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The role of arginine, homoarginine and nitric oxide in pregnancy

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Abstract

Normal pregnancy leads to profound maternal hemodynamic changes, including increased blood volume and vasodilatation. Several vasodilator mediators are implicated, including prostaglandins, carbon monoxide and nitric oxide (NO). Pre-eclampsia (PE) affects 3–10 % of pregnancies and is associated with increased maternal and perinatal morbidity and mortality. Around 8 % of pregnancies are complicated by intra-uterine growth restriction (IUGR), also associated with increased perinatal mortality and morbidity. PE and IUGR often co-exist. NO is essential for the formation of healthy endothelium, and in pregnancy promotes endovascular invasion by the cytotrophoblast. As interstitial trophoblasts invade the maternal spiral arteries in the uterine wall, they produce NO which acts on artery walls to create a low-resistance, high-caliber uteroplacental unit. If this process fails, the result is a high-resistance uteroplacental circulation. The hypoperfused and ischemic placenta releases antiangiogenic factors which mediate generalized endothelial dysfunction, oxidative stress and inflammatory mediators. It is these mediators that are implicated in both the fetal and maternal syndromes of PE and IUGR. Studies of NO and its modulator amino acids, including the precursors arginine and homoarginine and the NO synthesis inhibitor asymmetric dimethylarginine (ADMA), have investigated their role in both normal and pathological pregnancies. Many studies of PE (and, to a lesser extent, IUGR) have investigated maternal circulating ADMA, arginine and homoarginine levels. This article reviews and discusses the role of these amino acids in pregnancy. The results have shed some light on their role in these pathologies, but some of the findings have been conflicting and more research is needed. Nevertheless, therapeutic interventions that manipulate these guanidine–amino acids and their interactions hold real promise for the management of pregnancies complicated by PE and/or IUGR, and the results of ongoing studies are eagerly awaited.

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Abbreviations

ADMA:

Asymmetric dimethylarginine

cGMP:

Cyclic guanosine monophosphate

DDAH:

Dimethylarginine dimethylaminohydrolase

ELISA:

Enzyme-linked immunosorbent assay

eNOS:

Endothelial nitric oxide synthase

FMD:

Flow-mediated dilatation

GC–MS:

Gas chromatography–mass spectrometry

GC–MS/MS:

Gas chromatography–tandem mass spectrometry

GTN:

Glyceryl trinitrate

HPLC:

High-performance liquid chromatography

ISDN:

Isosorbide dinitrate

IUGR:

Intra-uterine growth restriction

LC–MS/MS:

Liquid chromatography–tandem mass spectrometry

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PE:

Pre-eclampsia

PlGF:

Placental growth factor

ROS:

Reactive oxygen species

sEng:

Soluble endoglin

sFlt-1:

Soluble Fms-like tyrosine kinase-1

SGA:

Small for gestational age

sGC:

Soluble guanylyl cyclase

TRPC:

Transient receptor potential cation (channels)

VEGF:

Vascular endothelial growth factor

References

  • Abe E, Matsubara K, Oka K, Kusanagi Y, Ito M (2008) Cytokine regulation of intercellular adhesion molecule-1 expression on trophoblasts in pre-eclampsia. Gynecol Obstet Investig 66:27–33

    Article  CAS  Google Scholar 

  • Abu-Soud HM, Wang J, Rousseau DL, Stuehr DJ (1999) Stopped-flow analysis of substrate binding to neuronal nitric oxide synthase. Biochemistry 38:12446–12451

    Article  CAS  PubMed  Google Scholar 

  • Akolekar R, Zaragoza E, Poon LCY, Pepes S, Nicolaides KH (2008) Maternal serum placental growth factor (PlGF) at 11–13 weeks of gestation in hypertensive disorders of pregnancy. Ultrasound Obstet Gynecol 32:732–739

    Article  CAS  PubMed  Google Scholar 

  • Akturk M et al (2010) Asymmetric dimethylarginine concentrations are elevated in women with gestational diabetes. Endocrine 38:134–141

    Article  CAS  PubMed  Google Scholar 

  • Alexander BT, Llinas MT, Kruckeberg WC, Granger JP (2004) l-arginine attenuates hypertension in pregnant rats with reduced uterine perfusion pressure. Hypertension 43:832–836

    Article  CAS  PubMed  Google Scholar 

  • Alpoim PN, Godoi LC, Freitas LG, Gomes KB, Dusse LM (2013) Assessment of l-arginine asymmetric 1 dimethyl (ADMA) in early-onset and late-onset (severe) preeclampsia. Nitric Oxide Biol Chem 33:81–82

    Article  CAS  Google Scholar 

  • Anderssohn M (2012) Severely decreased activity of placental dimethylarginine dimethylaminohydrolase in pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 161:152–156

    Article  CAS  PubMed  Google Scholar 

  • Bardin C, Piuze G, Papageorgiou A (2004) Outcome at 5 years of age of SGA and AGA infants born less than 28 weeks of gestation. Semin Perinatol 28:288–294

    Article  PubMed  Google Scholar 

  • Bassareo PP et al (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 

  • Battaglia FC, Lubchenco LO (1967) A practical classification of newborn infants by weight and gestational age. J Pediatr 71:159–163

    Article  CAS  PubMed  Google Scholar 

  • Baylis C et al (1998) Recent insights into the roles of nitric oxide and renin-angiotensin in the pathophysiology of preeclamptic pregnancy. Semin Nephrol 18:208–230

    CAS  PubMed  Google Scholar 

  • Bellamy L, Casas JP, Hingorani AD, Williams DJ (2007) PE and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 335:974–986

    Article  PubMed Central  PubMed  Google Scholar 

  • Bird IM, Zhang L, Magness RR (2003) Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function. Am J Physiol Regul Integr Comp Physiol 284:R245–R258

    Article  CAS  PubMed  Google Scholar 

  • Bo¨ger RH (2006) Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond. Ann Med 38:126–136

    Article  CAS  Google Scholar 

  • Bode-Boger SM, Boger RH, Kienke S, Junker W, Frolich JC (1996) Elevated arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary l-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun 219:598–603

    Article  CAS  PubMed  Google Scholar 

  • Boeldt DS, Grummer MA, Magness RR, Bird IM (2014) Altered VEGF-stimulated Ca2 + signaling in part underlies pregnancy-adapted eNOS activity in UAEC. J Endocrinol 223:1–11

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Böger RH et al (2010) The role of nitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiology of preeclampsia. Gynecol Obstet Invest 69:1–13

    Article  PubMed  CAS  Google Scholar 

  • Braekke K, Ueland PM, Harsem NK, Staff AC (2009) Asymmetric dimethylarginine in the maternal and fetal circulation in pre-eclampsia. Pediatr Res 66:411–415

    Article  CAS  PubMed  Google Scholar 

  • Calver A, Collier J, Leone A, Moncada S, Vallance P (1993) Effect of local intra-arterial asymmetric dimethylarginine (ADMA) on the forearm arteriolar bed of healthy volunteers. J Hum Hypertens 7:193–194

    CAS  PubMed  Google Scholar 

  • Cantwell R et al (2011) Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006–2008. The eighth report of the confidential enquiries into maternal deaths in the United Kingdom. BJOG 118(Suppl 1):1–203

    PubMed  Google Scholar 

  • Cardounel AJ (2007) Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem 282:879–887

    Article  CAS  PubMed  Google Scholar 

  • Churchill D, Duley L (2002) Interventionist versus expectant care for severe PE before term. Cochrane Database Syst Rev. doi:10.1002/14651858.CD003106

    Google Scholar 

  • Dastjerdi MV, Hosseini S, Bayani L (2012) Sildenafil citrate and uteroplacental perfusion in fetal growth restriction. J Res Med Sci 17:632–636

    PubMed Central  PubMed  Google Scholar 

  • Davenpeck KL, Gauthier TW, Lefer AM (1994) Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation. Gastroenterology 107:1050–1058

    CAS  PubMed  Google Scholar 

  • Demir B et al (2012) The role of homocysteine, asymmetric dimethylarginine and nitric oxide in pre-eclampsia. J Obstet Gynaecol 32:525–528

    Article  CAS  PubMed  Google Scholar 

  • Dorniak-Wall T, Grivell RM, Dekker GA, Hague W, Dodd JM (2013) The role of l-arginine in the prevention and treatment of pre-eclampsia: a systematic review of randomised trials. J Hum Hypertens 28:1–6

    Google Scholar 

  • Duley L (2009) The global impact of pre-eclampsia and eclampsia. Semin Perinatol 33:130–137

    Article  PubMed  Google Scholar 

  • Dunk C et al (2000) Angiopoietin-1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development. Am J Pathol 156:2185–2199

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ehsanipoor RM et al (2013) Nitric oxide and carbon monoxide production and metabolism in preeclampsia. Reprod Sci 20:542–548

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ellis J et al (2001) Levels of dimethylarginines and cytokines in mild and severe pre-eclampsia. Acta Obstet Gynecol Scand 80:602–608

    Article  CAS  PubMed  Google Scholar 

  • Fickling SA, Williams D, Vallance P, Nussey SS, Whitley GS (1993) Plasma concentrations of endogenous inhibitor of nitric oxide synthesis in normal pregnancy and pre-eclampsia. Lancet 342:242–243

    Article  CAS  PubMed  Google Scholar 

  • Foidart JM, Munaut C, Chantraine F, Akolekar R, Nicolaides KH (2010) Maternal plasma soluble endoglin at 11–13 weeks’ gestation in pre-eclampsia. Ultrasound Obstet Gynecol 35:680–687

    PubMed  Google Scholar 

  • Förstermann U (2006) Endothelial NO synthase as a source of NO and superoxide. Eur J Clin Pharmacol 62:5–12

    Article  CAS  Google Scholar 

  • Froen JF, Gardosi JO, Thurmann A, Francis A, Stray-Pedersen B (2004) Restricted fetal growth in sudden intrauterine unexplained death. Acta Obstet Gynecol Scand 83:801–807

    Article  PubMed  Google Scholar 

  • Gauthier TW, Scalia R, Murohara T, Guo JP, Lefer AM (1995) Nitric oxide protects against leukocyte-endothelium interactions in the early stages of hypercholesterolemia. Arterioscler Thromb Vasc Biol 15:1652–1659

    Article  CAS  PubMed  Google Scholar 

  • Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA (2001) Pathophysiology of hypertension during pre-eclampsia linking placental ischemia with endothelial dysfunction. Hypertension 38:718–722

    Article  CAS  PubMed  Google Scholar 

  • Gumus II et al (2012) The association between serum asymmetric dimethyl arginine levels and a history of gestational diabetes among healthy women. Blood Coagul Fibrinolysis 23:391–395

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T et al (1995) Estrogen increases endothelial nitric oxide by a receptor-mediated system. Biochem Biophys Res Commun 214:847–855

    Article  CAS  PubMed  Google Scholar 

  • Hecker M, Walsh DT, Vane JR (1991) On the substrate specificity of nitric oxide synthase. FEBS Lett 294:221–224

    Article  CAS  PubMed  Google Scholar 

  • Hediger M et al (1998) Growth of infants and young children born small or large for gestational age: findings from the Third National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med 152:1225–1231

    Article  CAS  PubMed  Google Scholar 

  • Holden DP, Fickling SA, Whitley GS, Nussey SS (1998) Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol 178:551–556

    Article  CAS  PubMed  Google Scholar 

  • Irgens HU, Reisaeter L, Irgens LM, Lie RT (2001) Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 323:1213–1217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Johal T, Lees CC, Everett TR, Wilkinson IB (2014) The nitric oxide pathway and possible therapeutic options in pre-eclampsia. Br J Clin Pharmacol 78:244–257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kadyrov M et al (2003) Preeclampsia and maternal anemia display reduced apoptosis and opposite invasive phenotypes of extravillous trophoblast. Placenta 24:540–548

    Article  CAS  PubMed  Google Scholar 

  • Kakui K et al (2003) Expression of nitric oxide synthase isoforms in the human placenta is not altered by labor. Endocr J 50:535–544

    Article  CAS  PubMed  Google Scholar 

  • Kalidindi M, Velauthar L, Khan K, Aquilina J (2012) The role of nitrates in the prevention of preeclampsia. Curr Opin Obstet Gynecol 24:361–367

    Article  PubMed  Google Scholar 

  • Khalil A, Jauniaux E, Cooper D, Harrington K (2009) Pulse wave analysis in normal pregnancy: a prospective longitudinal study. PLoS One 4:e6134

    Article  PubMed Central  PubMed  CAS  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 

  • Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF (2006) WHO analysis of causes of maternal death: a systematic review. Lancet 367:1066–1074

    Article  PubMed  Google Scholar 

  • Kielstein JT, Zoccali C (2005) Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis 46:186–202

    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  PubMed Central  CAS  PubMed  Google Scholar 

  • Kim YJ et al (2006) Reduced l-arginine level and decreased placental eNOS activity in pre-eclampsia. Placenta 27:438–444

    Article  CAS  PubMed  Google Scholar 

  • Laskowska M, Laskowska K, Terbosh M, Oleszczuk J (2013a) A comparison of maternal serum levels of endothelial nitric oxide synthase, asymmetric dimethylarginine, and homocysteine in normal and preeclamptic pregnancies. Med Sci Monit 19:430–437

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Laskowska M, Laskowska K, Oleszczuk J (2013b) Differences in the association between maternal serum homocysteine and ADMA levels in women with pregnancies complicated by preeclampsia and/or intrauterine growth restriction. Hypertens Pregnancy 32:83–93

    Article  CAS  PubMed  Google Scholar 

  • Lee P et al (2003) International small for gestational age advisory board consensus development conference statement: management of short children born small for gestational age. Pediatrics 111:1253–1261

    Article  PubMed  Google Scholar 

  • Levine RJ et al (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683

    Article  CAS  PubMed  Google Scholar 

  • Levine RJ, CPEP Study Group et al (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005 (Erratum in: N Engl J Med 2006; 355:1840)

    Article  CAS  PubMed  Google Scholar 

  • Lienhardt A et al (2002) Amplitude of pubertal growth in short stature children with intrauterine growth retardation. Horm Res 57(Suppl 2):88–94

    Article  CAS  PubMed  Google Scholar 

  • Lundgren E et al (2001) Intellectual and psychological performance in males born small for gestational age with and without catch-up growth. Pediatr Res 50:91–96

    Article  CAS  PubMed  Google Scholar 

  • Lyengar R, Stuehr DJ, Marletta MA (1987) Macrophage synthesis of nitrite, nitrate, and N-nitrosamines: precursors and role of the respiratory burst. Proc Natl Acad Sci USA 84:6369–6373

    Article  Google Scholar 

  • Maas R et al (2004) Plasma concentrations of asymmetric dimethylarginine (ADMA) in Colombian women with pre-eclampsia. JAMA 291:823–824

    Article  CAS  PubMed  Google Scholar 

  • MacKay AP, Berg CJ, Atrash HK (2001) Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol 97:533–538

    Article  CAS  PubMed  Google Scholar 

  • Mandruzzato G et al (2008) Intrauterine restriction (IUGR). J Perinat Med 36:277–281

    Article  PubMed  Google Scholar 

  • Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N (2009) The Cost of preterm birth throughout childhood in England and Wales. Pediatrics 123:e312–e317

    Article  PubMed  Google Scholar 

  • Mao D et al (2010) Association of homocysteine, asymmetric dimethylarginine, and nitric oxide with pre-eclampsia. Arch Gynecol Obstet 282:371–375

    Article  CAS  PubMed  Google Scholar 

  • Martens-Lobenhoffer J, Bode-Böger SM (2012) Quantification of l-arginine, asymmetric dimethylarginine and symmetric dimethylarginine in human plasma: a step improvement in precision by stable isotope dilution mass spectrometry. J Chromatogr B 904:140–143

    Article  CAS  Google Scholar 

  • Matsubara K, Abe E, Ochi H, Kusanagi Y, Ito M (2003) Changes in serum concentrations of tumor necrosis factor α and adhesion molecules in normal pregnant women and those with pregnancy-induced hypertension. J. Obstet Gynaecol Res 29:422–426

    Article  CAS  PubMed  Google Scholar 

  • Matsubara K, Matsubara Y, Hyodo S, Katayama T, Ito M (2010) Role of nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. J Obstet Gynaecol Res 36:239–247

    Article  CAS  PubMed  Google Scholar 

  • Meher S, Duley L (2007) Nitric oxide for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 18(2):CD006490

    Google Scholar 

  • Mittermayer F et al (2002) Circulating concentrations of asymmetrical dimethyl l-arginine are increased in women with previous gestational diabetes. Diabetes 45:1372–1378

    CAS  Google Scholar 

  • Molnar M et al (1994) Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation. Am J Obstet Gynecol 170:1458–1466

    Article  CAS  PubMed  Google Scholar 

  • Morales-Roselló J et al (2014) Changes in fetal Doppler indices as a marker of failure to reach growth potential at term. Ultrasound Obstet Gynecol 43:303–310

    Article  PubMed  Google Scholar 

  • Myatt L, Brewer AS, Langdon G, Brockman DE (1992) Attenuation of the vasoconstrictor effects of thromboxane and endothelin by nitric oxide in the human fetal-placental circulation. Am J Obstet Gynecol 166:224–230

    Article  CAS  PubMed  Google Scholar 

  • Myatt L et al (1997a) Inducible (type II) nitric oxide synthase in human placental villous tissue of normotensive, preeclamptic and intrauterine growth-restricted pregnancy. Placenta 18:261–265

    Article  CAS  PubMed  Google Scholar 

  • Myatt L, Eis AL, Brockman DE, Greer IA, Lyall F (1997b) Endothelial nitric oxide synthase in placental villous tissue from normal, pre-eclamptic and intrauterine growth restricted pregnancies. Hum Reprod 12:167–172

    Article  CAS  PubMed  Google Scholar 

  • Neri I et al (2006) Effect of L-arginine on blood pressure in pregnancy-induced hypertension: a randomized placebo-controlled trial. J Matern Fetal Neonatal Med 19:277–281

    Article  CAS  PubMed  Google Scholar 

  • Nevzati E et al (2015) Estrogen induces nitric oxide production via nitric oxide synthase activation in endothelial cells. Acta Neurochir Suppl 120:141–145

    PubMed  Google Scholar 

  • Noris MI et al (2004) l-arginine depletion in preeclampsia orients nitric oxide synthase toward oxidant species. Hypertension 43:614–622

    Article  CAS  PubMed  Google Scholar 

  • Noris M, Perico N, Remuzzi G (2005) Mechanisms of disease: pre-eclampsia. Nat Clin Prac Nephrol 1:98–114 quiz 120

    Article  CAS  Google Scholar 

  • Pallotto EK, Kilbride HW (2006) Perinatal outcome and later implications of intrauterine growth restriction. Clin Obstet Gynecol 49:257–269

    Article  PubMed  Google Scholar 

  • Pettersson A, Hedner T, Milsom I (1998) Increased circulating concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in pre-eclampsia. Acta Obstet Gynecol Scand 77:808–813

    Article  CAS  PubMed  Google Scholar 

  • Pimentel AM et al (2013) l-arginine-nitric oxide pathway and oxidative stress in plasma and platelets of patients with pre-eclampsia. Hypertens Res 36:783–788

    Article  CAS  PubMed  Google Scholar 

  • Powers RW (2008) Elevated asymmetric dimethylarginine concentrations precede clinical pre-eclampsia, but not pregnancies with small-for-gestational-age infants. Am J Obstet Gynecol 198:112.e1–117.e1

    Article  CAS  Google Scholar 

  • Raw A, Gallaher M, Powers RW (2014) Arginine and Asymmetric Dimethylarginine in pregnant women with major depression. Psychosom Med 76:430–436

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA (2005) Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 366:1797–1803

    Article  PubMed  Google Scholar 

  • Redman CWG (1991) Pre-eclampsia and the placenta. Placenta 12:301–308

    Article  CAS  PubMed  Google Scholar 

  • Refuerzo J et al (2006) Sildenafil citrate and fetal outcome in pregnant rats. Fetal Diagn Ther 21:259–263

    Article  PubMed  Google Scholar 

  • Richardus JH, Graafmans WC, Verloove-Vanhorick SP, Mackenbach JP (2003) Differences in perinatal mortality and suboptimal care between 10 European regions: results of an international audit. Br J Obstet Gynaecol 110:97–105

    Article  Google Scholar 

  • Rizos D et al (2012) Levels of asymmetric dimethylarginine throughout normal pregnancy and in pregnancies complicated with preeclampsia or had a small for gestational age baby. J Matern Fetal Neonatal Med 25:1311–1315

    Article  CAS  PubMed  Google Scholar 

  • Roberts JM, Redman CW (1993) Pre-eclampsia: more than pregnancy-induced hypertension. Lancet 341:1447–1451

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Aparicio P et al (2008) Effects of sildenafil on the fetal growth of guinea pigs and their ability to survive induced intrapartum asphyxia. Am J Obstet Gynaecol 198:127.e1–127.e6

    Article  CAS  Google Scholar 

  • Sandrim VC et al (2008) Nitric oxide formation is inversely related to serum levels of antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia. Hypertension 52:402–407

    Article  CAS  PubMed  Google Scholar 

  • Sandrim VC et al (2010a) Interethnic differences in ADMA concentrations and negative association with nitric oxide formation in preeclampsia. Clin Chim Acta 411:1457–1460

    Article  CAS  PubMed  Google Scholar 

  • Sandrim VC et al (2010b) Increased circulating cell-free hemoglobin levels reduce nitric oxide bioavailability in preeclampsia. Free Radic Biol Med 49:493–500

    Article  CAS  PubMed  Google Scholar 

  • Sandrim VC et al (2011) Alterations in cyclic GMP levels in preeclampsia may reflect increased B-type natriuretic peptide levels and not impaired nitric oxide activity. Clin Biochem 44:1012–1014

    Article  CAS  PubMed  Google Scholar 

  • Sandvik MK et al (2013) Preeclampsia in healthy women and endothelial dysfunction 10 years later. Am J Obstet Gynecol 209:569.e1–569.e10

    Article  Google Scholar 

  • Santibanez JF et al (2007) Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. J Cell Physiol 210:456–468

    Article  CAS  PubMed  Google Scholar 

  • Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P (1990) Inhibition of endothelium-derived relaxing factor in the pathogenesis of pre-eclampsia. Lancet 336:1030–1032

    Article  CAS  PubMed  Google Scholar 

  • Satterfield MC, Bazer FW, Spencer TE, Wu G (2010) Sildenafil citrate treatment enhances amino acid availability in the conceptus and fetal growth in an ovine model of intrauterine growth restriction. J Nutr 140:251–258

    Article  CAS  PubMed  Google Scholar 

  • Savvidis A et al (2011) Correlation between asymmetric dimethylarginine maternal plasma levels and preeclampsia. Clin Exp Obstet Gynecol 38:134–136

    CAS  PubMed  Google Scholar 

  • Savvidou MD et al (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 

  • Schwedhelm E (2005) Quantification of ADMA: analytical approaches. Vasc Med 10(Suppl 1):S89–S95

    Article  PubMed  Google Scholar 

  • Sibai BM, Stella CL (2009) Diagnosis and management of atypical preeclampsia-eclampsia. Am J Obstet Gynecol 200:481.e1–481.e7

    Article  Google Scholar 

  • Siroen MP et al (2006) No compensatory upregulation of placental dimethylarginine dimethylaminohydrolase activity in preeclampsia. Gynecol Obstet Invest 62:7–13

    Article  CAS  PubMed  Google Scholar 

  • Sladek SM, Magness RR, Conrad KP (1997) Nitric oxide and pregnancy. Am J Physiol 272:R441–R463

    CAS  PubMed  Google Scholar 

  • Smith GC, Pell JP, Walsh D (2001) Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 1,29,290 births. Lancet 357:2002–2006

    Article  CAS  PubMed  Google Scholar 

  • Speer PD et al (2008) Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants. Am J Obstet Gynecol 198:112–117

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Stanley J et al (2012) Sildenafil citrate rescues fetal growth in the catechol-O-methyl transferase knockout mouse model. Hypertension 59:1021–1028

    Article  CAS  PubMed  Google Scholar 

  • Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R (2010) Pre-eclampsia. Lancet 376:631–644

    Article  PubMed  Google Scholar 

  • Stein C et al (1996) Fetal growth and coronary heart disease in south india. Lancet 348:1269–1273

    Article  CAS  PubMed  Google Scholar 

  • Strauss R (2000) Adult functional outcome of those born small for gestational age: twenty-six-year follow-up of the 1970 British Birth Cohort. JAMA 283:625–632

    Article  CAS  PubMed  Google Scholar 

  • Sung IK, Vohr B, Oh W (1991) Growth and neurodevelopmental outcome of very low birth weight infants with intrauterine growth retardation: comparison with control subjects matched by birth weight and gestational age. J Pediatr 123:618–624

    Article  Google Scholar 

  • Szarka A, Rigó J, Lázár L, Beko G, Molvarec A (2010) Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and pre-eclampsia determined by multiplex suspension array. BMC Immunol 11:59

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Telejko B et al (2009) Circulating asymmetric dimethylarginine, endothelin-1 and cell adhesion molecules in women with gestational diabetes. Acta Diabetol 46:303–308

    Article  CAS  PubMed  Google Scholar 

  • Ten Dijke P, Goumans MJ, Pardali E (2008) Endoglin in angiogenesis and vascular diseases. Angiogenesis 11:79–89

    Article  CAS  PubMed  Google Scholar 

  • Toporsian M et al (2005) A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ Res 96:684–692

    Article  CAS  PubMed  Google Scholar 

  • Tsikas D (2008) Determination of asymmetric dimethylarginine in biological fluids: a paradigm for a successful analytical story. Curr Opin Clin Nutr Metab Care 11:592–600

    Article  CAS  PubMed  Google Scholar 

  • Tsikas D et al (2000a) Assessment of nitric oxide synthase activity in vitro and in vivo by gas chromatography-mass spectrometry. J Chromatogr B Biomed Sci Appl 742:143–153

    Article  CAS  PubMed  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 

  • Turan F, Ilhan N, Kaman D, Ateş K, Kafkasli A (2010) Glu298Asp polymorphism of the endothelial nitric oxide synthase gene and plasma concentrations of asymmetric dimethylarginine in Turkish pre-eclamptic women without fetal growth retardation. J Obstet Gynaecol Res 36:495–501

    Article  CAS  PubMed  Google Scholar 

  • Vadillo-Ortega F et al (2011) Effect of supplementation during pregnancy with l-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. BMJ (Clin Res Ed) 342:d2901

    Article  Google Scholar 

  • Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of NO synthesis in chronic renal failure. Lancet 339:572–575

    Article  CAS  PubMed  Google Scholar 

  • Valtonen P et al (2008) Serum l-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. Circ J 72:1879–1884

    Article  CAS  PubMed  Google Scholar 

  • Venkatesha S et al (2006) Soluble endoglin contributes to the pathogenesis of pre- eclampsia. Nat Med 12:642–649

    Article  CAS  PubMed  Google Scholar 

  • von Dadelszen P, Magee LA, Roberts J (2003) Subclassification of pre-eclampsia. Hypertens Pregnancy 22:143–148

    Article  Google Scholar 

  • von Dadelszen P, Menzies JM, Payne B, PIERS (PEIntegrated Estimate of RiSk) Study Group (2009) Predicting adverse outcomes in women with severe pre-eclampsia. Semin Perinatol 33:152–157

    Article  Google Scholar 

  • Von Dadelszen P et al (2011) Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. Br J Obstet Gynaecol 118:624–628

    Article  CAS  Google Scholar 

  • Wareing M et al (2005) Sildenafil citrate (viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab 90:2550–2555

    Article  CAS  PubMed  Google Scholar 

  • World Health Organization (2005) Make every mother and child count. world health report, 2005. World Health Organization, Geneva

    Google Scholar 

  • Xia W et al (2015) Asymmetric dimethylarginine is associated with high-sensitivity C-reactive protein and early carotid atherosclerosis in women with previous gestational diabetes mellitus. Endocrine 48:528–532

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y et al (1997) Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest 99:2139–2151

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhu Y, Evans MI (2001) Estrogen modulates the expression of l-arginine:glycine amidinotransferase in chick liver. Mol Cell Biochem 221:139–145

    Article  CAS  PubMed  Google Scholar 

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None of the authors has any conflict of interest.

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All studies reported here were approved by the local ethics committees.

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Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, St. George’s Hospital, St.George’s Healthcare NHS Trust, Blackshaw Road, Tooting, London, SW17 OQT, UK

    Asma Khalil & Lotte Hardman

  2. Institute for Women’s Health, University College London, London, NW1 2PG, UK

    Pat O´Brien

Authors
  1. Asma Khalil
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  2. Lotte Hardman
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  3. Pat O´Brien
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Correspondence to Asma Khalil.

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Khalil, A., Hardman, L. & O´Brien, P. The role of arginine, homoarginine and nitric oxide in pregnancy. Amino Acids 47, 1715–1727 (2015). https://doi.org/10.1007/s00726-015-2014-1

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  • DOI: https://doi.org/10.1007/s00726-015-2014-1

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