A1) was increased (p&lt;0.05) in pups born to hypercholesterolemic mothers but normalized in pups from PS‐supplemented mothers. Compared with the CH group, pups from PS‐supplemented mothers demonstrated increased transcription of liver X receptor (LXR) and its target gene adenosine triphosphate binding cassette G8 (ABCG8). No difference (p&gt;0.05) in the transcription of hepatic oxysterol binding proteins (OSBP 3, 8, and 7) was observed between the groups. These results suggest that, beyond increased circulating cholesterol, newly‐weaned offspring from hypercholesterolemic mothers have enhanced serum oxysterol concentrations and that maternal PS supplementation attenuates this response.Support or Funding InformationSupported by the National Institute for Complementary and Alternative Medicine.

Maternal Diet‐Induced Hypercholesterolemia Programs Lipoprotein Metabolism by Increasing VLDL Particle Number and Size in C57BL6/J Mouse Progeny

Early exposure to excessive cholesterol, in utero or in the early postnatal life, may program lipid metabolism in later life and predispose adult offspring to cardiovascular disease risk. However, little is known regarding the influence of maternal hypercholesterolemia on blood lipids and lipoprotein distribution throughout the life course. To better understand the influence of maternal hypercholesterolemia on blood lipids and lipoprotein distribution in offspring, blood lipid phenotyping was performed on newly‐weaned offspring (postnatal day 21) and chow‐fed adult offspring (postnatal day 84) born to mothers fed a chow diet or a chow diet supplemented with 0.15% cholesterol throughout gestation and lactation (n=6/group). Blood lipids including total‐C, HDL‐C, and LDL‐C were measured with enzymatic assay, and blood lipoprotein particle number and size were determined through nuclear magnetic resonance spectroscopy. Maternal serum total‐C during gestation (week 2) was higher (p≤0.05) in cholesterol‐supplemented dams compared with chow‐fed dams (87.5 ± 3.7 vs. 67.0 ± 3.5 mg/dL). Newly‐weaned and adult pups from chow or cholesterol‐supplemented mothers did not differ (p≥0.05) in serum lipid profile (total‐C, LDL‐C, or HDL‐C) or LDL and HDL particle number and size. However, both newly‐weaned pups and adult offspring born to cholesterol‐supplemented mothers demonstrated an increase (p≤0.05) in VLDL particle number and VLDL size compared with offspring from chow‐fed mothers. These results suggest that early exposure to cholesterol through maternal diet‐induced hypercholesterolemia influences VLDL distribution and size in newly‐weaned mouse offspring that persists into adulthood.Support or Funding InformationSupported by the National Institute for Complementary and Alternative Medicine.

Neonatal high-density lipoprotein from pregnancies with maternal supraphysiological hypercholesterolemia impairs nitric oxide synthase activity in human umbilical vein endothelial cells

Neonatal high-density lipoprotein from pregnancies with maternal supraphysiological hypercholesterolemia impairs nitric oxide synthase activity in human umbilical vein endothelial cells

Human maternal supraphysiological hypercholesterolemia leads to endothelial dysfunction of the placental microvasculature

Human maternal supraphysiological hypercholesterolemia leads to endothelial dysfunction of the placental microvasculature

Modulation of cholesterol transport by maternal hypercholesterolemia in human full-term placenta.

The significance of maternal cholesterol transporting to the fetus under normal as well as pathological circumstances is less understood. The objective of this study was to observe the effects of maternal hypercholesterolemia on placental cholesterol transportation. Human full-time placenta, maternal and venous cord blood were sampled at delivery from the pregnant women with serum total cholesterol (TC) concentrations at third trimester higher than 7.25 mM (n = 19) and the pregnant women with normal TC concentrations (n = 19). Serum lipids and expression of genes related to cholesterol transportation were measured by western blot or real-time PCR. The results indicated that serum TC, high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) levels were significantly increased, in pregnancies, but decreased in cord blood in hypercholesterolemic group compared to the matched control group. All the subjects were no-drinking, non-smoker, and gestational disease free. The mRNA expression of lipoprotein receptors, including LDLR and VLDLR were significantly increased, while the protein expression of PCSK9 was significantly increased in hypercholesterolemic placenta. In conclusion, maternal hypercholesterolemia might decrease the transportation of cholesterol from mother to fetus because of the high levels of PCSK9 protein expression.

Modulation of cholesterol transport by maternal hypercholesterolemia in human full-term placenta.

Modulation of cholesterol transport by maternal hypercholesterolemia in human full-term placenta.

Maternal Hypercholesterolemia Associated with Nicotine Exposure in Adulthood May Induce Kidney Injury in Male Rats if Hypomagnesemia Occurs

Background/Aims: Maternal hypercholesterolemia is a risk factor to renal injury in rat pups at adulthood, especially if they feed a cholesterol-enriched diet after weaning. However, the renal function of male pups of dams with hypercholesterolemia (PH) that were fed a regular chow from weaning to adulthood needs investigation, particularly those exposed to an adverse risk such as nicotine. Methods: We evaluated the renal function of PH animals and we compared the data with those found in male pups of control dams (PC) at 3- and 6-month-old by inulin clearance. Moreover, we investigated the effect of nicotine treatment for 8 days in both PH and PC animals at 6 months old via metabolic function studies and by renal histological analysis. Results: Inulin clearance and other renal function parameters were similar in PH and PC animals at 3 and 6 months old. Nevertheless, the PH group showed significant differences with regard to histological analysis despite a similar number of glomeruli. The glomerular area of PH animals was significantly smaller than that measured in PC animals, and the fractional interstitial area was significantly larger in PH animals than that measured in PC animals at 3 months old. With regard to nicotine treatment, we observed a trend for a reduction in creatinine clearance in both PC and PH groups, but only PH animals showed hypomagnesemia and the highest fractional interstitial area. Conclusions: The offspring exposed to a high cholesterol milieu during intrauterine and neonatal life may show a silent kidney injury at adulthood that may be aggravated by nicotine exposure if hypomagnesemia occurs.

Influence of maternal hypercholesterolemia and phytosterol intervention during gestation and lactation on dyslipidemia and hepatic lipid metabolism in offspring of Syrian golden hamsters.

Although there is a normal physiological rise in maternal lipids during pregnancy, excessive maternal hyperlipidemia during pregnancy increases cardiovascular disease risk for both the mother and offspring. There are limited safe lipid-lowering treatment options for use during pregnancy, therefore, we evaluated the influence of maternal phytosterol (PS) supplementation on lipid and lipoprotein metabolism in mothers and progeny. Female Syrian golden hamsters were randomly assigned to three diets throughout prepregnancy, gestation, and lactation (n = 6/group): (i) Chow (Chow), (ii) chow with 0.5% cholesterol (CH), and (iii) chow with 0.5% CH and 2% PS (CH/PS). Compared with newly weaned pups from Chow dams, pups from dams fed the CH-enriched diet demonstrated increases (p < 0.05) in total-C, LDL-C, HDL-C, and total LDL and VLDL particle number. Pups from CH-fed mothers also exhibited higher hepatic CH concentration and differential mRNA expression pattern of CH regulatory genes. Pups from PS-supplemented dams demonstrated reductions (p < 0.05) in serum total-C, non-HDL-C, and LDL-C but also increased triglycerides compared with pups from CH-fed dams. Maternal PS supplementation reduced (p < 0.05) hepatic CH and increased the abundance of HMG-CoAr and LDLr protein in newly weaned pups compared with the CH group. Results suggest that maternal PS supplementation is largely effective in normalizing CH in pups born to mothers with hypercholesterolemia, however, the cause and long-term influence of increased triglyceride is not known.

Nitric Oxide is a Central Common Metabolite in Vascular Dysfunction Associated with Diseases of Human Pregnancy.

Preeclampsia (PE), gestational diabetes mellitus (GDM), and maternal supraphysiological hypercholesterolaemia (MSPH) are pregnancy-related conditions that cause metabolic disruptions leading to alterations of the mother, fetus and neonate health. These syndromes result in fetoplacental vascular dysfunction, where nitric oxide (NO) plays a crucial role. PE characterizes by abnormal increase in the placental blood pressure and a negative correlation between NO level and fetal weight, suggesting that increased NO level and oxidative stress could be involved. GDM courses with macrosomia along with altered function of the fetal cardiovascular system and fetoplacental vasculature. Even when NO synthesis in the fetoplacental vasculature is increased, NO bioavailability is reduced due to the higher oxidative stress seen in this disease. In MSPH, there is an early development of atherosclerotic lesions in fetal and newborn arteries, altered function of the fetoplacental vasculature, and higher markers of oxidative stress in fetal blood and placenta, thus, vascular alterations related with NO metabolism occur as a consequence of this syndrome. Potential mechanisms of altered NO synthesis and bioavailability result from transcriptional and post-translational NO synthases (NOS) modulation, including phosphorylation/dephosphorylation cycles, coupling/uncoupling of NOS, tetrahydrobiopterin bioavailability, calcium/calmodulin-NOS and caveolin-1-NOS interaction. Additionally, oxidative stress also plays a role in the reduced NO bioavailability. This review summarizes the available information regarding lower NO bioavailability in these pregnancy pathologies. A common NO-dependent mechanism in PE, GDM and MSPH contributing to fetoplacental endothelial dysfunction is described.