University of Groningen

Gestational diabetes mellitus and fetoplacental vasculature alterations Silva Lagos, Luis

DOI: 10.33612/diss.113056657

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Citation for published version (APA): 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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Adenosine kinase and cardiovascular fetal programming in gestational diabetes mellitus

Luis Silva1,2, Torsten Plösch3, Fernando Toledo1,4, Marijke M. Faas2,3, Luis Sobrevia1,5,6

1 Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile. 2 Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen 9700 RB, The Netherlands. 3 Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 4 Department of Basic Sciences, Faculty of Sciences, Universidad del Bío-Bío, Chillán 3780000, Chile. 5 Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain. 6 University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD 4029, Queensland, Australia.

Biochim Biophys Acta Mol Basis5 Dis. 2019, 165397.

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Abstract Gestational diabetes mellitus (GDM) is a detrimental condition for human pregnancy associated with endothelial dysfunction and endothelial inflammation in the fetoplacental vasculature and leads to increased cardio-metabolic risk in the offspring. In the fetoplacental vasculature, GDM is associated with altered adenosine metabolism. Adenosine is an important vasoactive molecule and is an intermediary and final product of transmethylation reactions in the cell. Adenosine kinase is the major regulator of adenosine levels. Disruption of this enzyme is associated with alterations in methylation-dependent gene expression regulation mechanisms, which are associated with the fetal programming phenomenon. Here we propose that cellular and molecular alterations associated with GDM can dysregulate adenosine kinase leading to fetal programming in the fetoplacental vasculature. This can contribute to the cardio-metabolic long-term consequences observed in offspring after exposure to GDM.

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Introduction Gestational diabetes mellitus (GDM) is defined as altered D- glucose tolerance diagnosed in the second or third trimester of pregnancy [1,2]. The global prevalence of GDM is 5-20% depending on the diagnostic criteria used [3]. It is associated with several risk factors, such as maternal overweight or obesity, supraphysiological gestational weight gain, pre-gestational insulin resistance, and ethnicity [1,4–8]. Women with GDM have a higher risk of developing type 2 diabetes mellitus (T2DM) and metabolic syndrome [4,9]. Also, the children born from GDM show an increased risk to develop D- glucose intolerance, obesity, and cardiovascular diseases later in life [9,10]. Thus, GDM-associated metabolic alterations in the intrauterine life suggest fetal programming [6,11–13]. Epigenetic mechanisms, such as DNA methylation and histone modifications play a crucial role in this phenomenon [14–17]. However, the understanding of the pathophysiological mechanisms of how this phenomenon is triggered and established requires further studies [15]. One of the tissues where fetal programming may take place is the fetal endothelium. It has been shown that the fetoplacental vasculature from GDM pregnancies display endothelial dysfunction where altered adenosine metabolism plays a role [18–22]. Adenosine is a vasoactive and anti-inflammatory nucleoside whose biological effects are mediated by adenosine receptors. It is also an important intermediary molecule in transmethylation reaction and an imbalance of adenosine level may have consequences in methylation- dependent gene expression regulation [23–27]. The major regulator of the intracellular adenosine level under physiological conditions is adenosine kinase (AK) [28]. AK is an enzyme that produces AMP from adenosine and ATP. Its activity is regulated by various factors, including nitric oxide (NO), intracellular pH (pHi), D-glucose, and insulin. Also, AK activity is under modulation by inflammatory factors, such as tumour necrosis factor (TNF- ) [28–32]. Interestingly, the above-mentioned modulators of AK activity are dysregulated in the fetoplacental endothelium in GDM⍺ pregnancies [18,20,21,33–37]. Therefore, AK activity is likely dysregulated in the fetoplacental vasculature from GDM pregnancies. In this review, we summarized the current findings in the fetoplacental vasculature from GDM with regard to endothelial dysfunction, endothelial activation, consequences of GDM in offspring and AK-mediated cellular effects. We propose that GDM causes alterations in the AK activity, a phenomenon that could be a

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mechanism of fetal programming in fetoplacental vasculature contributing to the cardiometabolic long-term consequences seen in fetuses exposed to an adverse intrauterine environment.

Fetal and offspring from GDM pregnancies GDM is a risk factor for several conditions during pregnancy, both for the mother and the fetus. In the mother, GDM is associated with supraphysiological gestational weight gain, pre-eclampsia, increased numbers of caesarean sections, and progression towards T2DM after delivery [3,4,38–42]. There are several reports on the prevalence and risk of fetal complications in a GDM pregnancy [1,2]. In general, fetuses to GDM mothers show macrosomia (prevalence ~7%, Odds ratio (OR) 2) [43–45], shoulder dystocia during vaginal birth (prevalence ~1%, OR 1.7) [46,47], congenital anomalies (prevalence ~1%, OR 1.4) [48–49], intrauterine death at term (prevalence ~5%, OR 2.9 for <90th weight percentile) [50], and stillbirth (prevalence varies from low, i.e. 2%, to higher values, i.e. 20% or more, depending on the study, OR ~2-5) [45,51–53], and caesarean section (prevalence 9%, OR ~3) [45,54,55]. Also, the fetus from GDM pregnancies have higher risk of complications at or shortly after delivery, such as respiratory distress syndrome (prevalence ~8%, OR 3.6) [56,57], neonatal hypoglycaemia first few hours after birth (prevalence ~25% mixing mild (≤47 mg glucose/dL) and severe (≤36 mg glucose/dL) hypoglycaemia; incidence ~34% for mild- and ~21% for severe hypoglycaemia; OR 2.5) [45,58,59], hyperbilirubinemia (prevalence ~10-60%, OR 1.8) [44,60], or hypocalcaemia (prevalence ~6%, OR 3) [45,61-64]. It is worth noting that reported GDM-associated fetal risks must be taken with caution since confounding or interrelated factors can change between studies. The lack of a unified diagnostic criteria for GDM, the gestational age in which GDM was diagnosed, therapeutic interventions, the influence of ethnic and genetic background among certain populations, may change the frequencies of these associated risks. Placentas from GDM pregnancies also display altered histological features, such as villous immaturity and increased angiogenesis [6]. These alterations could lead to placental dysfunction, altered mother- to-fetus and fetus-to-mother nutrient transport, and changes in placental gene expression which could underlie the fetal complications seen in GDM. GDM is not only deleterious in the antenatal and perinatal periods but it is also involved in long-term negative fetal outcome. Fetuses born to GDM pregnancies show higher prevalence of

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Fetoplacental endothelial dysfunction in GDM Since the human fetoplacental vasculature lacks innervation [18,67], the synthesis and bioavailability of endothelial-derived vasodilators and vasoconstrictors, such as NO, adenosine, and endothelin-1 are crucial to maintain a normal vascular tone in this vascular bed [8]. The synthesis of NO by the endothelial NO synthase (eNOS) requires the take up of l-arginine via the human cationic amino acid transporter 1 (hCAT-1) in human umbilical vein endothelial cells (HUVECs), a phenomenon that is maintained by activation of adenosine receptors by adenosine [22,24]. The latter phenomenon refers to the L-arginine/NO signalling (ALANO) pathway in cells from GDM pregnancies [24]. The fetoplacental vasculature from GDM pregnancies displays alterations in the ALANO pathway (20,24,68). Additionally, GDM and hyperglycaemia results in increased expression of the specific protein 1 (Sp1) and human DNA damage inducible transcript 3 transcription factors (DDIT3, also known as hCHOP) [21,69], increased extracellular concentration of adenosine and reduced expression and activity of the equilibrative nucleoside transporter 1 (hENT1) [20,21], and impaired endothelial insulin signalling and oxidative stress [20,21]. Interestingly, the relevance of these findings describing the ALANO pathway in GDM was highlighted as a potential vicious circle in which hyperglycaemia may play a crucial role in this disease- associated endothelial dysfunction [70]. Noteworthy, the alterations described can be found in the fetoplacental vasculature from GDM pregnancies even after achieving optimal glycaemia by following restricted diet or insulin treatment, i.e. insulin therapy [3,18,71]. Thus, cell programming possible triggered by the exposure to high D- glucose is likely [72,73]. The increased extracellular concentration of adenosine resulting from lower hENT1 activity results in activation of the four- member family of adenosine receptors, i.e. A1 adenosine receptors (A1AR), A2AAR, A2BAR, and A3AR [20,74–76]. Activation of A2AAR leads to higher activity of the ALANO signalling pathway in HUVECs from GDM pregnancies [24,68]. Interestingly, the potential role of the major regulator of intracellular adenosine level, AK, is still unknown in GDM pregnancies. Indirect evidence supports the

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possibility of impaired activity of this enzyme in HUVECs from GDM [77]. Increased NO synthesis resulting from an increased extracellular level of adenosine is seen in HUVECs from GDM [20,22]. However, reduced NO bioavailability is seen in GDM due to the increased generation of reactive oxygen-derived species (ROS), such as peroxynitrite, in this disease of pregnancy [78]. Dysregulation of the NO bioavailability and altered adenosine metabolism in the fetoplacental vasculature may induce impaired vasoreactivity and nutrient transport in GDM.

Fetoplacental endothelial activation in GDM The fetoplacental vasculature from GDM shows an increased proinflammatory and procoagulant state, i.e. endothelial cell activation, with increased expression of adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM) [79,80]. The latter is triggered not only by reduced NO bioavailability with the subsequent loss of NO- dependent anti-inflammatory and anticoagulant effects [81] but also by increasing the level of circulating pro-inflammatory cytokines, such as TNF- or interleukin-6 (IL-6) [82]. Interestingly, antagonists of A1AR inhibit the generation of TNF- in cord blood monocytes involving adenosine⍺ as a pro-inflammatory factor [83]. However, adenosine also prevented the decrease in⍺ TNF- -induced endothelial mitochondrial mass in human dermal microvascular endothelial cells [84]. On the other hand, TNF- reduced hENT1⍺ expression in bone- marrow-derived macrophages from wild-type mice [85] and in human B-lymphocyte cell lines⍺ [86]. Also, TNF- increased AK expression leading to lower intracellular adenosine level affecting regulatory mechanisms that lead to methylation-⍺dependent gene expression in animal models and HUVECs [87]. Therefore, the interactions between TNF- and adenosine may be altered since the imbalance in adenosine level and adenosine signalling in GDM. However, whether this phenomenon⍺ is present in the fetoplacental vasculature is yet to be unveiled.

Programming and epigenetics in GDM Newborns from mothers with GDM have a higher risk to develop adulthood diseases compared with newborns from normal/ healthy pregnancies [10,88,89]. The latter suggests that fetal programming is also a consequence of GDM resulting in higher risk of developing T2DM and obesity in offspring to GDM [6,90–94]. Epigenetic modifications are likely to play a role in the events that

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Chapter 5 lead to the programming of diseases in fetuses from GDM pregnancies [14,16,17,95–99]. Epigenetics refers to different cellular mechanisms that control gene expression without modifying the DNA sequence. Regulation of gene expression by epigenetics includes mechanisms such as DNA and histone methylation, DNA and histone acetylation, other histone modifications, and non-coding RNAs [100,101]. DNA methylation is an important mechanism of regulation of gene expression (Fig. 1) [16,102]. DNA methylation is reported in GDM, mainly in the placenta and human umbilical vein endothelial cells (HUVECs) and is one of the mechanisms likely responsible for the transmission and programming of cell metabolic disturbances after the fetal exposure to GDM [16,17,92,93,99,103,104]. DNA methylation is regulated by DNA methyltransferases (DNMTs), which transfer a methyl group from S-adenosylmethionine (SAM) to cytosine resulting in 5-methylcytosine [26]. In mammals, DNA methylation usually takes place in gene promoter regions of the genome with an extension greater than 0.5 kb and rich in cytosine- guanine dinucleotide (CpG dinucleotide), the so-called CpG islands [105–108]. Literature regarding alterations in DNA methylation in the placenta of women with GDM is contradictory (Table 1). In a small cohort of 50 patients from New York (USA) (maternal age >15 years) that included 26% Black, 62% Latin, 6% White, and 3% Asian ethnicity (adjusted for offspring sex, mother educational level, welfare status, marital status, and ethnicity) the placentas from GDM pregnancies showed lower global DNA methylation compared to placentas from healthy pregnancies [109]. This phenomenon was negatively associated to the body length and head circumference in newborns from women with GDM pregnancies. However, in the umbilical cord blood from the same GDM fetuses, there was no alteration in the global DNA methylation [109]. Thus, alterations in DNA methylation may be tissue and cell-specific. On the contrary, another study performed in 56 placentas from GDM (mean maternal age 31.9 years) and 974 from normal (mean maternal age 29.8 years) pregnancies from Caucasians women (92.7%) from Berlin (Germany) (adjusted for maternal age, body mass index at the beginning of pregnancy, miscarriages, ethnic background, and family history of T2DM) reported that GDM placentas show a significant increase in global DNA methylation [5]. Even when both of these studies adjusted the analysis of their data to possible confounder variables the apparent discrepancy in the reported results regarding global DNA methylation in GDM may be due to the different populations studied or the fact that women with GDM were not having this

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Figure 1. Adenosine as intermediary metabolite of DNA methylation cycle. Intracellular balance of adenosine depends on the activity of nucleoside transporters (NTs) and the activity of cytoplasmic and nuclear adenosine kinase (c-AK, n-AK). Adenosine and methionine are crucial to obtaining S- adenosylmethionine (SAM). SAM is the main methyl donor and is used by methyltransferases (MTs) in process as DNA and histone methylation, which constitute a mechanism of gene expression regulation. Methylation reactions have as product S-adenosylhomocysteine (SAH), which is an endogenous inhibitor of MTs. SAH is converted into adenosine and homocysteine (Hcy) by S- adenosylhomocysteine hydrolase. As an increase adenosine level can reverse the reaction mediated by SAHH it is converted into AMP in a process mediated by n- ADK. Extracellularly, adenosine activates a four-members family of adenosine receptors which can ( ) increase or ( ) decrease the level of cAMP, which has been suggested to increase⬆ the activity⬇ of SAHH. However, SAHH cAMP- dependent activity regulation remains to be elucidated in humans.

disease only but in coexistence with metabolic alterations such as pre-gestational maternal obesity (a metabolic disorder of pregnancy recently introduced as ‘gestational diabesity’) [8], pre-gestational maternal overweight, or showed supraphysiologycal gestational weight gain [110,111] or other obstetric complications. Some studies also focused on the methylation of specific genes in the placenta from GDM pregnancies. Interestingly, the expression of the transforming growth factor 2 (TGFB2) gene is increased in HUVECs from GDM compared with normal pregnancies [99]. The latter seems to result from hypomethylation (in the promoter CpG island 28545) and increased intermediate methylation of the TGFB2 genomic DNA. Even when the number of women with GDM analysed

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ABCA1 (for ATP binding cassette subfamily A member 1); ACYP2 (for acylphosphatase 2); ADIPOQ (for adiponectin, C1Q and collagen domain containing); AGTR2 (for angiotensin II receptor type 2); ALPK1 (for alpha kinase 1); ATP5A1 (for ATP synthase F1 subunit alpha); BTN1A1 (for butyrophilin subfamily 1 member A1); C14orf152 (also known as FAM181A, for family with sequence similarity 181 member A); C3orf31 (also known as TAM41 mitochondrial translocator assembly and maintenance homolog. Localization Chromosome 3, NC_000003.12); C6orf96 (also known as RMND1, for required for meiotic nuclear division 1 homolog); CP (for ceruloplasmin); CYB5R4 (for cytochrome b5 reductase 4); ENO2 (for enolase 2); EPS8L1 (for EPS8 like 1); ESX1 (for ESX homeobox 1); FLJ32569 (also known as PM20D1, for peptidase M20 domain containing 1); FLJ35773 (also known as MFSD6L, for major facilitator superfamily domain containing 6 like); FLJ45964 (for uncharacterized FLJ45964, hypothetical protein coding); GDM (gestational diabetes mellitus); GDMd (diet-treated GDM); GDMi (insulin-treated GDM); GPATCH2 (for G- patch domain containing 2); GPR42 (for G protein-coupled receptor 42); GSTM5 (for glutathione S-transferase mu 5); HDAC1 (for histone deacetylase 1); HIF3A (for hypoxia inducible factor 3 subunit alpha); IGT (impaired glucose tolerance); IL10 (for interleukin 10); INSL4 (for insulin like 4); LEP (for leptin); LINE1 (for long interspersed element-1); MEOX1 (for mesenchyme homeobox 1); MEST (for mesoderm specific transcript); MFAP4 (for microfibril associated protein 4); MGC3207 (also known as MRI 1, for methylthioribose-1-phosphate isomerase 1); MRPS33 (for mitochondrial ribosomal protein S33); NDUFA1 (for NADH:ubiquinone oxidoreductase subunit A1); NDUFB6 (for NADH:ubiquinone oxidoreductase subunit B6); NESPAS (also known as GNAS-AS1, for GNAS antisense RNA 1); NEU4 (for neuraminidase 4); NFE2 (for nuclear factor, erythroid 2); NHLH2 (for nescient helix-loop-helix 2); NR3C1 (for nuclear receptor subfamily 3 group C member 1); NYX (for nyctalopin); OR2L13 (for olfactory receptor family 2 subfamily L member 13); OR2L13 (for olfactory receptor family 2 subfamily L member 13); PBK (for PDZ binding kinase); PKHD1 (for fibrocystin/polyductin); PLAC8 (for placenta specific 8); PMP2 (for peripheral myelin protein 2); PON1 (for paraoxonase 1); POU2F1 (for POU class 2 homeobox 1); PPARA (for peroxisome proliferator activated receptor alpha); PPARGC1A (for PPARG coactivator 1 alpha); PRKCH (for protein kinase C eta); PSMD5 (for proteasome 26S subunit, non-ATPase 5); RHD (for Rh blood group D antigen); RPL17 (for ribosomal protein L17); SLC17A4 (for solute carrier family 17 member 4); SUSD1 (for sushi domain containing 1); TAS2R49 (for taste 2 receptor member 20); TDG (for thymine DNA glycosylase); TERF2IP (for TERF2 interacting protein); ZNF306 (for zinc finger with KRAB and SCAN domains 3).

Chapter 5 in this study was low (3 GDM versus 3 normal pregnancies), it is interesting noting that a potential disbalance between the degree of hypermethylation and intermediate methylation (hypermethylation/ intermediate methylation >1) could determine differential expression of specific genes in HUVECs from GDM. Thus, a potential ‘glycemic memory’ based on a proper balance between these phenomena in HUVECs from GDM pregnancies is likely. In a cohort of 82 Chinese Han women with singleton pregnancies, it was shown that the methylation of the CpG islands of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC- 1α) promoter (encoded by the PPARGC1A gene) in placental tissue associated with the maternal gestational D-glucose level [112]. Thus, placental DNA methylation may result from variations in the maternal glycaemia in pregnancy. In another study, 14 genes (paternally and maternally imprinted and non-imprinted genes) involved in metabolic programming were assayed for methylation in samples of umbilical cord blood and chorionic villous from pregnancies with GDM where the mother was treated with diet and insulin therapy (Table 1) [113]. In the umbilical cord blood obtained from the whole group of GDM pregnancies (i.e. diet and insulin- treated) 2 out of 14 genes (MEST (for mesoderm specific transcript) and NR3C1 (for nuclear receptor subfamily 3 group C member 1) showed decreased mean DNA methylation. Increased MEST expression, possibly caused by an impaired maternal imprinting, is associated with obesity and increased adipogenesis and adipocyte volume in humans [114]. Glucocorticoid receptor (encoded by the NR3C1 gene) is crucial in the regulation of hypothalamic/pituitary/ adrenal (HPA) axis and reduced methylation of this gene in leukocytes has been associated to depressive and anxiety disorders in healthy adults [115]. Moreover, umbilical cord blood from women with GDM treated with diet showed increased mean methylation of IL10 (for interleukin 10) and reduced mean methylation in NDUFB6 (for NADH:ubiquinone oxidoreductase subunit B6) and OCT4 which is also referred as POU5F1 (for POU class 5 homeobox 1) compared with healthy and insulin-treated GDM pregnancies. These findings suggest a possible beneficial role of insulin therapy on restoring or avoiding GDM-associated methylation alterations. In the chorionic villi, four out of 11 genes (MEST, PPARA, NR3C1, NESPAS) were hypomethylated in samples from GDM compared with normal pregnancies with no differences between GDM treatments [113]. Studies using microarrays to evaluate genes expression in umbilical cord blood and placentas from GDM showed

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gene associations with specific diseases or conditions, altered DNA methylation of genes associated with metabolic conditions, including diabetes mellitus [96], and also genes associated with prevention of oxidative damage, markers of cardiovascular complications, adipocyte differentiation-related genes, the insulin signalling response, and modulation of endocrine function [97,116]. All together the above-described findings suggest that DNA methylation may be a plausible mechanism of fetal programming in GDM. However, further follow up and functional studies are required to establish whether the findings in the placenta are also seen in fetal tissues and maintained during childhood or adulthood having an adverse impact on the health in youth and adulthood [15,97].

Adenosine and Adenosine Kinase Adenosine and DNA methylation Adenosine is an endogenous purine ribonucleoside that acts as a regulator of a myriad of cellular processes [117,118]. Cellular effects of adenosine are due to the activation of four members of G-protein coupled adenosine receptors [74–76,117,118]. Adenosine receptors have different affinities for adenosine and their activation will depend on the local extracellular concentration of this nucleoside. The cellular level of adenosine is regulated by a dynamic between the kinetic parameters for the efflux and influx of adenosine, depending on the level of this nucleoside in the intracellular and extracellular space. In the cardiovascular system, the concentration of adenosine between these two compartments is balanced by the activity of sodium-independent equilibrative nucleoside transporters (ENTs) [23,74,118,119]. An increase in the extracellular concentration of adenosine may result from several conditions including hyperglycaemia, hypoxia, exercise, reduced ENTs expression, inhibition of ENTs-mediated uptake (favoured maximal transport capacity, Vmax/Km, for influx [120,121]), increased ENTs-mediated release (favoured Vmax/Km for efflux), overexpression or activation of ectonucleotidases (v.g. cluster of differentiation 39 (CD39) and CD73) [118], impaired activity or expression of adenosine kinase [28,87,118,122], among others (Fig. 2). These phenomena result in the activation of all adenosine receptor subtypes since the extracellular adenosine concentration could reach 1 mol/L in pathological conditions such as GDM or preeclampsia [33,123–125] well within or over the range of the reported dissociation constant parameter for adenosine activation of adenosine receptors (0.1-5 mol/L) [18,24,118,126,127]. Thus, keeping a balance between the

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Figure 2 Regulation of adenosine level. The regulation of adenosine level depends on the activity of different enzymes in and outside the cell. Intracellularly, adenosine can be converted into AMP and inosine my adenosine kinase (AK) and adenosine deaminase (ADA), respectively. On the other hand, inside the cell, adenosine can be obtained by the activity of cytoplasmic 5`- nucleotidase (C5’-NTase) which degrades AMP. Also, adenosine is a product of methylation cycle after the clearance of S-adenosyl homocysteine (SAH) by SAH hydrolase (SAHH). In the extracellular space, adenosine results from the coordinated activity of CD39 which uses ATP to produce AMP, which later is degraded to adenosine by CD73. Adenosine can be converted into inosine by extracellular ADA. The level of adenosine can be regulated extra and intracellularly by the activity of concentrative or equilibrative nucleoside transporters (NTs). extracellular and intracellular adenosine concentration and bioavailability is crucial to achieve adenosine receptors-mediated signalling under physiological conditions [23,74,117,128–131]. Adenosine is one of the final products of the methylation cycle [26,87]. DNA methyltransferases (DNMT) are a family of four members (DNMT1, DNMT3A, DNMT3B and DNMT3-like (DNMT3L)), in which DNMT1, DNMT3A and DNMT3B have catalytic activity in contrast to DNMT3L that is catalytically inactive [132]. DNMTs catalyse DNA methylation by transferring a methyl group from S-adenosylmethionine (SAM) to the methyl group acceptor 5-methylcytosine (5mC) [132–136] (Fig. 1). The product of this DNMT-mediated reaction is the S-adenosylhomocysteine (SAH) [137]. The affinity of DNMTs for SAH is higher than for SAM, making likely that accumulation of SAH resulted in inhibition of DNMT activity [26,138,139]. Therefore, SAH is metabolised by the S- adenosylhomocysteine hydrolase (SAHH) to adenosine and

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homocysteine in order to avoid such inhibition of DNMTs [26]. However, the clearance of SAH by SAHH depends on an efficient removal of adenosine and homocysteine avoiding a potential reversed reaction increasing the formation of SAH from these two metabolites [118,119,140,141]. Potential accumulation of SAH may result in inhibition of DNMTs decreasing a global DNA methylation [26,118,140]. It is shown that cAMP increases the activity of SAHH in bovine kidney [142,143]. Since activation of the Gs protein- coupled A2AAR and A2BAR increased the cAMP generation in mammalian cells, a functional link between increased extracellular adenosine concentration, A2AAR and A2BAR activation, and activation of SAHH is likely. However, whether this mechanism occurs in human cells remains to be studied.

Adenosine kinase Adenosine kinase is a phosphoribosyltransferase that catalyses the conversion of adenosine into AMP using ATP (or ADP, described in rat AK [144]) as phosphate donor [145]. It is one of the enzymes involved in keeping a constant intracellular concentration of adenosine. The intracellular adenosine level is maintained via the generation of adenosine due to the breakdown of more complex molecules (v.g. AMP, SAH, ATP), degradation of adenosine by adenosine deaminase (ADA), or incorporation of adenosine into macroergic molecules, such as AMP by AK [118,146] (Fig. 2). The affinity of AK for adenosine is higher (100 nmol) compared with ADA (20-100 mol/L) suggesting that AK would be a major regulator of intracellular adenosine level under physiological conditions [27,28,87]. Unfortunately, there are no studies addressing whether AK expression and function are altered in GDM. The AK gene (ADK) is localized on chromosome 10q11-q24 in humans [147]. The whole sequence of ADK is 546 kb, being one of the largest genes in the human genome. However, the coding sequence for AK is only 1.1 kb, therefore this gene contains the highest intron/exon ratio of the known genome [28,119,145]. ADK codes for at least two isoforms of AK, a short or cytoplasmic (c-AK) and a long or nuclear (n-AK) isoform [28,145,148,149]. The difference between both isoforms is 21 amino acids in the N- terminal [148,150]. It is suggested that n-AK is involved in the maintenance of methylation reaction in the nucleus (e.g. DNA methylation) and c-AK maintains the clearance of intracellular adenosine [149,150].

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In animal models, a switch between the expression of both AK isoforms has been described during development [149,150]. In mouse hippocampal neurons, a decrease in the expression of n-AK is seen from the 4th until the 14th day postpartum [150]. On the contrary, an increase in c-AK expression was seen in the same period of time in glial cells. Thus, it is likely that at certain stages of the development and in response to specific stimuli one AK isoform predominates in a cell-specific manner. Differential expression of c- AK and n-AK is also seen in other mice organs, such as the pancreas where -pancreatic cells and exocrine pancreas express c-AK, while preferential n-AK expression is seen in β-pancreatic cells. In other organs such as the adipose tissue, there is a mixed expression of c-AK and n-AK [151]. It is reported that this regulation can also take place in different phases of the cell cycle, depending on energetic/ purinergic signalling before replication and the establishing of DNA methylation after the DNA replication. Even though the regulation of the transcriptional activity of this enzyme and how the differential expression of both isoforms is established is not yet well described. However, the Sp1 transcription factor seems to play a role in the differential expression of both AK isoforms causing a preferential increase of the expression of n-AK in rat hippocampal neurons [150]. In the latter study, two consecutive CpG islands at -755 bp from the transcriptional start site of the n-AK and one CpG island at -588 bp of the c-AK were identified. However, no methylation of these CpG islands was found in rat hippocampal neurons. Since the ADK is conserved in mammals, it is hypothesized that the expression of both isoforms could also be regulated by this mechanism in other cell types, including the endothelium from the human fetoplacental vasculature.

Adenosine kinase-dependent regulation of methylation cycle The role of AK can be deduced from knock-out studies in vitro and in vivo. Knock-out mice for AK resulted in higher levels of SAH and SAM in the liver. This result suggests that disrupting AK resulted in impaired clearance of adenosine and produced alterations in the methylation cycle, leading to the accumulation of SAH and SAM [152]. In HUVECs and murine aortic endothelial cells (MAECs), the knocking down of ADK leads to increased adenosine level and angiogenesis [87,152] and increased SAH and SAM levels [125]. The incubation of lysates from HUVECs with supraphysiological concentrations (10 µmol/L) of adenosine led to reduced DNMTs activity and the pharmacological inhibition of AK

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by 5'-iodotubercidin (ITU, 10 µmol/L) also reduced the global DNA methylation and associated with hypomethylation of VEGFR2 [27]. In addition, disruption of AK, and a subsequent increase of adenosine intracellular level, increased the mRNA expression of other proangiogenic genes, such as GATA4 (for GATA binding protein 4), NOS3 (for endothelial nitric oxide synthase isoform), DDAH1 (for dimethylarginine dimethylaminohydrolase 1), RUNX1 (for runt related transcription factor 1), SEMA5A (for semaphorin 5A), and BRCA1 (for BRCA1, DNA repair associated) [27]. All these results suggest that reducing the activity and expression of AK altered the methylation cycle in endothelial cells leading to an imbalance between pro- and anti-angiogenesis, thus reprogramming the cells to promote angiogenesis. In HUVECs, an inflammatory condition induced by TNF-α increased the expression of AK with a subsequent reduction of the intracellular adenosine level [87]. The knocking down of AK in this cell type reduced the expression of E-selectin, ICAM-1, or VCAM-1 in response to TNF-α in an adenosine receptors-independent manner. TNF-α induced dimethylation and trimethylation of histone 3 at lysine 4 (H3K4m2 and H3K4m3, respectively) and increased the binding of H3K4m2-m3 to the gene promoters of SELE (for selectin E), ICAM1 (for intercellular adhesion molecule 1), or VCAM1 (for vascular cell adhesion molecule 1) resulting in higher expression of the corresponding proteins. Nevertheless, the effect of TNF-α on gene expression was reduced in cells knock-down for ADK leading to reduced levels of endothelial inflammation markers [87].

Adenosine kinase in diabetes mellitus Adenosine metabolism and signalling play a role in diabetes mellitus and different studies in various models have explored adenosine from a therapeutic and also from a pathophysiological perspective [23,117]. Adenosine regulates insulin secretion and β-cell survival [117,151,153] but also regulates D-glucose homeostasis and lipid metabolism in different tissues such as adipose tissue, liver, and skeletal muscle [117]. Moreover, adenosine receptor activation leads to improved insulin response in the cardiovascular system [117,118], including the fetoplacental vasculature [19], and seems beneficial in avoiding vascular complications associated with diabetes mellitus such as diabetic nephropathy, atherosclerosis and diabetic retinopathy [117]. The above-mentioned results suggest a strong physiological link between adenosine and insulin, a phenomenon recently referred to as the insulin/adenosine associated signalling

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Chapter 5 axis [18,118]. However, it is crucial to consider that the adenosine concentration must be tightly regulated since reaching abnormal concentrations of this nucleoside leads to differential activation of adenosine receptors with the subsequent loss of its beneficial actions [23,117,118]. This is of relevance in diabetes mellitus where not only the adenosine concentration is altered but also the expression profile of adenosine receptors [22,24,117,126]. Since AK is the major regulator of adenosine level it is likely that these enzymes participate in the pathological mechanisms in diabetes mellitus. In kidneys from streptozotocin-induced diabetic mice, AK inhibition with ABT-702 reduced the D-glucose concentration, albuminuria, glomerular injury markers expression, oxidative stress, and increased eNOS expression and inflammatory parameters [29]. Additionally, human glomerular cells exposed to high D-glucose concentrations showed reduced expression of occludin, an effect that was AK-activation dependent. Authors attributed these reno-protective findings to A2AAR-mediated decrease in inflammation and reduction of the oxidative stress [29,154]. Since new evidence on the role of the intracellular adenosine and AK in inflammatory processes is described [73] other synergic or independent effects mediated by the accumulation of intracellular adenosine and modification in DNA and histone methylation cannot be discarded. In the pancreas from mouse and pig, inhibition of AK promotes β cell replication [151,155] and leads to D-glucose tolerance and improved D- glucose– stimulated insulin secretion in a mouse model of high fat- induced diabetes mellitus [155]. In the kidney, liver and heart of streptozotocin-induced diabetic rats, a decrease of ~50% in the cytosolic activity and expression of AK is reported, suggesting that diabetes mellitus is a condition that regulates AK [30]. This was also seen in HUVECs from GDM pregnancies which showed lower phosphorylated adenine nucleotides compared with cells from normal pregnancies, thus suggesting that the phosphorylation of adenosine mediated by AK was reduced in this pathological condition [77]. However, whether this reduction in adenine nucleotides in GDM was due to lower enzyme activity or expression and how GDM could lead to these changes remains unclear. In the mouse retina, inhibition AK also decreased the inflammation in diabetic retinopathy, suggesting that inhibition of these enzymes results in a protective role mediated by the increase of adenosine signalling associated with A2AAR activation. Human diabetes displays altered immune cell function and adenosine is a

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crucial regulator of immune cell function. Adenosine regulates T- lymphocyte activation, proliferation, cytokine production and lymphocyte-mediated cytolysis. Lymphocytes incubated with high D-glucose concentrations in the absence of insulin show reduced AK expression, increased release of adenosine and increased A 2AAR-dependent increased cAMP level. Surprisingly, suppression of AK expression and the adenosine-induced proliferation of T lymphocytes was prevented by treatment with insulin [31], suggesting a functional link between insulin and the transcriptional regulation of ADK. The latter was also seen in streptozotocin-induced diabetic rats after insulin treatment where the diabetes-reduced AK activity was restored [32]. Insulin restored cellular alterations in the fetoplacental vasculature from GDM [20]; however, the role of AK in this phenomenon remains to be elucidated. Since adenosine is involved in methylation- dependent gene expression regulatory mechanisms it is not possible to discard the involvement of DNA methylation or histone methylation in the described effects of AK.

Adenosine kinase and cardio-metabolic fetal programming in GDM GDM is associated with increased risk of fetal cardio- metabolic alterations [38]. Several studies in HUVECs and hPMECs exposed to high D-glucose or from GDM pregnancies show altered adenosine metabolism and adenosine receptor signalling [20,21,33,68,123,129,156,157]. Several reports also highlight the importance of AK and intracellular adenosine concentration in the methylation cycle. Disruption of AK and the subsequent dysregulation of intracellular adenosine level can epigenetically (mal)program the endothelium and other organs [27,87,152]. It is proposed that an orchestrated effect of factors associated with GDM, such as high D-glucose and inflammatory mediators could alter the activity of AK resulting in dysregulation of methylation reactions. The above-mentioned alterations may contribute to the increased cardio-metabolic risk in fetuses, infants, and adults from GDM pregnancies (Fig. 3). Also, restoration of a normal AK function in fetal endothelium exposed to GDM or high D- glucose could imply a new therapeutic target in order to reduce the cardiovascular consequences of GDM in adulthood.

Concluding remarks The fetoplacental vasculature from GDM pregnancies shows endothelial dysfunction, endothelial activation, and shows several

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Chapter 5 functional alterations that may be AK-mediated with short and long-term consequences for the offspring. The nuclear and cytoplasmic AK isoforms catalyze the transfer of the gamma- phosphate from ATP to adenosine leading to the generation of AMP. This phenomenon results in effective regulation of the intracellular and extracellular concentration of adenosine, positioning AK as the major regulator of the adenosine level under physiological conditions, controlling the broad biological effects of this nucleoside. GDM is a disease of pregnancy proposed to result in altered adenosine/L-arginine/nitric oxide (ALANO) signalling pathway with the involvement of A2AAR in the absence of insulin, or A1AR in response to insulin via activation of insulin receptor A isoform in the fetoplacental macrovascular endothelium. Altered ALANO via the activation of these adenosine receptor subtypes depends on the capacity of the endothelium to take up and metabolize adenosine thus reducing the extracellular concentration and limiting its broad biological effects. Epigenetic modifications altering the normal activity of transcription factors such as DDIT3 or Sp1 may result in abnormal ALANO signalling pathway in the placental vasculature. Therefore, a fine regulation of the adenosine concentration by AK in concert with the uptake of adenosine via hENTs in this type of endothelium is required. It is now clearer that DNA methylation may be a mechanism of fetal programming in diseases of pregnancy, including GDM. The intrauterine development is a stage where therapeutic interventions and the intergenerational transmission of pathological conditions, such as obesity and T2DM, could be efficiently prevented. Thus, understanding the pathophysiological mechanisms associated to GDM, in which AK may play a role, could contribute to avoid or restore the GDM-associated increased cardiovascular risk observed in GDM offspring. Intracellular and extracellular adenosine regulation mediated by AK is important for the biological actions of this nucleoside regarding adenosine receptor’s signalling and methylation-dependent gene expression regulatory mechanisms. Thus, as summarised in Figure 3, it is likely that GDM-associated pathophysiology will result in altered AK activity contributing to the fetal programming in the fetoplacental vasculature.

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Figure 3 Adenosine kinase in gestational diabetes as responsible of cardio-metabolic fetal programming. Gestational diabetes mellitus (GDM) is a condition in the mother that can alter placental function and also condition the fetal health. GDM can trigger diverse systemic and cellular responses, leading to an impaired intrauterine environment. All these alterations can dysregulate either the activity or expression of adenosine kinase (AK) resulting in altered adenosine regulation and methylation cycle, which is crucial to maintain a normal DNA and histone methylation. Imbalanced methylation cycle can result in impaired gene expression pattern and increased ( ) cardio-metabolic risk in fetuses exposed to GDM to suffer cardiovascular conditions⬆ later in life. Nitric oxide (NO), Specific protein 1 (Sp1), human cationic amino acid transporter 1 (hCAT-1), homocysteine (Hcy), human equilibrative nucleoside transporter 1 (hENT1), ( ) reduced. ⬇ References [1] American Diabetes Association (ADA), Classification and diagnosis of diabetes: standards of medical care in diabetes—2018, Diabetes Care 41 (2018) S13–S27. [2] American Diabetes Association (ADA), Position statement: Standar of medical care in diabetes 2014, Diabetes Care 37 (2014) S14–S80. [3] M. Subiabre, L. Silva, F. Toledo, M. Paublo, M.A. López, M.P. Boric, L. Sobrevia, Insulin therapy and its consequences for the mother, fetus, and newborn in gestational diabetes mellitus, Biochim. Biophys. Acta - Mol. Basis Dis. 1864 (2018) 2949–2956. [4] C. Spaight, J. Gross, A. Horsch, J.J. Puder, Gestational diabetes mellitus, Endocr. Dev. 31 (2016) 163–178. [5] 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. [6] L.J. Monteiro, J.E. Norman, G.E. Rice, S.E. Illanes, Fetal programming and gestational diabetes mellitus, Placenta 48 (2016) S54–S60. [7] O. Langer, Y. Yogev, E.M.J. Xenakis, B. Rosenn, Insulin and glyburide therapy: Dosage, severity level of gestational diabetes, and pregnancy outcome, Am. J. Obstet. Gynecol. 192 (2005) 134–139. [8] R. Villalobos-Labra, P.J. Sáez, M. Subiabre, L. Silva, F. Toledo, F. Westermeier, F. Pardo, M. Farías, L. Sobrevia, Pre-pregnancy maternal obesity associates with endoplasmic reticulum stress in human umbilical vein endothelium, Biochim.

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