Cross-sectional and longitudinal lipid determination studies in pregnant women reveal an association between increased maternal LDL cholesterol concentrations and reduced human umbilical vein relaxation

Leiva, Andrea; Salsoso, Rocío; Sáez, Tamara; Sanhueza, Carlos; Pardo, Fabián; Sobrevía, Luis

doi:10.1016/j.placenta.2015.05.012

Cited by 37 publications

(33 citation statements)

References 37 publications

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“…Pregnant women with TC < 280 mg/dL were included in the MPH group, and those with TC ≥ 280 md/dL in the MSPH group. The cut-off value for MSPH reflected values at which human fetoplacental endothelial and vascular dysfunction have been previously reported 1,2,4,5,[7][8][9]24 . The exclusion criteria were maternal obesity at term of pregnancy, pre-gestational and gestational diabetes, preeclampsia, intrauterine growth restriction, foetal malformations and other maternal pathologies as described previously 9 .…”

Section: Methodsmentioning

confidence: 99%

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

Fuenzalida

Cantin

Kallol

et al. 2020

Sci Rep

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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 .

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Section: Methodsmentioning

confidence: 99%

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

Fuenzalida

Cantin

Kallol

et al. 2020

Sci Rep

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“…Interestingly, MSPH has been described as well in normal pregnancies as in pregnancies with GDM and preeclampsia (Barrett et al, 2014; Herrera and Ortega-Senovilla, 2010; Leiva et al, 2015b;Napoli et al, 1997;Marseille-Tremblay et al, 2008;Sánchez-Vera et al, 2007) In normal pregnancies MSPH is associated with vascular alterations at birth (Leiva et al, 2013(Leiva et al, , 2015a(Leiva et al, , 2015b(Leiva et al, , 2016Napoli et al, 1997Napoli et al, , 1999 and during childhood (Napoli et al, 1999). Additionally, MSPH was associated with increased human cationic amino acid transporter (hCAT)mediated L-arginine transport without changes in the protein abundance of the transporter as well as increased expression and activity of arginases (Leiva et al, 2013).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…is an imbalance of circulating cholesterol levels with high levels of LDL-cholesterol and low levels of HDL-cholesterol as well increased levels of triglycerides (The National Cholesterol Education Programme (NCEP) Adult Treatment Panel III (ATP III), 2002). This disorder can occur under diverse pathological conditions as well as manifest as a physiological condition during pregnancy,where the maternal cholesterol levels increase by more than 40%(Leiva et al, 2015b;Palinski, 2014).Dyslipidaemia is the main risk factor associated with the development of atherosclerosis in adults and in a growing foetus, leading to chronic inflammation and altered oxidative status and subsequent endothelial dysfunction(Egan et al, 2016;Napoli et al, 1997). For this reason, developing strategies to control the plasma lipid levels and therefore the atherosclerotic process is essential to controlling this condition, at least in adults (Figure 3).…”

mentioning

confidence: 99%

Adenosine receptors: Modulators of lipid availability that are controlled by lipid levels

Leiva

Guzmán-Gutiérrez

Contreras-Duarte

et al. 2017

Molecular Aspects of Medicine

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Adenosine as well as agonists and antagonists for the four adenosine receptor subtypes (A1R, A2AR, A2BR and A3R) play a role in several key physiological and pathophysiological processes, including the regulation of vascular tone, thrombosis, immune response, inflammation, and angiogenesis. This review focuses on the adenosine-mediated regulation of lipid availability in the cell and in the systemic circulation as well in humans and animal models. Therefore, adenosine, mainly by acting on A1R, inhibits lipolysis activity, leading to reduction of the circulating fatty acid levels. This nucleoside can also participate in the early development of atherosclerosis by inhibiting the formation of foam cells via stimulation of cholesterol efflux through A2AR expressed on macrophages and reduction of the inflammatory process by activating A2AR and A2BR. Adenosine also appears to modulate intracellular cholesterol availability in Niemann-Pick type C1 disease and Alzheimer disease via A2AR and A3, respectively. Remarkably, the role of adenosine receptors in the regulation of plasma total cholesterol and triglyceride levels has been studied in animal models. Thus, an anti-atherogenic role for A2BR as well as a pro-atherogenic role of A2AR and A1 have been proposed; A3R has not been shown to participate in the control of lipid levels or the development of atherosclerosis. Surprisingly, and despite the role of A2A in the inhibition of foam cell formation among isolated cells, this receptor appears to be pro-atherogenic in mice. Remarkably, the role of adenosine receptors in human dyslipidaemia and atherosclerosis must to be elucidated. Additionally, it has been reported that increased lipid levels impair the effects of adenosine/adenosine receptors in controlling vascular tone, and we speculate on the possibility that this impairment could be due to alterations in the composition of the membrane microdomains where the adenosine receptors are located. Finally, a possible role for adenosine/adenosine receptors in the phenomena of dyslipidaemia in pregnancy has been proposed.

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“…In addition, treatment of HUVECs with low-density lipoprotein (LDL) activated UPR and interleukins expression (Gora et al, 2010 ). Certainly, further research is necessary in order to understand whether insulin treatment during pregnancy in women with GDM or coursing without or with supraphysiological hypercholesterolaemia (Leiva et al, 2015 ) leads to a beneficial or detrimental result on overall angiogenic mechanisms involving or not ERS and/or UPS pathways in the human fetoplacental vasculature.…”

Section: Placental Angiogenesismentioning

confidence: 99%

“…Even when is known that human CHOP (hCHOP) is activated by NO leading to reduced expression of SLC291A gene [for human equilibrative nucleoside transporter 1 (hENT1)] (Farías et al, 2010 ), and that hCHOP activity is modulated by insulin (Sáez et al, 2014 ), nothing is clear regarding a potential involvement of ARs and/or IRs in this phenomenon. On the other hand, pregnant women coursing with supraphysiological hypercholesterolemia show altered fetoplacental NO-dependent and L-arginine transport-dependent vascular reactivity when plasma level of total cholesterol (TCh) is >280 mg/dL (Leiva et al, 2015 ). However, the vascular effect of maternal dyslipidaemia, or whether ERS and changes in cell signaling and/or expression of ARs or IRs in these alterations is not yet reported.…”

Section: Introductionmentioning

confidence: 99%

Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus

Sobrevía

Salsoso²,

Fuenzalida

et al. 2016

Front. Physiol.

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Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.

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Cross-sectional and longitudinal lipid determination studies in pregnant women reveal an association between increased maternal LDL cholesterol concentrations and reduced human umbilical vein relaxation

Cited by 37 publications

References 37 publications

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

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

Adenosine receptors: Modulators of lipid availability that are controlled by lipid levels

Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus

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