Browsing by Author "San Martín, R."

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    Equilibrative nucleoside transporter 1 expression is downregulated by hypoxia in human umbilical vein endothelium
    (2005) Casanello, P.; Torres, A.; Sanhueza, F.; González, M.; Farías, M.; Gallardo, V.; Pastor-Anglada, M.; San Martín, R.; Sobrevía Luarte, Luis Alberto
    Reduced oxygen level (hypoxia) induces endothelial dysfunction and release of the endogenous nucleosideadenosine. Human umbilical vein endothelium (HUVEC) function in an environment with 3% to 5% O2and exhibitefficient adenosine membrane transport via human equilibrative nucleoside transporters 1 (hENT1). We studied whetheradenosine 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 (Vmax) and maximal nitrobenzylthionosine (NBMPR, a high-affinity hENT1 protein ligand) binding, but increased extracellular adenosine concentration. Hypoxia also reducedhENT1 protein and mRNA levels, effects unaltered byN_x0001_-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]). Hypoxiareduced endothelial NOS (eNOS) activity and eNOS phosphorylation at Ser1177, but increased eNOS protein level.Hypoxia increased (1 to 3 hours), but reduced (24 hours) p42/44mapkphosphorylation. Thus, hypoxia-increasedextracellular adenosine may result from reduced hENT1-adenosine transport in HUVEC. Hypoxia effect seems not toinvolve NO, but p42/44mapkmay be required for the relatively rapid effect (1 to 3 hours) of hypoxia. These results couldbe important in diseases where the fetus is exposed to intrauterine environments poor in oxygen, such as intrauterinegrowth restriction, or where adenosine transport is altered, such as gestational diabetes.
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    Gestational Diabetes and the Adenosine/L-Arginine/Nitric Oxide (ALANO) Pathway in Human Umbilical Vein Endothelium
    (2006) San Martín, R.; Sobrevía Luarte, Luis Alberto
    Altered endothelial cell function is a key factor associated with vascular disorders and is critical in the fetal growth and development. Pregnancies affected by diseases such as gestational diabetes are associated with human umbilical vein endothelial dysfunction, a finding that has been associated with a high incidence of vascular complications during the adult life. Limited information is available addressing cellular mechanisms associated with altered human umbilical vein endothelial function in gestational diabetes. One of the key signalling pathways associated with altered vascular physiology is the synthesis of the vasodilator nitric oxide (NO) from the cationic amino acid L-arginine by the endothelium (i.e. the endothelial L-arginine/NO pathway). The activity of this signalling pathway is modulated by D-glucose, adenosine, insulin, and ATP, among other molecules, and is upregulated (transcriptional, post-transcriptional and post-translational levels) in gestational diabetes. This review focuses on the cellular and molecular mechanisms involved with elevated adenosine levels in fetal umbilical vein blood and the endothelial L-arginine/NO pathway activity in gestational diabetes. We suggest that a lower capacity of adenosine transport by the fetal endothelium in gestational diabetes leads to extracellular accumulation of this nucleoside and its higher bio-availability activates endothelial P1 type purinoceptors. A functional association between A2a purinoceptor subtype signalling and the activity of the L-arginine transport mediated by human cationic amino acid transporters and endothelial NO synthase activity (i.e. ‘ALANO pathway’) is proposed, revealing in part the mechanisms that account for human umbilical vein endothelial cell dysfunction programmed through the development of the fetus in gestational diabetes.