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Intrauterine Growth Retardation Is Associated With Reduced Activity and Expression of the Cationic Amino Acid Transport Systems y⁺/hCAT-1 and y⁺/hCAT-2B and Lower Activity of Nitric Oxide Synthase in Human Umbilical Vein Endothelial Cells

From the Department of Physiology (P.C., L.S.), Faculty of Biological Sciences, Cellular and Molecular Physiology Laboratory (CMPL) and the Department of Obstetrics and Gynaecology (P.C.), Faculty of Medicine, University of Concepcion, Concepcion, Chile.

Correspondence to Dr L. Sobrevia, Cellular and Molecular Physiology Laboratory (CMPL), Faculty of Biological Sciences, University of Concepcion, PO Box 160-C, Concepcion, Chile. E-mail lsobrev@ udec.cl

Intrauterine growth retardation (IUGR) is associated with vascular complications leading to hypoxia and abnormal fetal development. The effect of IUGR on L-arginine transport and nitric oxide (NO) synthesis was investigated in cultures of human umbilical vein endothelial cells (HUVECs). IUGR was associated with membrane depolarization and reduced L-arginine transport (V_max= 5.8±0.2 versus 3.3±0.1 pmol/µg protein per minute), with no significant changes in transport affinity (K_m=159±15 versus 137±14 µmol/L). L-Arginine transport was trans-stimulated (8- to 9-fold) in cells from normal and IUGR pregnancies. IUGR was associated with reduced production of L-[³H]citrulline from L-[³H] arginine, lower nitrite and intracellular L-arginine, L-citrulline, and cGMP. IUGR decreased hCAT-1 and hCAT-2B mRNA, and increased eNOS mRNA and protein levels. IUGR-associated inhibition of L-arginine transport and NO synthesis, and membrane depolarization were reversed by the NO donor S-nitroso-N-acetyl-L,D-penicillamine. In summary, endothelium from fetuses with IUGR exhibit altered L-arginine transport and NO synthesis (L-arginine/NO pathway), reduced expression and activity of hCAT-1 and hCAT-2B and reduced eNOS activity. Alterations in L-arginine/NO pathway could be critical for the physiological processes involved in the etiology of IUGR in human pregnancies.

Key Words: L-arginine • intrauterine growth retardation • nitric oxide • human • endothelium

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