University of Groningen Gestational diabetes mellitus and fetoplacental vasculature alterations Silva Lagos, Luis

University of Groningen

Gestational diabetes mellitus and fetoplacental vasculature alterations

Silva Lagos, Luis

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10.33612/diss.113056657

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2020

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Silva Lagos, L. (2020). Gestational diabetes mellitus and fetoplacental vasculature alterations: Exploring

the role of adenosine kinase in endothelial (dys)function. University of Groningen.

https://doi.org/10.33612/diss.113056657

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Introduction

Chapter 1

12

Gestational diabetes mellitus

Gestational diabetes mellitus (GMD) is defined as diabetes

diagnosed in the second or third trimester of pregnancy that was not

clearly overt diabetes prior to gestation [1,2]. GDM is associated with

increased maternal and fetal insulin resistance, hyperglycemia and

fetal hyperinsulinemia [3,4]. The diagnosis of GDM is mainly based

on the maternal glycemic state [1]. Screening for GDM is usually

performed between 24 and 28 weeks of gestation by testing for basal

glucose levels or a glucose challenge test [1].

The pathophysiology of GDM is related to the higher metabolic

requirements during pregnancy, to meet the nutritional demand of

the developing embryo/fetus. In pregnancy, the maternal body is

subjected to several physiological changes [5,6]. In the mother, a

decrease in the peripheral insulin sensitivity is observed, which

increases the glucose availability for the fetus [7]. However, to meet

her own demand for glucose, the mother increases her insulin

production. This is achieved by increasing the

ß-cell mass through

cellular hyperplasia, hypertrophy and transformation from ß-cell

progenitors [8]. In parallel, mothers show a physiological

hyperlipidemia to meet the lipid requirements of the developing fetus

[9]. It has been suggested that in GDM the physiological adaptation

of the pancreas to pregnancy is impaired [4], while the ß-cell function

is comparable in both conditions [4]. Since in GDM pregnancies a

higher insulin resistance in comparison to normal pregnancies is

observed [4], it is suggested that in GDM the maternal insulin

production is insufficient to overcome the pregnancy-associated

insulin resistance, therefore maternal hyperglycemia and GDM occur

[8].

GDM is detrimental for maternal and fetal health. During

pregnancy, GDM is a risk factor for other pregnancy complications,

such as preeclampsia and preterm delivery [10,11]. The fetus is at risk

for macrosomia and trauma at birth [10,12,13]. GDM also has long-

term consequences for both the mother and the fetus. In the mother,

GDM increases the risk of type 2 diabetes mellitus [1,13]. Therefore,

the GDM mothers must be controlled for diabetes post-partum [1]. In

the fetus, GDM increases the risk for cardio-metabolic conditions,

obesity and type 2 diabetes mellitus at adult age [13–17]. The long-

term impact of GDM on the offspring’s health is part of a

phenomenon known as fetal programming of diseases [18,19], in

which epigenetic mechanisms play a crucial role [20,21]. The GDM-

associated hyperglycemia is considered responsible for the long-term

effects of GDM [22].

The treatment of GDM follows a similar therapeutic approach as

the treatment of type 2 diabetes mellitus [1]. The main goal of the

GDM treatment is to normalize the maternal blood glucose levels to

acceptable values. The first therapeutic strategy is to subject the

mothers to a caloric and carbohydrate-restricted diet. However, if the

mother is unresponsive to diet and the glycemic values remain high,

pharmacological approaches are recommended [1,2,23]. Insulin

therapy, metformin and glyburide are the main second lines of

treatment for GDM [1,24–26]. However, since insulin does not cross

the placenta, insulin therapy is recommended for diet-unresponsive

mothers, in order to avoid possible negative effects on the fetus [1].

Fetoplacental vasculature in GDM

The fetoplacental vasculature is a target of the hyperglycemia

during GDM. This hyperglycemia induces fetoplacental endothelial

dysfunction and activation [27–31]. The endothelium of the

fetoplacental vasculature displays increased markers of inflammation,

such as intercellular adhesion molecule 1 (ICAM-1), E-selectin and

tumor necrosis factor alpha (TNF-⍺) receptor [27,31–34]. The

endothelial dysfunction in the fetoplacental vasculature is

characterized by dysregulated production of vasoactive and

vasoconstrictor factors by the endothelium [30,35–38]. The

fetoplacental vasculature lacks innervation and the control of the

vascular tone is mainly dependent on the locally-released molecules

[29,39]. Nitric oxide (NO) is a vasodilator and anti-inflammatory

molecule produced by the endothelial NO synthase (eNOS) [40]. In

GDM, the fetoplacental vasculature exhibits an increased endothelial

synthesis of NO, due to an increased transport of L-arginine, a

substrate for eNOS, and an increased expression and activity of eNOS

in response to a higher extracellular level of adenosine [30,37] (Fig.

1). This increased adenosine concentration is due to the increased

GDM-associated NO, which activates the human C/EBP homolog

protein 10 (hCHOP) leading to the transcriptional repression of the

equilibrative nucleoside transporter type 1 (hENT1) [41].

hENT1 facilitates the bidirectional flux (i.e. intra and

extracellular) of adenosine [30,42]. Adenosine is a nucleoside that

exerts its biological function mainly mediated by four adenosine

receptors [43]. Adenosine positively regulates NO synthesis, exerts

anti-inflammatory effects and is also a protective molecule under

stress conditions [43,44]. In GDM, the extracellular adenosine

Chapter 1

14

increases the expression and activity of the human cationic amino

acid transporter 1 (hCAT-1), the transporter for L-arginine [37], in

the fetoplacental vasculature endothelium. Moreover, adenosine

activates and increases eNOS and NO synthesis [37]. These

alterations lead to a vicious cycle of changes in the fetoplacental

vasculature resulting in persistent endothelial dysfunction in GDM

pregnancies [45] (Fig 1). However, it has not been determined where

the dysregulation begins.

Intra- and extracellular adenosine concentrations are not only

regulated by hENT1 [46]. Adenosine can be metabolized by different

enzymes [43]. Due to its high affinity for adenosine under

physiological conditions, adenosine kinase (AK) is considered the

major regulator of intracellular adenosine levels [47,48]. This enzyme

catalyzes the formation of adenosine monophosphate (AMP) using

adenosine and adenosine triphosphate (ATP) as phosphate donor

[47]. Two isoforms of this enzyme are described, the nuclear and the

cytoplasmic isoform (n-AK and c-AK, respectively) [49].

Adenosine is a final product of transmethylation reactions in

cells, responsible (among others) for methylation-dependent gene

expression regulation mechanisms [48,50]. Adenosine is formed by

the hydrolysis of S-adenosylhomocysteine (SAH) mediated by the

SAH hydrolase (SAHH). The reaction catalyzed by this enzyme is

bidirectional and the balance towards adenosine formation (i.e., SAH

hydrolysis) depends on the efficient clearance of adenosine, in which

n-AK plays a crucial role [48,51].

Although the role of adenosine in the fetoplacental vasculature

endothelium is well known, little is known about the role of AK.

Indirect evidence, however, suggests that human umbilical vein

endothelial cells (HUVECs) from GDM exhibit a lower activity of AK

as compared with HUVECs from healthy pregnancies [52]. Such a

lower AK activity might contribute to the accumulation of adenosine

observed in GDM fetoplacental vasculature and the endothelial

alterations triggered by this condition. Additionally, this might

contribute to the epigenetic alterations observed in placentas from

GDM [50,53,54].

Figure 1. Altered fetoplacental vascular endothelium from GDM pregnancies. In GDM, an increased

(

)

endothelial NO synthase (eNOS; NOS3), human cationic amino acid transporter 1 (hCAT-1; SLC7A1) occurs in the fetoplacental endothelium. The increased NO activates C/EBP homolog protein 10 (hCHOP). hCHOP binds to human equilibrative nucleoside transporter 1 (hENT1; SLC29A1) gene promoter reducing

(

)

and expression. The reduction of hENT1 (SLC29A1) expression might lead to an extracellular adenosine accumulation and activation of A2A adenosine receptors (AR). Activation of AR increases L-arginine transport with the subsequent increase in NO synthesis. In GDM human umbilical vein endothelial cells (HUVECs), a lower adenosine kinase (AK) activity has been suggested. This might contribute to the adenosine accumulation observed in GDM. However, whether this depends on nuclear or cytoplasmic AK isoform (n-AK and c-AK, respectively) remains to be elucidated.

References

[1] A.D. American Diabetes Association, 2. Classification and diagnosis of diabetes: Standards of medical care in diabetesd2019, Diabetes Care. 42 (2019) S13–S28. [2] M. Subiabre, L. Silva, F. Toledo, M. Paublo, M.A. López, M.P. Boric, L. Sobrevia,

Insulin therapy and its consequences for the mother, foetus, and newborn in gestational diabetes mellitus, Biochim. Biophys. Acta - Mol. Basis Dis. 1864 (2018) 2949–2956.

[3] X. Wang, T. Yang, J. Miao, H. Liu, K. Wu, J. Guo, J. Chen, T. Li, Correlation between maternal and fetal insulin resistance in pregnant women with gestational diabetes mellitus, Clin. Lab. 64 (2018) 945–953.

[4] S. Das, M.K. Behera, S. Misra, A.K. Baliarsihna, β-Cell Function and Insulin Resistance in Pregnancy and Their Relation to Fetal Development, Metab. Syndr. Relat. Disord. 8 (2009) 25–32.

[5] Z. Zeng, F. Liu, S. Li, Metabolic Adaptations in Pregnancy: A Review, Ann. Nutr. Metab. 70 (2017) 59–65.

[6] K.Y. Lain, P.M. Catalano, Metabolic changes in pregnancy, Clin. Obstet. Gynecol. 50 (2007) 938–948.

Chapter 1

16

Res. (2014) 3–5.

[8] D.J. Hill, Placental control of metabolic adaptations in the mother for an optimal pregnancy outcome. What goes wrong in gestational diabetes?, Placenta. 69 (2018) 162–168.

[9] A. Leiva, R. Salsoso, T. Sáez, C. Sanhueza, F. Pardo, L. Sobrevia, Cross-sectional and longitudinal lipid determination studies in pregnant women reveal an association between increased maternal LDL cholesterol concentrations and reduced human umbilical vein relaxation, Placenta. 36 (2015) 895–902.

[10] J.S. Hawkins, J.Y. Lo, B.M. Casey, D.D. McIntire, K.J. Leveno, Diet-treated gestational diabetes mellitus: comparison of early vs routine diagnosis, Am. J. Obstet. Gynecol. 198 (2008) 1–6.

[11] K. Köck, F. Köck, K. Klein, D. Bancher-Todesca, H. Helmer, Diabetes mellitus and the risk of preterm birth with regard to the risk of spontaneous preterm birth, J. Matern. Neonatal Med. 23 (2010) 1004–1008.

[12] C.L. Bryson, G.N. Ioannou, S.J. Rulyak, C. Critchlow, Association between Gestational Diabetes and Pregnancy-induced Hypertension, Am. J. Epidemiol. 158 (2003) 1148–1153.

[13] M. Maresh, R.W. Beard, Screening and Management of Gestational Diabetes Mellitus, in: Carbohydr. Metab. Pregnancy Newborn · IV, 1989: pp. 201–208. [14] P. Damm, A. Houshmand-Oeregaard, L. Kelstrup, J. Lauenborg, E.R. Mathiesen,

T.D. Clausen, Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark, Diabetologia. 59 (2016) 1396–1399.

[15] J. Wang, L. Pan, E. Liu, H. Liu, J. Liu, S. Wang, J. Guo, N. Li, C. Zhang, G. Hu, Gestational diabetes and offspring’s growth from birth to 6 years old, Int. J. Obes. 43 (2019) 663–672.

[16] M. Kawasaki, N. Arata, C. Miyazaki, R. Mori, T. Kikuchi, Y. Ogawa, E. Ota, Obesity and abnormal glucose tolerance in offspring of diabetic mothers: A systematic review and meta-analysis, PLoS One. 13 (2018) e0190676.

[17] The HAPO Study Cooperative Research, The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, N. Engl. J. Med. 358 (2008) 1991–2002.

[18] L. Garcia-Vargas, S.S. Addison, R. Nistala, D. Kurukulasuriya, J.R. Sowers, Gestational Diabetes and the Offspring: Implications in the Development of the Cardiorenal Metabolic Syndrome in Offspring, Cardiorenal Med. 2 (2012) 134–142. [19] A.M. Binder, J. LaRocca, C. Lesseur, C.J. Marsit, K.B. Michels, Epigenome-wide

and transcriptome-wide analyses reveal gestational diabetes is associated with alterations in the human leukocyte antigen complex, Clin. Epigenetics. 7 (2015) 79. [20] S.M. Ruchat, A.A. Houde, G. Voisin, J. St-Pierre, P. Perron, J.P. Baillargeon, D.

Gaudet, M.F. Hivert, D. Brisson, L. Bouchard, Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases, Epigenetics. 8 (2013) 935–943.

[21] C.R. Quilter, W.N. Cooper, K.M. Cliffe, B.M. Skinner, P.M. Prentice, L. Nelson, J. Bauer, K.K. Ong, M. Constância, W.L. Lowe, N.A. Affara, D.B. Dunger, Impact on offspring methylation patterns of maternal gestational diabetes mellitus and intrauterine growth restraint suggest common genes and pathways linked to subsequent type 2 diabetes risk, FASEB J. 28 (2014) 4868–4879.

[22] W.L. Lowe, L.P. Lowe, A. Kuang, P.M. Catalano, M. Nodzenski, O. Talbot, W.H. Tam, D.A. Sacks, D. McCance, B. Linder, Y. Lebenthal, J.M. Lawrence, M. Lashley, J.L. Josefson, J. Hamilton, C. Deerochanawong, P. Clayton, W.J. Brickman, A.R. Dyer, D.M. Scholtens, B.E. Metzger, Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow- up Study, Diabetologia. 62 (2019) 598–610.

[23] L. Sobrevia, R. Salsoso, T. Sáez, C. Sanhueza, F. Pardo, A. Leiva, Insulin therapy and fetoplacental vascular function in gestational diabetes mellitus, Exp. Physiol. 100 (2015) 231–238.

[24] D. Farrar, M. Simmonds, M. Bryant, T.A. Sheldon, D. Tuffnell, S. Golder, D.A. Lawlor, Treatments for gestational diabetes: A systematic review and meta-analysis, BMJ Open. 7 (2017) e015557.

Mellitus, in: Carbohydr. Metab. Pregnancy Newborn · IV, 2011: pp. 201–208. [26] K.W. Kelley, D.G. Carroll, A. Meyer, A review of current treatment strategies for

gestational diabetes mellitus, Drugs Context. 4 (2015) 212282.

[27] P. Di Fulvio, A. Pandolfi, G. Formoso, S. Di Silvestre, P. Di Tomo, A. Giardinelli, A. De Marco, N. Di Pietro, M. Taraborrelli, S. Sancilio, R. Di Pietro, M. Piantelli, A. Consoli, Features of endothelial dysfunction in umbilical cord vessels of women with gestational diabetes, Nutr. Metab. Cardiovasc. Dis. 24 (2014) 1337–1345. [28] J. Zhou, X. Ni, X. Huang, J. Yao, Q. He, K. Wang, T. Duan, Potential Role of

Hyperglycemia in Fetoplacental Endothelial Dysfunction in Gestational Diabetes Mellitus, Cell. Physiol. Biochem. 39 (2016) 1317–1328.

[29] A. Leiva, F. Pardo, M.A. Ramírez, M. Farías, P. Casanello, L. Sobrevia, Fetoplacental vascular endothelial dysfunction as an early phenomenon in the programming of human adult diseases in subjects born from gestational diabetes mellitus or obesity in pregnancy, Exp. Diabetes Res. 2011 (2011).

[30] G. Vásquez, F. Sanhueza, R. Vásquez, M. González, R. San Martín, P. Casanello, L. Sobrevia, Role of adenosine transport in gestational diabetes-induced L-arginine transport and nitric oxide synthesis in human umbilical vein endothelium, J. Physiol. 560 (2004) 111–122.

[31] H. Giri, S. Chandel, L.S. Dwarakanath, S. Sreekumar, M. Dixit, Increased endothelial inflammation, sTie-2 and arginase activity in umbilical cords obtained from gestational diabetic mothers, PLoS One. 8 (2013) e84546.

[32] T. Sáez, P. de Vos, J. Kuipers, L. Sobrevia, M.M. Faas, Fetoplacental endothelial exosomes modulate high D-glucose-induced endothelial dysfunction, Placenta. 66 (2018) 26–35.

[33] S.A. Sultan, W. Liu, Y. Peng, W. Roberts, D. Whitelaw, A.M. Graham, The Role of Maternal Gestational Diabetes in Inducing Fetal Endothelial Dysfunction, J. Cell. Physiol. 230 (2015) 2695–2705.

[34] X. Zhou, J. Liao, H. Pan, S. Zhou, Correlation of TNF-a, TNFR1 and adiponectin levels with HOMA-IR in patients with gestational diabetes mellitus, n.d.

[35] F. Westermeier, C. Salomón, M. Farías, P. Arroyo, B. Fuenzalida, T. Sáez, R. Salsoso, C. Sanhueza, E. Guzmán-Gutiérrez, F. Pardo, A. Leiva, L. Sobrevia, 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 (2015) 37–49.

[36] C. Salomón, F. Westermeier, C. Puebla, P. Arroyo, E. Guzmán-Gutiérrez, F. Pardo, A. Leiva, P. Casanello, L. Sobrevia, Gestational diabetes reduces adenosine transport in human placental microvascular endothelium, an effect reversed by insulin, PLoS One. 7 (2012).

[37] E. Guzmán-Gutiérrez, F. Westermeier, C. Salomón, M. González, F. Pardo, A. Leiva, L. Sobrevia, Insulin-increased L-arginine transport requires A2A adenosine receptors activation in human umbilical vein endothelium, PLoS One. 7 (2012). [38] M. Subiabre, L. Silva, R. Villalobos-Labra, F. Toledo, M. Paublo, M.A. López, R.

Salsoso, F. Pardo, A. Leiva, L. Sobrevia, Maternal insulin therapy does not restore foetoplacental endothelial dysfunction in gestational diabetes mellitus, Biochim. Biophys. Acta - Mol. Basis Dis. 1863 (2017) 2987–2998.

[39] S.B. Fox, T.Y. Khong, Lack of innervation of human umbilical cord. An immunohistological and histochemical study, Placenta. 11 (1990) 59–62.

[40] U. Förstermann, T. Münzel, Endothelial Nitric Oxide Synthase in Vascular Disease, Circulation. 113 (2006) 1708–1714.

[41] M. Farías, C. Puebla, F. Westermeier, M.J. Jo, M. Pastor-Anglada, P. Casanello, L. Sobrevia, Nitric oxide reduces SLC29A1 promoter activity and adenosine transport involving transcription factor complex hCHOP-C/EBPα in human umbilical vein endothelial cells from gestational diabetes, Cardiovasc. Res. 86 (2010) 45–54. [42] F. Pardo, P. Arroyo, C. Salomón, F. Westermeier, R. Salsoso, T. Sáez, E. Guzmán-

Gutiérrez, A. Leiva, L. Sobrevia, Role of equilibrative adenosine transporters and adenosine receptors as modulators of the human placental endothelium in gestational diabetes mellitus, Placenta. 34 (2013) 1121–1127.

[43] L. Silva, M. Subiabre, J. Araos, T. Sáez, R. Salsoso, F. Pardo, A. Leiva, R. San Martín, F. Toledo, L. Sobrevia, Insulin/adenosine axis linked signalling, Mol.

Chapter 1

18

Aspects Med. 55 (2017) 45–61.

[44] B.B. Fredholm, Adenosine - A physiological or pathophysiological agent?, J. Mol. Med. 92 (2014) 201–206.

[45] A. Pandolfi, N. Di Pietro, High glucose, nitric oxide, and adenosine: A vicious circle in chronic hyperglycaemia?, Cardiovasc. Res. 86 (2010) 9–11.

[46] C.G. Dulla, S.A. Masino, Physiologic and metabolic regulation of adenosine: Mechanisms, in: Adenosine A Key Link between Metab. Brain Act., Springer New York, New York, NY, 2013: pp. 87–107.

[47] J. Park, R.S. Gupta, Adenosine metabolism, adenosine kinase, and evolution, in: Adenosine A Key Link between Metab. Brain Act., Springer New York, 2013: pp. 23–54.

[48] D. Boison, Adenosine Kinase: Exploitation for Therapeutic Gain, Pharmacol. Rev. (2013).

[49] X.A. Cui, B. Singh, J. Park, R.S. Gupta, Subcellular localization of adenosine kinase in mammalian cells: The long isoform of AdK is localized in the nucleus, Biochem. Biophys. Res. Commun. 388 (2009) 46–50.

[50] L. Silva, T. Plösch, F. Toledo, M.M. Faas, L. Sobrevia, Adenosine kinase and cardiovascular fetal programming in gestational diabetes mellitus, Biochim. Biophys. Acta - Mol. Basis Dis. (2019).

[51] D. Boison, L. Scheurer, V. Zumsteg, T. Rulicke, P. Litynski, B. Fowler, S. Brandner, H. Mohler, Neonatal hepatic steatosis by disruption of the adenosine kinase gene, Proc. Natl. Acad. Sci. 99 (2002) 6985–6990.

[52] L. Sobrevia, S.M. Jarvis, D.L. Yudilevich, Adenosine transport in cultured human umbilical vein endothelial cells is reduced in diabetes, Am. J. Physiol. Physiol. 267 (1994) C39–C47.

[53] B. Kerr, A. Leiva, M. Farías, S. Contreras-Duarte, F. Toledo, F. Stolzenbach, L. Silva, L. Sobrevia, Foetoplacental epigenetic changes associated with maternal metabolic dysfunction, Placenta. 69 (2018) 146–152.

[54] C. Reichetzeder, S.E. Dwi Putra, T. Pfab, T. Slowinski, C. Neuber, B. Kleuser, B. Hocher, Increased global placental DNA methylation levels are associated with gestational diabetes, Clin. Epigenetics. 8 (2016) 82.