Objective-Human pregnancy that courses with maternal supraphysiological hypercholesterolemia (MSPH) correlates with atherosclerotic lesions in fetal arteries. It is known that hypercholesterolemia associates with endothelial dysfunction in adults, a phenomenon where nitric oxide (NO) and arginase are involved. However, nothing is reported on potential alterations in the fetoplacental endothelial function in MSPH. The aim of this study was to determine whether MSPH alters fetal vascular reactivity via endothelial arginase/urea and l-arginine transport/NO signaling pathways. Approach and Results-Total cholesterol <280 mg/dL was considered as maternal physiological hypercholesterolemia (n=46 women) and ≥280 mg/dL as MSPH (n=28 women). Maternal but not fetal total cholesterol and low-density lipoprotein-cholesterol levels were elevated in MSPH. Umbilical veins were used for vascular reactivity assays (wire myography), and primary cultures of umbilical vein endothelial cells to determine arginase, endothelial NO synthase (eNOS), and human cationic amino acid transporter 1 and human cationic amino acid transporter 2A/B expression and activity. MSPH reduced calcitonine gene-related peptide-umbilical vein relaxation and increased intima/media ratio (histochemistry), as well as reduced eNOS activity (l-citrulline synthesis from l-arginine, eNOS phosphorylation/dephosphorylation), but increased arginase activity and arginase II protein abundance. Arginase inhibition increased eNOS activity and l-arginine transport capacity without altering human cationic amino acid transporter 1 or human cationic amino acid transporter 2A/B protein abundance in maternal physiological hypercholesterolemia and MSPH. Conclusions-MSPH is a pathophysiological condition altering umbilical vein reactivity because of fetal endothelial dysfunction associated with arginase and eNOS signaling imbalance. We speculate that elevated maternal circulating cholesterol is a factor leading to fetal endothelial dysfunction, which could have serious consequences to the growing fetus. Maternal Hypercholesterolemia in Pregnancy AssociatesWith Umbilical Vein Endothelial Dysfunction Leiva et al MSPH and Umbilical Vein Endothelial Dysfunction 2445NO synthases. Because NO synthesis depends on l-arginine uptake in human placenta endothelium, 10-17 MSPH could result in altered l-arginine transport and NO synthesis, that is, the l-arginine/NO pathway, in fetal endothelium.l-Arginine uptake occurs predominantly via the human cationic amino acid transporters (hCATs) family.13 hCATs family includes ≥5 members, that is, hCAT-1, hCAT-2A, hCAT-2B, hCAT-3, and hCAT-4, 12,13 of which the high-affinity, lowcapacity hCAT-1 is the main isoform expressed in human umbilical vein endothelial cells (HUVEC), 15,16 a cell type exposed to oxygen-and nutrient-enriched blood (ie, arteriallike blood, reaching fetal circulation).18 Interestingly, altered hCAT-1 activity could result in abnormal NO synthesis in HUVEC. 10,11,15,17 Hypercholesterolemia also associates with reduced endotheli...

Pregnancy is a physiological condition characterized by a progressive, weeks of gestationdependent increase in maternal triglycerides hypertriglyceridemia and total cholesterol hypercholesterolemia [ -]. In some cases a misadaptation occurs and these levels increase over a physiological range and dyslipidemia is recognized [ ]. This condition occurs in some pregnancies coursing without associated pregnancy alterations [i.e., maternal supraphysiological hypercholesterolemia MSPH ] and in pregnancies coursing with pathologies as preeclampsia and gestational diabetes mellitus GDM [ , ].GDM is widely associated with endothelial dysfunction of the placenta mainly triggered by hyperinsulinemia, hyperglycemia, and changes in nucleoside extracellular concentration and dyslipidemia associated with this pathology could play a role in this phenomenon since dyslipidemia is a risk factor to develop endothelial dysfunction and atherosclerosis [ ]. Additionally, GDM predisposes to an accelerated development of cardiovascular disease CVD in adult life and as most of pregnancies with GDM course with elevated dyslipidemia, is feasible found a pathological link between dyslipidemia in GDM pregnancies and development of CVD later in life [ , ].The hypertrygliceridemia described in GDM is directly related with the fetal macrosomia characteristic of this pathology, and a positive correlation between maternal triglycerides levels and neonatal body weight or fat mass has been found in GDM [ , ]. Even when hypercholesterolemia, described in GDM, is not related with the fetal macrosomia, could be related with fetal endothelial dysfunction and later development of cardiovascular diseases in the adulthood [ ].Although lipid traffic through the placenta is restrictive, a correlation between maternal and fetal blood cholesterol in the first and second trimesters of pregnancy has been established, suggesting that maternal cholesterol level could alter normal development of the fetus [ ]. In fact it has been reported that due to altered lipid metabolism in the placenta as a result of high maternal blood cholesterol, atherogenesis, a clinical complication commonly appearing in adults, probably begins in fetal life with similar factors altered at the mother, the fetus and the placenta [ , ].In this regard, GDM correlates with placental macro and microvascular endothelial dysfunction, also considered as early marker of atherosclerosis, and neonates from GDM pregnancies have significant increase in the aortic intima-media thickness and higher lipid content, both considered as subclinical markers of atherosclerosis, conditions that will potentially increase the atherosclerotic process later in life [ , ].Since the lack of information in the literature, nothing is yet available about the potential effect of hypercholesterolemia in GDM pregnancies regarding development of endothelial dysfunction and atherosclerosis in human fetoplacental vasculature [ ], however cumulative evidence shows that high levels of blood cholesterol modify the endothelial fu...