Equilibrative Nucleoside (ENTs) and Cationic Amino Acid (CATs) Transporters: Implications in Foetal Endothelial Dysfunction in Human Pregnancy Diseases

Abstract

Gestational diabetes (GD, characterized by abnormal D-glucose metabolism), intrauterine growth restriction (IUGR, a disease associated with reduced oxygen delivery (hypoxia) to the foetus), and preeclampsia (PE, a pregnancy complication characterized by high blood pressure, proteinuria and increased vascular resistance), induce foetal endothelial dysfunction with implications in adult life and increase the risk of vascular diseases. Synthesis of nitric oxide (NO) and uptake of L-arginine (the NO synthase (NOS) substrate) and adenosine (a vasoactive endogenous nucleoside) by the umbilical vein endothelium is altered in pregnancies with GD, IUGR or PE. Mechanisms underlying these alterations include differential expression of equilibrative nucleoside transporters (ENTs), cationic amino acid transporters (CATs), and NOS. Modulation of ENTs, CATs, and NOS expression and activity in endothelium involves protein kinase C (PKC), mitogen-activated protein kinases p42 and p44 (p42/44(mapk)), calcium, and phosphatidyl inositol 3 kinase (PI3k), among others. Elevated extracellular D-glucose and hypoxia alter human endothelial function. However, information regarding the transcriptional modulation of ENTs, CATs, and NOS is limited. This review focuses on the effect of transcriptional and post-transcriptional regulatory mechanisms involved in the modulation of ENTs and CATs, and NOS expression and activity, and the consequences for foetal endothelial function in GD, IUGR and PE. The available information will contribute to a better understanding of the cell and molecular basis of the altered vascular endothelial function in these pregnancy diseases and will emphasize the key role of this type of epithelium in placental function and the normal foetal development and growth.

Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: Interactions with placental renin-angiotensin system

“…Interestingly, adenosine also raises intracellular [Ca 2+ ] via cyclic AMP under these conditions. Of note, activation of AT4R can produce endogenous vasodilatory nitric oxide via activation of endothelial nitric oxide synthase (eNOS) [15] and likewise, adenosine increases nitric oxide synthesis from feto-placental endothelium [16,17].…”

Epigenetics: New Concepts of Old Phenomena in Vascular Physiology

“…In this scenario, epigenetic modifications that were initially proposed as important mechanisms are supported by growing evidence in type 2 diabetes and their key role in normal development. The vascular system represents a good candidate to explore, not only because of its proved susceptibility to be programmed, but since it has been shown that pregnancy pathologies such as, IUGR, gestational diabetes and preeclampsia induce metabolic changes that can be seen in fetal endothelium [4,5]. Some of these changes include alterations in pathways related with the normal vascular function and remodelling (i.e.…”

“…Some of these changes include alterations in pathways related with the normal vascular function and remodelling (i.e. Adenosine-L-Arginine-NO signalling pathway and hypoxia) [4,5]; moreover, it has been shown that NO production and hypoxia regulate epigenetic-related enzymes in endothelial and non-endothelial cells [82][83][84].…”

“…To date, studies in low birth offspring who later developed type 2 diabetes have shown direct evidence of some epigenetic hallmarks in the promoter of genes related with glucose metabolism and insulin signalling. However, in the vascular system, whose development is strongly influenced by epigenetic mechanisms [2,3], there is scarce data available that can explain the altered responses observed in foetal endothelial cells from different pregnancy related diseases [4,5]. …”

Adenosine Receptors in Health and Disease

“…VEGF is the unique mitogen that acts specifically in endothelial cells by activating VEGFR (Olsson et al, 2006;Kerbel, 2008). Activation of VEGFR triggers intracellular signalling pathways that involve increased NO synthesis (Roy et al, 2008;Casanello et al, 2007), a gas that seems to be determinant in endothelial cell proliferation in the fetal-placental unit (Escudero and Sobrevia, 2008). Ado could contribute up to 50-70% of the angiogenic response in some condition such as hypoxia (Adair, 2005) via a direct mitogenic effect on endothelium (Auchampach, 2007) or by regulating the production of pro-angiogenic substances, such as VEGF and IL-8 (Feoktistov et al, 2002;2004;Clark et al, 2007) or anti-angiogenic factors such as thrombospondin 1 (Desai et al, 2005) from endothelial and immune cells (Auchampach, 2007).…”