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(Circulation Research. 2005;97:16.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Equilibrative Nucleoside Transporter 1 Expression Is Downregulated by Hypoxia in Human Umbilical Vein Endothelium

Paola Casanello, Alberto Torres, Felipe Sanhueza, Marcelo González, Marcelo Farías, Victoria Gallardo, Marçal Pastor-Anglada, Rody San Martín, Luis Sobrevia

From the Cellular and Molecular Physiology Laboratory (CMPL) (P.C., A.T., F.S., M.G., M.F., V.G., R.S.M., L.S.), Department of Obstetrics and Gynaecology, Medical Research Centre (CIM), School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago; Universidad de Concepción (V.G.), Chile; and the Departament de Bioquímica i Biologia Molecular (M.P.-A.), Universitat de Barcelona, Spain.

Correspondence to Dr Luis Sobrevia, Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics and Gynaecology, Medical Research Centre (CIM), School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, P.O. Box 114-D, Santiago, Chile. E-mail sobrevia{at}med.puc.cl

Reduced oxygen level (hypoxia) induces endothelial dysfunction and release of the endogenous nucleoside adenosine. Human umbilical vein endothelium (HUVEC) function in an environment with 3% to 5% O₂ and exhibit efficient adenosine membrane transport via human equilibrative nucleoside transporters 1 (hENT1). We studied whether adenosine transport and hENT1 expression are altered by hypoxia in HUVEC. Hypoxia (0 to 24 hours, 2% and 1% O₂) reduced maximal hENT1-adenosine transport velocity (V_max) and maximal nitrobenzylthionosine (NBMPR, a high-affinity hENT1 protein ligand) binding, but increased extracellular adenosine concentration. Hypoxia also reduced hENT1 protein and mRNA levels, effects unaltered by N-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase [NOS] inhibitor) or PD-98059 (inhibitor of mitogen-activated protein kinase kinase 1 and 2 [MEK1/2]). Hypoxia reduced endothelial NOS (eNOS) activity and eNOS phosphorylation at Ser¹¹⁷⁷, but increased eNOS protein level. Hypoxia increased (1 to 3 hours), but reduced (24 hours) p42/44^mapk phosphorylation. Thus, hypoxia-increased extracellular adenosine may result from reduced hENT1-adenosine transport in HUVEC. Hypoxia effect seems not to involve NO, but p42/44^mapk may be required for the relatively rapid effect (1 to 3 hours) of hypoxia. These results could be important in diseases where the fetus is exposed to intrauterine environments poor in oxygen, such as intrauterine growth restriction, or where adenosine transport is altered, such as gestational diabetes.

Key Words: endothelium • hypoxia • adenosine

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