Skip to main content
Log in

Inverse correlation between maternal plasma asymmetric dimethylarginine (ADMA) and birthweight percentile in women with impaired placental perfusion: circulating ADMA as an NO-independent indicator of fetal growth restriction?

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

l-Arginine (Arg) is the enzymatic precursor of nitric oxide (NO) which has multiple biological functions. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO. We hypothesized that the ADMA and SDMA have additional biological functions in pregnancy, beyond NO synthesis, and may play a role in the regulation of birthweight (BW). To investigate this issue, we measured the plasma concentration of ADMA, SDMA, Arg and the NO metabolites nitrite and nitrate, at 23–25 weeks of gestation in women with normal placental function (Group 1) and in women with impaired placental perfusion; 19 of these women had normal outcome (Group 2), 14 had a fetus that was growth restricted (Group 3), and 10 women eventually developed preeclampsia (Group 4). BW percentile was found to inversely correlate with maternal plasma ADMA concentration in Group 3 (r = − 0.872, P < 0.001) and in Group 4 (r = − 0.800, P < 0.05). But, BW percentile did not correlate with the maternal plasma concentration of Arg, SDMA, nitrate or nitrite. Our results suggest that maternal plasma ADMA concentration is an important indicator of fetal growth restriction in women with impaired placental perfusion independent of NO.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ADMA:

Asymmetric dimethylarginine

AGA:

Appropriate for gestational age

BW:

Birthweight

FGR:

Fetal growth restriction

FMD:

Flow-mediated dilatation

GA:

Gestational age

GH:

Growth hormone

GHD:

Growth hormone deficiency

IGF-1:

Insulin-like growth factor-1

IUGR:

Intrauterine growth restriction

LGA:

Large for gestational age

NO:

Nitric oxide

NOS:

Nitric oxide synthase

eNOS:

Endothelial NOS

PE:

Preeclampsia

PRMT:

Protein arginine methyltransferase

SDMA:

Symmetric dimethylarginine

SGA:

Small for gestational age

References

  • Albaiges G, Missfelder-Lobos H, Lees C, Parra M, Nicolaides KH (2000) One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks’ gestation. Obstet Gynecol 96:559–564

    CAS  PubMed  Google Scholar 

  • Bassareo PP, Puddu M, Flore G, Deidda M, Manconi E, Melis A, Fanos V, Mercuro G (2012) Could ADMA levels in young adults born preterm predict an early endothelial dysfunction? Int J Cardiol 159:217–219

    Article  CAS  PubMed  Google Scholar 

  • Böger RH, Diemert A, Schwedhlm E, Lüneburg N, Maas R, Hecher K (2010) The role of nitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiology of preeclampsia. Gynecol Obstet Investig 69:1–13

    Article  Google Scholar 

  • Buck A, Kayacelebi AA, Chobanyan-Jürgens K, Illsinger S, Bohnhorst B, Beckmann B, Hanff E, Das AM, Tsikas D, Lücke T (2017) Comprehensive analysis of the l-arginine/l-homoarginine/nitric oxide pathway in preterm neonates: potential roles for homoarginine and asymmetric dimethylarginine in foetal growth. Amino Acids 49:783–794

    Article  CAS  PubMed  Google Scholar 

  • Chiavaroli V, Diesse L, de Giorgis T, Giannini C, Marcovecchio ML, Chiarelli F, Mohn A (2014) Is asymmetric dimethylarginine associated with being born small and large for gestational age? Antioxid Redox Signal 20:2317–2322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cockell AP, Poston L (1997) Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia. Hypertension 30:247–251

    Article  CAS  PubMed  Google Scholar 

  • Davey DA, MacGillivray I (1988) The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 158:892–898

    Article  CAS  PubMed  Google Scholar 

  • De Barbieri A, Benassi C (1950) Action of insulin on methylation of guanidoacetic acid in liver homogenates. Boll Soc Ital Biol Sper 26:1435–1436

    Google Scholar 

  • Emrich IE, Zawada AM, Martens-Lobenhoffer J, Fliser D, Wagenpfeil S, Heine GH, Bode-Böger SM (2017) Symmetric dimethylarginine (SDMA) outperforms asymmetric dimethylarginine (ADMA) and other methylarginines as a predictor of renal and cardiovascular outcome in non-dialysis chronic kidney disease. Clin Res Cardiol. https://doi.org/10.1007/s00392-017-1172-4

    PubMed  Google Scholar 

  • Förstermann U, Neufang B (1985) Endothelium-dependent vasodilation by melittin: are lipoxygenase products involved? Am J Physiol 249:H14–H19

    PubMed  Google Scholar 

  • Genre F, López-Mejías R, Rueda-Gotor J, Miranda-Filloy JA, Ubilla B, Villar-Bonet A, Carnero-López B, Gómez-Acebo I, Blanco R, Pina T, González-Juanatey C, Llorca J, González-Gay MA (2014) IGF-1 and ADMA levels are inversely correlated in nondiabetic ankylosing spondylitis patients undergoing anti-TNF-alpha therapy. Biomed Res Int 2014:671061

    PubMed  PubMed Central  Google Scholar 

  • Gumus E, Atalay MA, Cetinkaya Demir B, Sahin Gunes E (2016) Possible role of asymmetric dimethylarginine (ADMA) in prediction of perinatal outcome in preeclampsia and fetal growth retardation related to preeclampsia. J Matern Fetal Neonatal Med 29:3806–3811

    Article  CAS  PubMed  Google Scholar 

  • Hasdai D, Rizza RA, Holmes DR Jr, Richardson DM, Cohen P, Lerman A (1998) Insulin and insulin-like growth factor-I cause coronary vasorelaxation in vitro. Hypertension 32:228–234

    Article  CAS  PubMed  Google Scholar 

  • Ignarro LJ, Gold ME, Buga GM, Byrns RE, Wood KS, Chaudhuri G, Frank G (1989) Basic polyamino acids rich in arginine, lysine, or ornithine cause both enhancement of and refractoriness to formation of endothelium-derived nitric oxide in pulmonary artery and vein. Circ Res 64:315–329

    Article  CAS  PubMed  Google Scholar 

  • Intapad S, Dasinger JH, Fahling JM, Backstrom MA, Alexander BT (2017) Testosterone is protective against impaired glucose metabolism in male intrauterine growth-restricted offspring. PLoS One 12:e0187843

    Article  PubMed  PubMed Central  Google Scholar 

  • Izhar U, Hasdai D, Richardson DM, Cohen P, Lerman A (2000) Insulin and insulin-like growth factor-I cause vasorelaxation in human vessels in vitro. Coron Artery Dis 11:69–76

    Article  CAS  PubMed  Google Scholar 

  • Khalil AA, Tsikas D, Akolekar R, Jordan J, Nicolaides KH (2013) Asymmetric dimethylarginine, arginine and homoarginine at 11-13 weeks’ gestation and preeclampsia: a case-control study. J Hum Hypertens 27:38–43

    Article  CAS  PubMed  Google Scholar 

  • Khalil A, Hardman L, O Brien P (2015) The role of arginine, homoarginine and nitric oxide in pregnancy. Amino Acids 47:1715–1727

    Article  CAS  PubMed  Google Scholar 

  • Kielstein JT, Impraim B, Simmel S, Bode-Böger SM, Tsikas D, Frölich JC, Hoeper MM, Haller H, Fliser D (2004) Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 109:172–177

    Article  CAS  PubMed  Google Scholar 

  • Kielstein A, Tsikas D, Galloway GP, Mendelson JE (2007) Asymmetric dimethylarginine (ADMA)—a modulator of nociception in opiate tolerance and addiction? Nitric Oxide 17:55–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein S, Carroll JA, Chen Y, Henry MF, Henry PA, Ortonowski IE, Pintucci G, Beavis RC, Burgess WH, Rifkin DB (2000) Biochemical analysis of the arginine methylation of high molecular weight fibroblast growth factor-2. J Biol Chem 275:3150–3157

    Article  CAS  PubMed  Google Scholar 

  • Kleinbongard P, Dejam A, Lauer T, Rassaf T, Schindler A, Picker O et al (2003) Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med 35:790–796

    Article  CAS  PubMed  Google Scholar 

  • Kleinbongard P, Dejam A, Lauer T, Jax T, Kerber S, Gharini P et al (2006) Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 40:295–302

    Article  CAS  PubMed  Google Scholar 

  • Langen J, Kayacelebi AA, Beckmann B, Weigt-Usinger K, Carmann C, Hörster I, Lilienthal E, Richter-Unruh A, Tsikas D, Lücke T (2015) Homoarginine (hArg) and asymmetric dimethylarginine (ADMA) in short stature children without and with growth hormone deficiency: hArg and ADMA are involved differently in growth in the childhood. Amino Acids 47:1875–1883

    Article  CAS  PubMed  Google Scholar 

  • Laskowska M, Laskowska K, Leszczyńska-Gorzelak B, Oleszczuk J (2011) Asymmetric dimethylarginine in normotensive pregnant women with isolated fetal intrauterine growth restriction: a comparison with preeclamptic women with and without intrauterine growth restriction. J Matern Fetal Neonatal Med 24:936–942

    Article  CAS  PubMed  Google Scholar 

  • Laskowska M, Laskowska K, Oleszczuk J (2015) The relation of maternal serum eNOS, NOSTRIN and ADMA levels with aetiopathogenesis of preeclampsia and/or intrauterine fetal growth restriction. J Matern Fetal Neonatal Med 28:26–32

    Article  CAS  PubMed  Google Scholar 

  • López-Alarcón M, Montalvo-Velarde I, Vital-Reyes VS, Hinojosa-Cruz JC, Leaños-Miranda A, Martínez-Basila A (2015) Serial determinations of asymmetric dimethylarginine and homocysteine during pregnancy to predict pre-eclampsia: a longitudinal study. BJOG 122:1586–1592

    Article  PubMed  Google Scholar 

  • Martín-Estal I, de la Garza RG, Castilla-Cortázar I (2016) Intrauterine growth retardation (IUGR) as a novel condition of insulin-like growth factor-1 (IGF-1) deficiency. Rev Physiol Biochem Pharmacol 170:1–35

    Article  PubMed  Google Scholar 

  • McKay MK, Hester RL (1996) Role of nitric oxide, adenosine, and ATP-sensitive potassium channels in insulin-induced vasodilation. Hypertension 28:202–208

    Article  CAS  PubMed  Google Scholar 

  • Moonen RM, Huizing MJ, Cavallaro G, González-Luis GE, Bas-Suárez P, Bakker JA, Villamor E (2014) Plasma levels of dimethylarginines in preterm very low birth weight neonates: its relation with perinatal factors and short-term outcome. Int J Mol Sci 16:19–39

    Article  PubMed  PubMed Central  Google Scholar 

  • Morales Y, Cáceres T, May K, Hevel JM (2016) Biochemistry and regulation of the protein arginine methyltransferases (PRMTs). Arch Biochem Biophys 590:138–152

    Article  CAS  PubMed  Google Scholar 

  • Poon LC, Volpe N, Muto B, Syngelaki A, Nicolaides KH (2012) Birthweight with gestation and maternal characteristics in live births and stillbirths. Fetal Diagn Ther 32:156–165

    Article  PubMed  Google Scholar 

  • Possomato-Vieira JS, Khalil RA (2016) Mechanisms of endothelial dysfunction in hypertensive pregnancy and preeclampsia. Adv Pharmacol 77:361–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richir MC, van Leeuwen PA, van den Berg A, Wessels R, Twisk JW, Rauwerda JA, Teerlink T, de Vries TP, van Elburg RM (2008) Plasma ADMA concentrations at birth and mechanical ventilation in preterm infants: a prospective pilot study. Pediatr Pulmonol 43:1161–1166

    Article  PubMed  Google Scholar 

  • Saleh L, Verdonk K, Visser W, van den Meiracker AH, Danser AH (2016) The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia. Ther Adv Cardiovasc Dis 10:282–293

    Article  CAS  PubMed  Google Scholar 

  • Sandvik MK, Leirgul E, Nygård O, Ueland PM, Berg A, Svarstad E, Vikse BE (2013) Preeclampsia in healthy women and endothelial dysfunction 10 years later. Am J Obstet Gynecol 209:569.e1–569.e10

    Article  Google Scholar 

  • Savvidou MD, Hingorani AD, Tsikas D, Frölich JC, Vallance P, Nicolaides KH (2003) Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 361:1511–1517

    Article  CAS  PubMed  Google Scholar 

  • Schlesinger S, Sonntag SR, Lieb W, Mass R (2016) Asymmetric and symmetric dimethylarginine as risk markers for total mortality and cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. PLoS One 11:e0165811

    Article  PubMed  PubMed Central  Google Scholar 

  • Setola E, Monti LD, Lanzi R, Lucotti P, Losa M, Gatti E, Galluccio E, Oldani M, Fermo I, Giovannelli M, Bosi E, Piatti P (2008) Effects of growth hormone treatment on arginine to asymmetric dimethylarginine ratio and endothelial function in patients with growth hormone deficiency. Metabolism 57:1685–1690

    Article  CAS  PubMed  Google Scholar 

  • Speer PD, Powers RW, Frank MP, Harger G, Markovic N (2008) Roberts JM (2008) Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants. Am J Obstet Gynecol 198:112.e1–112.e7

    Article  Google Scholar 

  • Takaya J, Tanabe Y, Kuroyanagi Y, Kaneko K (2017) Relationship between asymmetric dimethylarginine in umbilical cord plasma and birth weight follows a U-shaped curve. Endocr J 64:431–436

    Article  PubMed  Google Scholar 

  • Thomas G, Mostaghim R, Ramwell PW (1986) Endothelium dependent vascular relaxation by arginine containing polypeptides. Biochem Biophys Res Commun 141:446–451

    Article  CAS  PubMed  Google Scholar 

  • Thum T, Fleissner F, Klink I, Tsikas D, Jakob M, Bauersachs J, Stichtenoth DO (2007a) Growth hormone treatment improves markers of systemic nitric oxide bioavailability via insulin-like growth factor-I. J Clin Endocrinol Metab 92:4172–4179

    Article  CAS  PubMed  Google Scholar 

  • Thum T, Hoeber S, Froese S, Klink I, Stichtenoth DO, Galuppo P, Jakob M, Tsikas D, Anker SD, Poole-Wilson PA, Borlak J, Ertl G, Bauersachs J (2007b) Age-dependent impairment of endothelial progenitor cells is corrected by growth-hormone-mediated increase of insulin-like growth-factor-1. Circ Res 100:434–443

    Article  CAS  PubMed  Google Scholar 

  • Thum T, Fleissner F, Klink I, Tsikas D, Stichtenoth D, Ertl G, Bauersachs J (2007c) Growth hormone treatment improves markers of systemic nitric oxide bioavailability via the insulin-like growth factor-1. Importance for endothelial progenitor cells. J Stem Cells Regen Med 2:115–116 (eCollection 2007)

    CAS  PubMed  Google Scholar 

  • Tsikas D (2000) Simultaneous derivatization and quantification of the nitric oxide metabolites nitrite and nitrate in biological fluids by gas chromatography/mass spectrometry. Anal Chem 72:4064–4072

    Article  CAS  PubMed  Google Scholar 

  • Tsikas D (2015) Circulating and excretory nitrite and nitrate: their value as measures of nitric oxide synthesis, bioavailability and activity is inherently limited. Nitric Oxide 45:1–3

    Article  CAS  PubMed  Google Scholar 

  • Tsikas D (2017) Does the inhibitory action of asymmetric dimethylarginine (ADMA) on the endothelial nitric oxide synthase activity explain its importance in the cardiovascular system? The ADMA paradox. J Controv Biomed Res 3:16–22

    Article  Google Scholar 

  • Tsikas D, Kayacelebi AA (2014) Do homoarginine and asymmetric dimethylarginine act antagonistically in the cardiovascular system? Circ J 78:2094–2095

    Article  PubMed  Google Scholar 

  • Tsikas D, Kinzel M (2017) Associations between asymmetric dimethylarginine (ADMA), nitrite-dependent renal carbonic anhydrase activity and plasma testosterone levels in hypogonadal men. Hell J Cardiol. https://doi.org/10.1016/j.hjc.2017.10.004

  • Tsikas D, Savvidou M (2017) Plasma oleic acid oxide in women at risk of preeclampsia correlates inversely with birthweight percentile. JSM Biochem Mol Biol 4:1028

    Google Scholar 

  • Tsikas D, Wu G (2015) Homoarginine, arginine, and relatives: analysis, metabolism, transport, physiology, and pathology. Amino Acids 47:1697–1702

    Article  CAS  PubMed  Google Scholar 

  • Tsikas D, Junker W, Frölich JC (1998) Determination of dimethylated arginines in human plasma by high-performance liquid chromatography. J Chromatogr B 705:174–176

    Article  CAS  Google Scholar 

  • Tsikas D, Sandmann J, Savva A, Luessen P, Böger RH, Gutzki FM, Mayer B, Frölich JC (2000a) Assessment of nitric oxide synthase activity in vitro and in vivo by gas chromatography–mass spectrometry. J Chromatogr B 742:143–153

    Article  CAS  Google Scholar 

  • Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Frölich JC (2000b) Endogenous nitric oxide synthase inhibitors are responsible for the l-arginine paradox. FEBS Lett 478:1–3

    Article  CAS  PubMed  Google Scholar 

  • Vida G, Sulyok E, Lakatos O, Ertl T, Martens-Lobenhoffer J, Bode-Böger SM (2009) Plasma levels of asymmetric dimethylarginine in premature neonates: its possible involvement in developmental programming of chronic diseases. Acta Paediatr 98:437–441

    Article  CAS  PubMed  Google Scholar 

  • Williams DJ, Vallance PJ, Neild GH, Spencer JA, Imms FJ (1997) Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol 272:H748–H752

    CAS  PubMed  Google Scholar 

  • Wu MM, Yang F, Qu Y, Mu DZ (2017) Effects of maternal folate deficiency on the methylation of insulin-like growth factor system in the offspring rats. Zhongguo Dang Dai Er Ke Za Zhi 19:470–474

    PubMed  Google Scholar 

  • Yaron M, Izkhakov E, Sack J, Azzam I, Osher E, Tordjman K, Stern N, Greenman Y (2016) Arterial properties in acromegaly: relation to disease activity and associated cardiovascular risk factors. Pituitary 19:322–331

    Article  CAS  PubMed  Google Scholar 

  • Yuan J, Wang X, Xie Y, Wang Y, Dong L, Li H, Zhu T (2017) Circulating asymmetric dimethylarginine and the risk of preeclampsia: a meta-analysis based on 1338 participants. Oncotarget 8:43944–43952

    PubMed  PubMed Central  Google Scholar 

  • Zobel EH, von Scholten BJ, Reinhard H, Persson F, Teerlink T, Hansen TW et al (2017) Symmetric and asymmetric dimethylarginine as risk markers of cardiovascular disease, all-cause mortality and deterioration in kidney function in persons with type 2 diabetes and microalbuminuria. Cardiovasc Diabetol 16:88

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The initial study was supported by The Fetal Medicine Foundation (UK Registered Charity number: 1037116).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dimitrios Tsikas.

Ethics declarations

Ethical statement

The study was approved by the Local REC and all the patients gave written informed consent.

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

Additional information

Handling Editor: J. Marshal.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsikas, D., Bollenbach, A. & Savvidou, M.D. Inverse correlation between maternal plasma asymmetric dimethylarginine (ADMA) and birthweight percentile in women with impaired placental perfusion: circulating ADMA as an NO-independent indicator of fetal growth restriction?. Amino Acids 50, 341–351 (2018). https://doi.org/10.1007/s00726-017-2522-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-017-2522-2

Keywords

Navigation