Maternal hypercholesterolemia in pregnancy associates with umbilical vein endothelial dysfunction: role of endothelial nitric oxide synthase and arginase II.
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.


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.
From the Cellular and Molecular Physiology Laboratory, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile (A.L., C.D.d.M., R.S., T.S., F.A., M.F., E.G.-G., F.P., L.S.); Biomedical Research Centre, Department of Biomedical Sciences, School of Medicine, Universidad de Valparaíso, Valparaíso, Chile (S.S.M.); Obstetrics and Gynecology Unit, Clínica Alemana, Temuco, Chile (F.A.); and the University of Queensland Centre for Clinical Research, Faculty of Health Sciences, The University of Queensland, Herston, Queensland, Australia (L.S.).
Andrea
A
Leiva
Camila Diez
CD
de Medina
Rocío
R
Salsoso
Tamara
T
Sáez
Sebastián
S
San Martín
Fernando
F
Abarzúa
Marcelo
M
Farías
Enrique
E
Guzmán-Gutiérrez
Fabián
F
Pardo
Luis
L
Sobrevia
D000328:Adult; D001119:Arginase / Q000378:metabolism*; D027201:Cationic Amino Acid Transporter 1 / Q000378:metabolism; D027202:Cationic Amino Acid Transporter 2 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007700:Kinetics; D008055:Lipids / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D011264:Pregnancy Trimesters / Q000378:metabolism; D015398:Signal Transduction; D014471:Umbilical Veins / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D014508:Urea / Q000378:metabolism; D055815:Young Adult
D027201:Cationic Amino Acid Transporter 1; D027202:Cationic Amino Acid Transporter 2; D008055:Lipids; D009569:Nitric Oxide; D014508:Urea; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C477631:ARG2 protein, human; D001119:Arginase
arginase; cholesterol; endothelium; nitric oxide; pregnancy