Abstract
Regulation of blood flow depends on the systemic and local release of vasoactive molecules including the endogenous nucleoside adenosine. Vasodilation caused by adenosine results from the activation of adenosine receptors (ARs) at the vascular endothelium and smooth muscle. Adenosine receptors are four subtypes, i.e. A1AR, A2AAR, A2BAR and A3AR, of which A2AAR and A2BAR activation in the endothelium lead to increased generation of nitric oxide and relaxation of the underlying smooth muscle cell layer. Adenosine also causes vasoconstriction via a mechanism involving A1AR activation by increasing the release of vasoconstrictors. Adenosine increases the sensitivity of vascular tissues from diseases coursing with insulin resistance, including gestational diabetes mellitus (GDM) and obesity. ARs also play a role in obesity since they modulate D-glucose homeostasis, inflammation and adipogenesis. Agonists and/or antagonists of high selectivity for ARs may result in reversing the obesity state since normalises lipolysis and insulin sensitivity. A considerable fraction of pregnant women with GDM show with pregestational obesity and/or supraphysiological gestational weight gain. These conditions associated with reduced vascular responsiveness to adenosine and insulin. However, it is unclear whether GDM plus obesity in pregnancy could worsen these alterations in the foetoplacental vascular function. This chapter summarises available findings that address the potential involvement of ARs to modulate human foetoplacental vasculature in GDM and obesity in pregnancy.
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American Diabetes Association (ADA) (2017) Classification and diagnosis of diabetes. Diabetes Care 40:S11–S24
Antonioli L, Blandizzi C, Csóka B et al (2015) Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations. Nat Rev Endocrinol 11:228–241
Badillo P, Salgado P, Bravo P et al (2017) High plasma adenosine levels in overweight/obese pregnant women. Purinergic Signal 13:479–488
Brown MA, North L, Hargood J (1990) Uteroplacental Doppler ultrasound in routine antenatal care. Aust N Z J Obstet Gynaecol 30:303–307
Brown J, Grzeskowiak L, Williamson K et al (2017a) Insulin for the treatment of women with gestational diabetes. Cochrane Database Syst Rev 11:CD012037
Brown J, Alwan NA, West J et al (2017b) Lifestyle interventions for the treatment of women with gestational diabetes. Cochrane Database Syst Rev 5:CD011970
Brown J, Martis R, Hughes B et al (2017c) Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. Cochrane Database Syst Rev 1:CD011967
Budohoski L, Challiss RA, McManus B et al (1984) Effects of analogues of adenosine and methyl xanthines on insulin sensitivity in soleus muscle of the rat. FEBS Lett 167:1–4
Burnstock G (2016) Purinergic signalling and endothelium. Curr Vasc Pharmacol 14:130–145
Burnstock G (2017) The involvement of purinergic signalling in obesity. Purinergic Signal 14:97–108
Buscariollo DL, Fang X, Greenwood V et al (2014) Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice. PLoS One 9:e87547
Challiss RA, Richards SJ, Budohoski L (1992) Characterization of the adenosine receptor modulating insulin action in rat skeletal muscle. Eur J Pharmacol 226:121–128
Chiarello DI, Salsoso R, Toledo F et al (2018) Foetoplacental communication via extracellular vesicles in normal pregnancy and preeclampsia. Mol Aspects Med 60:69–80
Ciaraldi TP (1988) The role of adenosine in insulin action coupling in rat adipocytes. Mol Cell Endocrinol 60:31–41
Crist G, Xu B, LaNoue L et al (1998) Tissue-specific effects of in vivo adenosine receptor blockade on glucose uptake in Zucker rats. FASEB J 12:1301–1308
Crist G, Xu B, Berkich D et al (2001) Effects of adenosine receptor antagonism on protein tyrosine phosphatase in rat skeletal muscle. Int J Biochem Cell Biol 33:817–830
Dhalla A, Wong M, Voshol P et al (2007) A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents. Am J Physiol Endocrinol Metab 292:E1358–E1363
Escudero C, Casanello P, Sobrevia L (2008) Human equilibrative nucleoside transporters 1 and 2 may be differentially modulated by A2B adenosine receptors in placenta microvascular endothelial cells from pre-eclampsia. Placenta 29:816–825
Farías M, Puebla C, Westermeier F et al (2010) Nitric oxide reduces SLC29A1 promoter activity and adenosine transport involving transcription factor complex hCHOP-C/EBPalpha in human umbilical vein endothelial cells from gestational diabetes. Cardiovasc Res 86:45–54
Figler R, Wang G, Srinivasan S et al (2011) Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans. Diabetes 60:669–679
Fleming I (2010) Molecular mechanisms underlying the activation of eNOS. Pflugers Arch 459:793–806
Fredholm BB (2010) Adenosine receptors as drug targets. Exp Cell Res 316:1284–1288
Fredholm BB (2014) Adenosine-a physiological or pathophysiological agent? J Mol Med (Berl) 92:201–206
Fredholm BB, Ijzerman AP, Jacobson KA et al (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev 63:1–34
Fredholm BB, Yang J, Wang Y (2017) Low, but not high, dose caffeine is a readily available probe for adenosine actions. Mol Aspects Med 55:20–25
GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH et al (2017) Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 377:13–27
Gharibi B, Abraham A, Ham J et al (2012) Contrasting effects of A1 and A2b adenosine receptors on adipogenesis. Int J Obes 36:397–406
Gnad T, Scheibler S, von Kügelgen I (2014) Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516:395–399
Guzmán-Gutiérrez E, Westermeier F, Salomón C et al (2012) Insulin-increased L-arginine transport requires A(2A) adenosine receptors activation in human umbilical vein endothelium. PLoS One 7:e41705
Guzmán-Gutiérrez E, Armella A, Toledo F et al (2016) Insulin requires A1 adenosine receptors expression to reverse gestational diabetes-increased L-arginine transport in human umbilical vein endothelium. Purinergic Signal 12:175–190
Headrick JP, Ashton KJ, Rose'meyer RB et al (2013) Cardiovascular adenosine receptors: expression, actions and interactions. Pharmacol Ther 140:92–111
Henriksson P, Eriksson B, Forsum E et al (2014) Gestational weight gain according to Institute of Medicine recommendations in relation to infant size and body composition. Pediatr Obes 10:388–394
Holness MJ, Zariwala G, Walker CG et al (2012) Adipocyte pyruvate dehydrogenase kinase 4 expression is associated with augmented PPARγ upregulation in early-life programming of later obesity. FEBS Open Bio 2:32–36
Kaartinen J, Hreniuk S, Martin L et al (1991) Attenuated adenosine-sensitivity and decreased adenosine-receptor number in adipocyte plasma membranes in human obesity. Biochem J 279:17–22
Kurlak LO, Williams PJ, Bulmer JN et al (2015) Placental expression of adenosine A(2A) receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system. Placenta 36:611–613
Lewis RM, Desoye G (2017) Placental lipid and fatty acid transfer in maternal overnutrition. Ann Nutr Metab 70:228–231
Lönnroth P, Appell KC, Wesslau C et al (1988) Insulin-induced subcellular redistribution of insulin-like growth factor II receptors in the rat adipose cell. Counterregulatory effects of isoproterenol, adenosine, and cAMP analogues. J Biol Chem 263:15386–15391
Maguire MH, Szabó I, Valkó IE et al (1998) Simultaneous measurement of adenosine and hypoxanthine in human umbilical cord plasma using reversed-phase highperformance liquid chromatography with photodiode-array detection and on-line validation of peak purity. J Chromatogr B Biomed Sci Appl 707:33–41
Pandolfi A, Di Pietro N (2010) High glucose, nitric oxide, and adenosine: a vicious circle in chronic hyperglycaemia? Cardiovasc Res 86:9–11
Pardo F, Silva L, Sáez T et al (2015) Human supraphysiological gestational weight gain and fetoplacental vascular dysfunction. Int J Obes 39:1264–1273
Pardo F, Villalobos-Labra R, Chiarello DI et al (2017) Molecular implications of adenosine in obesity. Mol Asp Med 55:90–101
Pardo F, Villalobos-Labra R, Sobrevia B et al (2018) Extracellular vesicles in obesity and diabetes mellitus. Mol Aspects Med In Press. https://doi.org/10.1016/j.mam.2017.11.010
Peleli M, Fredholm B, Sobrevia L et al (2017) Pharmacological targeting of adenosine receptor signalling. Mol Asp Med 55:4–8
Pietryga M, Brazert J, Wender-Ozegowska E et al (2006) Placental Doppler velocimetry in gestational diabetes mellitus. J Perinat Med 34:108–110
Sáez T, De Vos P, Sobrevia L et al (2018a) Is there a role for exosomes in foetoplacental endothelial dysfunction in gestational diabetes mellitus? Placenta 61:48–54
Sáez T, Salsoso R, Leiva A et al (2018b) Human umbilical vein endothelium-derived exosomes play a role in foetoplacental endothelial dysfunction in gestational diabetes mellitus. Biochim Biophys Acta 1864:499–508
Salomón C, Westermeier F, Puebla C et al (2012) Gestational diabetes reduces adenosine transport in human placental microvascular endothelium, an effect reversed by insulin. PLoS One 7:e40578
Salsoso R, Guzmán-Gutiérrez E, Sáez T et al (2015) Insulin restores L-arginine transport requiring adenosine receptors activation in umbilical vein endothelium from late-onset preeclampsia. Placenta 36:287–296
Salsoso R, Farías M, Gutiérrez J et al (2017) Adenosine and preeclampsia. Mol Asp Med 55:126–139
San Martín R, Sobrevia L (2006) Gestational diabetes and the adenosine/L-arginine/nitric oxide (ALANO) pathway in human umbilical vein endothelium. Placenta 27:1–10
Schoelch C, Kuhlmann J, Gossel M et al (2004) Characterization of adenosine-A1 receptor-mediated antilipolysis in rats by tissue microdialysis, 1H-spectroscopy, and glucose clamp studies. Diabetes 53:1920–1926
Silva L, Subiabre M, Araos J et al (2017) Insulin/adenosine axis linked signaling. Mol Asp Med 55:45–61
Sobrevia L, Abarzúa F, Nien JK et al (2011) Review: Differential placental macrovascular and microvascular endothelial dysfunction in gestational diabetes. Placenta 32:S159–S164
Sobrevia L, Salsoso R, Sáez T et al (2015) Insulin therapy and fetoplacental vascular function in gestational diabetes mellitus. Exp Physiol 100:231–238
Sobrevia L, Salsoso R, Fuenzalida B et al (2016) Insulin is a key modulator of fetoplacental endothelium metabolic disturbances in gestational diabetes mellitus. Front Physiol 7:119
Subiabre M, Silva L, Villalobos-Labra R et al (2017) Maternal insulin therapy does not restore foetoplacental endothelial dysfunction in gestational diabetes mellitus. Biochim Biophys Acta Mol basis Dis 1863:2987–2998
Subiabre M, Silva L, Toledo F et al (2018) Insulin therapy and its consequences for the mother, foetus, and newborn in gestational diabetes mellitus. Biochim Biophys Acta doi: https://doi.org/10.1016/j.bbadis.2018.06.005
Tieu J, Shepherd E, Middleton P et al (2017) Dietary advice interventions in pregnancy for preventing gestational diabetes mellitus. Cochrane Database Syst Rev 1:CD006674
Trojner Bregar A, Tul N, Fabjan Vodušek V et al (2017) A dose-response relation exists between different classes of pre-gravid obesity and selected perinatal outcomes. Arch Gynecol Obstet 296:465–468
United Nations General Assembly (2015) Transforming our world: The 2030 agenda for sustainable development http://www.un.org/en/development/desa/population/migration/generalassembly/docs/globalcompact
Vásquez G, Sanhueza F, Vásquez R et al (2004) Role of adenosine transport in gestational diabetes-induced L-arginine transport and nitric oxide synthesis in human umbilical vein endothelium. J Physiol 560:111–122
Villalobos-Labra R, Silva L, Subiabre M et al (2017) Akt/mTOR role in human foetoplacental vascular insulin resistance in diseases of pregnancy. J Diabetes Res 2017:5947859
von Versen-Höynck F, Rajakumar A, Bainbridge SA et al (2009) Human placental adenosine receptor expression is elevated in preeclampsia and hypoxia increases expression of the A2A receptor. Placenta 30:434–442
Westermeier F, Salomón C, González M et al (2011) Insulin restores gestational diabetes mellitus-reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium. Diabetes 60:1677–1687
Westermeier F, Salomón C, Farías M et al (2015) Insulin requires normal expression and signaling of insulin receptor A to reverse gestational diabetes-reduced adenosine transport in human umbilical vein endothelium. FASEB J 29(1):37–49
World Health Organization (2017) Obesity and overweight. Fact sheet http://www.who.int/mediacentre/factsheets/fs311/en/
Wu L, Meng J, Shen Q et al (2017) Caffeine inhibits hypothalamic A(1)R to excite oxytocin neuron and ameliorate dietary obesity in mice. Nat Commun 8:15904
Wyatt AW, Steinert JR, Wheeler-Jones CP et al (2002) Early activation of the p42/44MAPK pathway mediates adenosine-induced nitric oxide production in human endothelial cells: a novel calcium-insensitive mechanism. FASEB J 16:1584–1594
Xu B, Berkich D, Crist G et al (1998) A1 adenosine receptor antagonism improves glucose tolerance in Zucker rats. Am J Phys 274:E271–E279
Acknowledgements
Authors thank Mrs. Amparo Pacheco from CMPL, PUC, for technical and secretarial assistance. This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) (grant numbers 1150377 and 11150083), Chile.
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Pardo, F., Sobrevia, L. (2018). Adenosine Receptors in Gestational Diabetes Mellitus and Maternal Obesity in Pregnancy. In: Borea, P., Varani, K., Gessi, S., Merighi, S., Vincenzi, F. (eds) The Adenosine Receptors. The Receptors, vol 34. Humana Press, Cham. https://doi.org/10.1007/978-3-319-90808-3_22
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DOI: https://doi.org/10.1007/978-3-319-90808-3_22
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