title: Tetrahydrobiopterin Role in human umbilical vein endothelial dysfunction in maternal supraphysiological hypercholesterolemia.
abstract: Maternal physiological hypercholesterolemia (MPH) allows a proper foetal development; however, maternal supraphysiological hypercholesterolemia (MSPH) associates with foetal endothelial dysfunction and early development of atherosclerosis. MSPH courses with reduced endothelium-dependent dilation of the human umbilical vein due to reduced endothelial nitric oxide synthase activity compared with MPH. Whether MSPH modifies the availability of the nitric oxide synthase cofactor tetrahydrobiopterin is unknown. We investigated whether MSPH-associated lower umbilical vein vascular reactivity results from reduced bioavailability of tetrahydrobiopterin. Total cholesterol <7.2mmol/L was considered as maternal physiological hypercholesterolemia (n=72 women) and ≥7.2mmol/L as MSPH (n=35 women). Umbilical veins rings were used for vascular reactivity assays (wire myography), and primary cultures of human umbilical vein endothelial cells (HUVECs) to measure nitric oxide synthase, GTP cyclohydrolase 1, and dihydrofolate reductase expression and activity, as well as tetrahydrobiopterin content. MSPH reduced the umbilical vein rings relaxation caused by calcitonine gene-related peptide, a phenomenon partially improved by incubation with sepiapterin. HUVECs from MSPH showed lower nitric oxide synthase activity (l-citrulline synthesis from l-arginine) without changes in its protein abundance, as well as reduced tetrahydrobiopterin level compared with MPH, a phenomenon reversed by incubation with sepiapterin. Expression and activity of GTP cyclohydrolase 1 was lower in MSPH, without changes in dihydrofolate reductase expression. MSPH is a pathophysiological condition reducing human umbilical vein reactivity due to lower bioavailability of tetrahydrobiopterin leading to lower NOS activity in the human umbilical vein endothelium.
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile. Electronic address: aaleiva@uc.cl.
authors.forename: Andrea
authors.initials: A
authors.lastname: Leiva
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Fuenzalida
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Salsoso
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
authors.forename: Eric
authors.initials: E
authors.lastname: Barros
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Basic Sciences, Faculty of Sciences, Universidad del Bío-Bío, Chillán 3780000, Chile.
authors.forename: Fernando
authors.initials: F
authors.lastname: Toledo
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Cellular Signaling and Differentiation Laboratory (CSDL), School of Medical Technology, Health Sciences Faculty, Universidad San Sebastian, Santiago 7510157, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Gutiérrez
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
authors.forename: Fabián
authors.initials: F
authors.lastname: Pardo
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD 4029, Queensland, Australia. Electronic address: sobrevia@med.puc.cl.
authors.forename: Luis
authors.initials: L
authors.lastname: Sobrevia
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006136:GTP Cyclohydrolase / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism* / Q000473:pathology; D011622:Pterins / Q000494:pharmacology*; D014471:Umbilical Veins / Q000378:metabolism* / Q000473:pathology
chemical_list: D011622:Pterins; C011552:tetrahydropterin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006136:GTP Cyclohydrolase
keywords: Cholesterol; Endothelium; Foetal; Pregnancy; Tetrahydrobiopterin