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

Abstract

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.

• Authors: Andrea Leiva, Camila Diez de Medina, Rocío Salsoso, Tamara Sáez, Sebastián San Martín, Fernando Abarzúa, Marcelo Farías, Enrique Guzmán-Gutiérrez, Fabián Pardo, Luis Sobrevia
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 10 Pg. 2444-53 (Oct 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23950140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cationic Amino Acid Transporter 1
• Cationic Amino Acid Transporter 2
• Lipids
• Nitric Oxide
• Urea
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• ARG2 protein, human
• Arginase

Topics

• Adult
• Arginase (metabolism)
• Cationic Amino Acid Transporter 1 (metabolism)
• Cationic Amino Acid Transporter 2 (metabolism)
• Cells, Cultured
• Female
• Human Umbilical Vein Endothelial Cells (enzymology, pathology)
• Humans
• Hypercholesterolemia (blood, enzymology, pathology, physiopathology)
• Kinetics
• Lipids (blood)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Pregnancy
• Pregnancy Complications (blood, enzymology, pathology, physiopathology)
• Pregnancy Trimesters (metabolism)
• Signal Transduction
• Umbilical Veins (enzymology, pathology, physiopathology)
• Urea (metabolism)
• Young Adult