天然化合物S-烯丙基-L-半胱氨酸治疗子痫前期的相关研究
|
摘要
【目的】
先兆子痫（Preeclampsia, PE）是造成胎儿生长受限及围产儿死亡的重要原因。氧化应激和血管扩张调控系统紊乱是PE的主要发病机制。S烯丙基L半胱氨酸（S allyl L cysteine, SAC）是大蒜提取物中最丰富的化合物之一，具有多种生物活性。本研究主要探讨SAC对胎盘组织中重要的内源性血管舒张调控信号通路——NO/cGMP信号通路的影响，及氧化应激状态下SAC对该信号通路的作用。
【方法】
采用体外培养人早孕绒毛滋养细胞株（TEV1细胞）和胎盘绒毛组织的方法检测SAC的作用。TEV1细胞和人胎盘绒毛组织分成以下各组：SAC干预组，H2O2干预组，H2O2+SAC联合干预组。通过流式细胞仪检测细胞内ROS水平，并采用硝酸还原酶法检测NO分泌量，放射免疫分析法测定cGMP水平，免疫组化和Western blot法检测TEV1细胞中eNOS的表达。
【结果】
研究结果显示，H2O2干预增加TEV1细胞中ROS的产生，且显著降低TEV1细胞和胎盘绒毛组织中的NO和cGMP水平，与对照组相比差异具有统计学意义（p<0.05）。H2O2干预组相比对照组，TEV1细胞eNOS表达也显著下降（p<0.05）。H2O2+SAC联合干预组相比H2O2干预组，ROS的量明显减少，且NO、cGMP和eNOS的水平明显高于H2O2干预组（p<0.05），与对照组水平无显著差异。此外，在非氧化应激状态下，SAC干预可呈剂量依赖性的增加TEV1细胞和胎盘绒毛组织中的NO和cGMP水平（p<0.05），而eNOS表达水平无显著改变。当TEV1细胞在eNOS抑制剂（L NAME）和NO供体（Sodium nitroprusside，SNP）共同存在的条件下培养时，SAC干预仍然能增加NO水平，且差异有统计学意义（p<0.05）。
【结论】
本研究结果表明在非氧化应激状态下SAC能增加TEV1细胞和胎盘绒毛组织中NO和cGMP水平；且SAC可抵御H2O2诱导产生的氧化应激对NO/cGMP信号通路的损害作用；提示SAC具有治疗PE的潜在作用。
Objective
Preeclampsia (PE) is a major cause of fetal growth restriction and perinatal mortality,which involves oxidative stress and vasodilator signaling disorder. S allyl L cysteine (SAC)is one of the most abundant compounds in garlic extracts, and possesses several biologicalactivities. This research was designed to investigate the effects of SAC on the NO/cGMPsignaling pathway in placenta, as well as the protective effects of SAC againstH2O2induced oxidative insults to the pathway.
Method
TEV1cells and placental explants were used to detect the effects of SAC. TEV1cells and human placental explants were separately exposed to SAC, H2O2, or acombination of H2O2and SAC. Intracellular ROS was detected by flow cytometry; the NOlevel was detected, and the cGMP level was simultaneously measured by the method ofradioimmunoassay; the expression of eNOS in TEV1cells was measured byimmunochemistry and Western blot.
Result
The results showed that H2O2treatment increased ROS production in TEV1cells andsignificantly decreased NO and cGMP levels either in TEV1cells or placental explantscompared to the control groups (p<0.05). The expression of eNOS in TEV1cells alsosignificantly decreased in H2O2treated group compared to the control group (p<0.05).Co treatment of H2O2and SAC significantly decreased ROS productions, and increasedNO, cGMP and eNOS levels compared to the H2O2treated alone groups (p<0.05), whichwere all reverted back to near control levels. Further more, SAC treatment increased NOand cGMP levels of TEV1cells and placental explants in a dose dependent manner even atnon oxidative stress status (p<0.05). However, when the TEV1cells were cultured in thepresence of eNOS inhibitor (L NAME) and NO donor (SNP), additional SAC treatmentstill significantly increased the NO level in comparison with SAC non treated group(p<0.05).
Conclusion
In conclusion, these results demonstrate that oxidative stress (H2O2mediated) caninduce insults to NO/cGMP pathway, while SAC could antagonize these insults. And SACalso possesses the ability to increase NO and cGMP levels at non oxidative stress status inTEV1cells and placenta explants. SAC is therefore hypothesized to be a potential drug forPE treatment.
先兆子痫（Preeclampsia, PE）是造成胎儿生长受限及围产儿死亡的重要原因。氧化应激和血管扩张调控系统紊乱是PE的主要发病机制。S烯丙基L半胱氨酸（S allyl L cysteine, SAC）是大蒜提取物中最丰富的化合物之一，具有多种生物活性。本研究主要探讨SAC对胎盘组织中重要的内源性血管舒张调控信号通路——NO/cGMP信号通路的影响，及氧化应激状态下SAC对该信号通路的作用。
【方法】
采用体外培养人早孕绒毛滋养细胞株（TEV1细胞）和胎盘绒毛组织的方法检测SAC的作用。TEV1细胞和人胎盘绒毛组织分成以下各组：SAC干预组，H2O2干预组，H2O2+SAC联合干预组。通过流式细胞仪检测细胞内ROS水平，并采用硝酸还原酶法检测NO分泌量，放射免疫分析法测定cGMP水平，免疫组化和Western blot法检测TEV1细胞中eNOS的表达。
【结果】
研究结果显示，H2O2干预增加TEV1细胞中ROS的产生，且显著降低TEV1细胞和胎盘绒毛组织中的NO和cGMP水平，与对照组相比差异具有统计学意义（p<0.05）。H2O2干预组相比对照组，TEV1细胞eNOS表达也显著下降（p<0.05）。H2O2+SAC联合干预组相比H2O2干预组，ROS的量明显减少，且NO、cGMP和eNOS的水平明显高于H2O2干预组（p<0.05），与对照组水平无显著差异。此外，在非氧化应激状态下，SAC干预可呈剂量依赖性的增加TEV1细胞和胎盘绒毛组织中的NO和cGMP水平（p<0.05），而eNOS表达水平无显著改变。当TEV1细胞在eNOS抑制剂（L NAME）和NO供体（Sodium nitroprusside，SNP）共同存在的条件下培养时，SAC干预仍然能增加NO水平，且差异有统计学意义（p<0.05）。
【结论】
本研究结果表明在非氧化应激状态下SAC能增加TEV1细胞和胎盘绒毛组织中NO和cGMP水平；且SAC可抵御H2O2诱导产生的氧化应激对NO/cGMP信号通路的损害作用；提示SAC具有治疗PE的潜在作用。
Objective
Preeclampsia (PE) is a major cause of fetal growth restriction and perinatal mortality,which involves oxidative stress and vasodilator signaling disorder. S allyl L cysteine (SAC)is one of the most abundant compounds in garlic extracts, and possesses several biologicalactivities. This research was designed to investigate the effects of SAC on the NO/cGMPsignaling pathway in placenta, as well as the protective effects of SAC againstH2O2induced oxidative insults to the pathway.
Method
TEV1cells and placental explants were used to detect the effects of SAC. TEV1cells and human placental explants were separately exposed to SAC, H2O2, or acombination of H2O2and SAC. Intracellular ROS was detected by flow cytometry; the NOlevel was detected, and the cGMP level was simultaneously measured by the method ofradioimmunoassay; the expression of eNOS in TEV1cells was measured byimmunochemistry and Western blot.
Result
The results showed that H2O2treatment increased ROS production in TEV1cells andsignificantly decreased NO and cGMP levels either in TEV1cells or placental explantscompared to the control groups (p<0.05). The expression of eNOS in TEV1cells alsosignificantly decreased in H2O2treated group compared to the control group (p<0.05).Co treatment of H2O2and SAC significantly decreased ROS productions, and increasedNO, cGMP and eNOS levels compared to the H2O2treated alone groups (p<0.05), whichwere all reverted back to near control levels. Further more, SAC treatment increased NOand cGMP levels of TEV1cells and placental explants in a dose dependent manner even atnon oxidative stress status (p<0.05). However, when the TEV1cells were cultured in thepresence of eNOS inhibitor (L NAME) and NO donor (SNP), additional SAC treatmentstill significantly increased the NO level in comparison with SAC non treated group(p<0.05).
Conclusion
In conclusion, these results demonstrate that oxidative stress (H2O2mediated) caninduce insults to NO/cGMP pathway, while SAC could antagonize these insults. And SACalso possesses the ability to increase NO and cGMP levels at non oxidative stress status inTEV1cells and placenta explants. SAC is therefore hypothesized to be a potential drug forPE treatment.
引文
1. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternalendothelium: the role of antiangiogenic factors and implications for later cardiovasculardisease. Circulation2011;123:28562869.
2. Myatt L. Review: Reactive oxygen and nitrogen species and functional adaptation ofthe placenta. Placenta2010;31Suppl:S6669.
3. Pollheimer J, Knofler M. The role of the invasive, placental trophoblast in humanpregnancy. Wien Med Wochenschr2012;162:187190.
4. Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. JSoc Gynecol Investig2004;11:342352.
5. Pijnenborg R, Vercruysse L, Carter AM. Deep trophoblast invasion and spiral arteryremodelling in the placental bed of the lowland gorilla. Placenta2011;32:586591.
6. Mandala M, Osol G. Physiological remodelling of the maternal uterine circulationduring pregnancy. Basic Clin Pharmacol Toxicol2012;110:1218.
7. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre eclampsia. Lancet2010;376:631644.
8. Chen JZ, Sheehan PM, Brennecke SP, Keogh RJ. Vessel remodelling, pregnancyhormones and extravillous trophoblast function. Mol Cell Endocrinol2012;349:138144.
9. Friebe A, Koesling D. The function of NO sensitive guanylyl cyclase: what we canlearn from genetic mouse models. Nitric Oxide2009;21:149156.
10. Boger RH, Diemert A, Schwedhelm E, Luneburg N, Maas R, Hecher K. The role ofnitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiologyof preeclampsia. Gynecol Obstet Invest2010;69:113.
11. Gao Y. The multiple actions of NO. Pflugers Arch2010;459:829839.
12. Valdes G, Corthorn J. Review: The angiogenic and vasodilatory utero placentalnetwork. Placenta2011;32Suppl2:S170175.
13. Krause BJ, Hanson MA, Casanello P. Role of nitric oxide in placental vasculardevelopment and function. Placenta2011;32:797805.
14. Groesch KA, Torry RJ, Wilber AC, Abrams R, Bieniarz A, Guilbert LJ, Torry DS.Nitric oxide generation affects pro and anti angiogenic growth factor expression inprimary human trophoblast. Placenta2011;32:926931.
15. Boeldt DS, Yi FX, Bird IM. eNOS activation and NO function: pregnancy adaptiveprogramming of capacitative entry responses alters nitric oxide (NO) output in vascularendothelium new insights into eNOS regulation through adaptive cell signaling. JEndocrinol2011;210:243258.
16. Ehsanipoor RM, Fortson W, Fitzmaurice LE, Liao WX, Wing DA, Chen DB, Chan K.Nitric Oxide and Carbon Monoxide Production and Metabolism in Preeclampsia.Reprod Sci2012.
17. Demir B, Demir S, Pasa S, Guven S, Atamer Y, Atamer A, Kocyigit Y. The role ofhomocysteine, asymmetric dimethylarginine and nitric oxide in pre eclampsia. J ObstetGynaecol2012;32:525528.
18. Ramesar SV, Drewes SE, Gathiram P, Moodley J, Mackraj I. The effect ofKraussianone2(Kr2), a natural pyrano isoflavone from Eriosema kraussianum, in anL NAME induced pre eclamptic rat model. Phytother Res2012;26:13751380.
19. Murphy SR, LaMarca B, Cockrell K, Arany M, Granger JP. L arginine supplementationabolishes the blood pressure and endothelin response to chronic increases in plasmasFlt1in pregnant rats. Am J Physiol Regul Integr Comp Physiol2012;302:R259263.
20. Howlader MZ, Parveen S, Tamanna S, Khan TA, Begum F. Oxidative stress andantioxidant status in neonates born to pre eclamptic mother. J Trop Pediatr2009;55:363367.
21. Clerici G, Slavescu C, Fiengo S, Kanninen TT, Romanelli M, Biondi R, Di Renzo GC.Oxidative stress in pathological pregnancies. J Obstet Gynaecol2012;32:124127.
22. Gohil JT, Patel PK, Gupta P. Evaluation of oxidative stress and antioxidant defence insubjects of preeclampsia. J Obstet Gynaecol India2011;61:638640.
23. Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol2011;25:287299.
24. Siddiqui IA, Jaleel A, Tamimi W, Al Kadri HM. Role of oxidative stress in thepathogenesis of preeclampsia. Arch Gynecol Obstet2010;282:469474.
25. Aris A, Benali S, Ouellet A, Moutquin JM, Leblanc S. Potential biomarkers ofpreeclampsia: inverse correlation between hydrogen peroxide and nitric oxide early inmaternal circulation and at term in placenta of women with preeclampsia. Placenta2009;30:342347.
26. Farrow KN, Lakshminrusimha S, Reda WJ, Wedgwood S, Czech L, Gugino SF, DavisJM, et al. Superoxide dismutase restores eNOS expression and function in resistancepulmonary arteries from neonatal lambs with persistent pulmonary hypertension. Am JPhysiol Lung Cell Mol Physiol2008;295:L979987.
27. Poniedzialek Czajkowska E, Marciniak B, Kimber Trojnar Z, Leszczynska Gorzelak B,Oleszczuk J. Nitric oxide in normal and preeclamptic pregnancy. Curr PharmBiotechnol2011;12:743749.
28. Duley L, Gulmezoglu AM, Henderson Smart DJ, Chou D. Magnesium sulphate andother anticonvulsants for women with pre eclampsia. Cochrane Database Syst Rev2010:CD000025.
29. Magee LA, Abalos E, von Dadelszen P, Sibai B, Easterling T, Walkinshaw S. How tomanage hypertension in pregnancy effectively. Br J Clin Pharmacol2011;72:394401.
30. Mert I, Oruc AS, Yuksel S, Cakar ES, Buyukkagnici U, Karaer A, Danisman N. Role ofoxidative stress in preeclampsia and intrauterine growth restriction. J Obstet GynaecolRes2012;38:658664.
31. Rahman K. Studies on free radicals, antioxidants, and co factors. Clin Interv Aging2007;2:219236.
32. Wibowo N, Purwosunu Y, Sekizawa A, Farina A, Idriansyah L, Fitriana I. Antioxidantsupplementation in pregnant women with low antioxidant status. J Obstet GynaecolRes2012;38:11521161.
33. Chen Q, Jones D, Stone P, Ching LM, Chamley L. Vitamin C enhances phagocytosis ofnecrotic trophoblasts by endothelial cells and protects the phagocytosing endothelialcells from activation. Placenta2009;30:163168.
34. Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, et al.eNOS deficiency acts through endothelin to aggravate sFlt1inducedpre eclampsia like phenotype. J Am Soc Nephrol2012;23:652660.
35. Gui S, Jia J, Niu X, Bai Y, Zou H, Deng J, Zhou R. Arginine supplementation forimproving maternal and neonatal outcomes in hypertensive disorder of pregnancy: Asystematic review. J Renin Angiotensin Aldosterone Syst2013.
36. Vadillo Ortega F, Perichart Perera O, Espino S, Avila Vergara MA, Ibarra I, Ahued R,Godines M, et al. Effect of supplementation during pregnancy with L arginine andantioxidant vitamins in medical food on pre eclampsia in high risk population:randomised controlled trial. BMJ2011;342:d2901.
37. Korokin MV, Pokrovsky MV, Novikov OO, Gureev VV, Denisyuk TA, Korokina LV,Polyanskaya OS, et al. Effect of L arginine, vitamin B6and folic acid on parameters ofendothelial dysfunction and microcirculation in the placenta in modeling ofL NAME induced NO deficiency. Bull Exp Biol Med2011;152:7072.
38. Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy.Oxid Med Cell Longev2011;2011:841749.
39. Reinhart KM, Coleman CI, Teevan C, Vachhani P, White CM. Effects of garlic onblood pressure in patients with and without systolic hypertension: a meta analysis. AnnPharmacother2008;42:17661771.
40. Ried K, Frank OR, Stocks NP, Fakler P, Sullivan T. Effect of garlic on blood pressure: asystematic review and meta analysis. BMC Cardiovasc Disord2008;8:13.
41. McInnes GT. Lowering blood pressure for cardiovascular risk reduction. J HypertensSuppl2005;23:S38.
42. Lawson LD, Gardner CD. Composition, stability, and bioavailability of garlic productsused in a clinical trial. J Agric Food Chem2005;53:62546261.
43. Ried K, Frank OR, Stocks NP. Aged garlic extract lowers blood pressure in patientswith treated but uncontrolled hypertension: a randomised controlled trial. Maturitas2010;67:144150.
44. Asdaq SM, Inamdar MN. Potential of garlic and its active constituent, S allyl cysteine,as antihypertensive and cardioprotective in presence of captopril. Phytomedicine2010;17:10161026.
45. Al Qattan KK, Thomson M, Al Mutawa'a S, Al Hajeri D, Drobiova H, Ali M. Nitricoxide mediates the blood pressure lowering effect of garlic in the rat two kidney,one clip model of hypertension. J Nutr2006;136:774S776S.
46. Kim KM, Chun SB, Koo MS, Choi WJ, Kim TW, Kwon YG, Chung HT, et al.Differential regulation of NO availability from macrophages and endothelial cells bythe garlic component S allyl cysteine. Free Radic Biol Med2001;30:747756.
47. Maldonado PD, Alvarez Idaboy JR, Aguilar Gonzalez A, Lira Rocha A, Jung Cook H,Medina Campos ON, Pedraza Chaverri J, et al. Role of allyl group in the hydroxyl andperoxyl radical scavenging activity of S allylcysteine. J Phys Chem B2011;115:1340813417.
48. Padmanabhan M, Prince PS. Preventive effect of S allylcysteine on lipid peroxides andantioxidants in normal and isoproterenol induced cardiotoxicity in rats: ahistopathological study. Toxicology2006;224:128137.
49. Saravanan G, Ponmurugan P. Beneficial effect of S allylcysteine (SAC) on bloodglucose and pancreatic antioxidant system in streptozotocin diabetic rats. Plant FoodsHum Nutr2010;65:374378.
50. Atif F, Yousuf S, Agrawal SK. S allyl L cysteine diminishes cerebral ischemia inducedmitochondrial dysfunctions in hippocampus. Brain Res2009;1265:128137.
51. Segoviano Murillo S, Sanchez Gonzalez DJ, Martinez Martinez CM, Cruz C,Maldonado PD, Pedraza Chaverri J. S allylcysteine ameliorates ischemia andreperfusion induced renal damage. Phytother Res2008;22:836840.
1. Drose S, Brandt U. Molecular mechanisms of superoxide production by themitochondrial respiratory chain. Adv Exp Med Biol2012;748:145169.
2. Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol2011;25:287299.
3. Demir B, Demir S, Atamer Y, Guven S, Atamer A, Kocyigit Y, Hekimoglu A, et al.Serum levels of lipids, lipoproteins and paraoxonase activity in pre eclampsia. J IntMed Res2011;39:14271431.
4. Mihu D, Sabau L, Costin N, Ciortea R, Malutan A, Mihu CM. Implications of maternalsystemic oxidative stress in normal pregnancy and in pregnancy complicated bypreeclampsia. J Matern Fetal Neonatal Med2012;25:944951.
5. Boij R, Svensson J, Nilsson Ekdahl K, Sandholm K, Lindahl TL, Palonek E, Garle M,et al. Biomarkers of coagulation, inflammation, and angiogenesis are independentlyassociated with preeclampsia. Am J Reprod Immunol2012;68:258270.
6. Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced inflammatory andregulatory cytokines in pregnancy and the etiology of preeclampsia. SeminImmunopathol2007;29:151162.
7. Lamarca B. The role of immune activation in contributing to vascular dysfunction andthe pathophysiology of hypertension during preeclampsia. Minerva Ginecol2010;62:105120.
8. Ong SS, Baker PN, Mayhew TM, Dunn WR. Remodeling of myometrial radial arteriesin preeclampsia. Am J Obstet Gynecol2005;192:572579.
9. Hung TH, Skepper JN, Burton GJ. In vitro ischemia reperfusion injury in term humanplacenta as a model for oxidative stress in pathological pregnancies. Am J Pathol2001;159:10311043.
10. Redman CW, Sargent IL. Placental stress and pre eclampsia: a revised view. Placenta2009;30Suppl A:S3842.
11. Lee SM, Romero R, Lee YJ, Park IS, Park CW, Yoon BH. Systemic inflammatorystimulation by microparticles derived from hypoxic trophoblast as a model forinflammatory response in preeclampsia. Am J Obstet Gynecol2012;207:337e331338.
12. Zavalza Gomez AB. Obesity and oxidative stress: a direct link to preeclampsia? ArchGynecol Obstet2011;283:415422.
13. Aris A, Benali S, Ouellet A, Moutquin JM, Leblanc S. Potential biomarkers ofpreeclampsia: inverse correlation between hydrogen peroxide and nitric oxide early inmaternal circulation and at term in placenta of women with preeclampsia. Placenta2009;30:342347.
14. Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy.Oxid Med Cell Longev2011;2011:841749.
15. Kodera Y, Suzuki A, Imada O, Kasuga S, Sumioka I, Kanezawa A, Taru N, et al.Physical, chemical, and biological properties of s allylcysteine, an amino acid derivedfrom garlic. J Agric Food Chem2002;50:622632.
16. Amagase H, Petesch BL, Matsuura H, Kasuga S, Itakura Y. Intake of garlic and itsbioactive components. J Nutr2001;131:955S962S.
17. Medina Campos ON, Barrera D, Segoviano Murillo S, Rocha D, Maldonado PD,Mendoza Patino N, Pedraza Chaverri J. S allylcysteine scavenges singlet oxygen andhypochlorous acid and protects LLC PK(1) cells of potassium dichromate inducedtoxicity. Food Chem Toxicol2007;45:20302039.
18. Chung LY. The antioxidant properties of garlic compounds: allyl cysteine, alliin, allicin,and allyl disulfide. J Med Food2006;9:205213.
19. Kim JM, Lee JC, Chang N, Chun HS, Kim WK. S Allyl L cysteine attenuates cerebralischemic injury by scavenging peroxynitrite and inhibiting the activity of extracellularsignal regulated kinase. Free Radic Res2006;40:827835.
20. Maldonado PD, Alvarez Idaboy JR, Aguilar Gonzalez A, Lira Rocha A, Jung Cook H,Medina Campos ON, Pedraza Chaverri J, et al. Role of allyl group in the hydroxyl andperoxyl radical scavenging activity of S allylcysteine. J Phys Chem B2011;115:1340813417.
21. Ho SE, Ide N, Lau BH. S allyl cysteine reduces oxidant load in cells involved in theatherogenic process. Phytomedicine2001;8:3946.
22. Kalayarasan S, Sriram N, Sureshkumar A, Sudhandiran G. Chromium (VI) inducedoxidative stress and apoptosis is reduced by garlic and its derivative S allylcysteinethrough the activation of Nrf2in the hepatocytes of Wistar rats. J Appl Toxicol2008;28:908919.
23. Cindrova Davies T, Spasic Boskovic O, Jauniaux E, Charnock Jones DS, Burton GJ.Nuclear factor kappa B, p38, and stress activated protein kinase mitogen activatedprotein kinase signaling pathways regulate proinflammatory cytokines and apoptosis inhuman placental explants in response to oxidative stress: effects of antioxidant vitamins.Am J Pathol2007;170:15111520.
24. Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM. Periconceptional multivitaminuse reduces the risk of preeclampsia. Am J Epidemiol2006;164:470477.
25. Catov JM, Nohr EA, Bodnar LM, Knudson VK, Olsen SF, Olsen J. Association ofpericonceptional multivitamin use with reduced risk of preeclampsia amongnormal weight women in the Danish National Birth Cohort. Am J Epidemiol2009;169:13041311.
26. Klemmensen A, Tabor A, Osterdal ML, Knudsen VK, Halldorsson TI, Mikkelsen TB,Olsen SF. Intake of vitamin C and E in pregnancy and risk of pre eclampsia:prospective study among57346women. BJOG2009;116:964974.
1. Hall CN, Garthwaite J. What is the real physiological NO concentration in vivo? NitricOxide2009;21:92103.
2. Gao Y. The multiple actions of NO. Pflugers Arch2010;459:829839.
3. Hofmann F, Bernhard D, Lukowski R, Weinmeister P. cGMP regulated protein kinases(cGK). Handb Exp Pharmacol2009:137162.
4. Fleissner F, Thum T. Critical role of the nitric oxide/reactive oxygen species balance inendothelial progenitor dysfunction. Antioxid Redox Signal2011;15:933948.
5. Bian K, Doursout MF, Murad F. Vascular system: role of nitric oxide in cardiovasculardiseases. J Clin Hypertens (Greenwich)2008;10:304310.
6. van Hinsbergh VW. Endothelium role in regulation of coagulation and inflammation.Semin Immunopathol2012;34:93106.
7. Popolo A, Autore G, Pinto A, Marzocco S. Oxidative stress in cardiovascular diseaseand chronic renal failure. Free Radic Res2013.
8. Jezek P, Hlavata L. Mitochondria in homeostasis of reactive oxygen species in cell,tissues, and organism. Int J Biochem Cell Biol2005;37:24782503.
9. Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in thepathogenesis of hypertension: focus on nitric oxide, endothelial derived hyperpolarizingfactors, and prostaglandins. J Clin Hypertens (Greenwich)2012;14:198205.
10. Poniedzialek Czajkowska E, Marciniak B, Kimber Trojnar Z, Leszczynska Gorzelak B,Oleszczuk J. Nitric oxide in normal and preeclamptic pregnancy. Curr PharmBiotechnol2011;12:743749.
11. Ehsanipoor RM, Fortson W, Fitzmaurice LE, Liao WX, Wing DA, Chen DB, Chan K.Nitric Oxide and Carbon Monoxide Production and Metabolism in Preeclampsia.Reprod Sci2012.
12. Dai B, Liu T, Zhang B, Zhang X, Wang Z. The polymorphism for endothelial nitricoxide synthase gene, the level of nitric oxide and the risk for pre eclampsia: Ameta analysis. Gene2013.
13. Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, et al.eNOS deficiency acts through endothelin to aggravate sFlt1inducedpre eclampsia like phenotype. J Am Soc Nephrol2012;23:652660.
14. Murphy SR, LaMarca B, Cockrell K, Arany M, Granger JP. L arginine supplementationabolishes the blood pressure and endothelin response to chronic increases in plasmasFlt1in pregnant rats. Am J Physiol Regul Integr Comp Physiol2012;302:R259263.
15. Groesch KA, Torry RJ, Wilber AC, Abrams R, Bieniarz A, Guilbert LJ, Torry DS. Nitricoxide generation affects pro and anti angiogenic growth factor expression in primaryhuman trophoblast. Placenta2011;32:926931.
16. Bamberger AM, Koglin M, Kempfert J, Loning T, Scholz H, Behrends S. Expressionand tissue localization of soluble guanylyl cyclase in the human placenta using novelantibodies directed against the alpha(2) subunit. J Clin Endocrinol Metab2001;86:909912.
17. Ayling LJ, Whitley GS, Aplin JD, Cartwright JE. Dimethylargininedimethylaminohydrolase (DDAH) regulates trophoblast invasion and motility througheffects on nitric oxide. Hum Reprod2006;21:25302537.
18.Novaro V, Colman Lerner A, Ortega FV, Jawerbaum A, Paz D, Lo Nostro F, Pustovrh C,et al. Regulation of metalloproteinases by nitric oxide in human trophoblast cells inculture. Reprod Fertil Dev2001;13:411420.
19. Tsukimori K, Komatsu H, Fukushima K, Kaku T, Nakano H, Wake N. Inhibition ofnitric oxide synthetase at mid gestation in rats is associated with increases in arterialpressure, serum tumor necrosis factor alpha, and placental apoptosis. Am J Hypertens2008;21:477481.
20. Chang CC, Chang TY, Yu CH, Tsai ML. Induction of VE cadherin in rat placentaltrophoblasts by VEGF through a NO dependent pathway. Placenta2005;26:234241.
21. Bir SC, Xiong Y, Kevil CG, Luo J. Emerging role of PKA/eNOS pathway in therapeuticangiogenesis for ischaemic tissue diseases. Cardiovasc Res2012;95:718.
22. Nagarajan S, Rajendran S, Saran U, Priya MK, Swaminathan A, Siamwala JH, Sinha S,et al. Nitric oxide protects endothelium from cadmium mediated leakiness. Cell Biol Int2013.
23. de Pace V, Chiossi G, Facchinetti F. Clinical use of nitric oxide donors and L arginine inobstetrics. J Matern Fetal Neonatal Med2007;20:569579.
24. Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy.Oxid Med Cell Longev2011;2011:841749.
25. Matsubara K, Matsubara Y, Hyodo S, Katayama T, Ito M. Role of nitric oxide andreactive oxygen species in the pathogenesis of preeclampsia. J Obstet Gynaecol Res2010;36:239247.
26. Kim KM, Chun SB, Koo MS, Choi WJ, Kim TW, Kwon YG, Chung HT, et al.Differential regulation of NO availability from macrophages and endothelial cells bythe garlic component S allyl cysteine. Free Radic Biol Med2001;30:747756.
27. Asdaq SM, Inamdar MN. Potential of garlic and its active constituent, S allyl cysteine,as antihypertensive and cardioprotective in presence of captopril. Phytomedicine2010;17:10161026.
28. Hwang YP, Kim HG, Choi JH, Do MT, Chung YC, Jeong TC, Jeong HG. S Allylcysteine attenuates free fatty acid induced lipogenesis in human HepG2cells throughactivation of the AMP activated protein kinase dependent pathway. J Nutr Biochem2013.
29. Segoviano Murillo S, Sanchez Gonzalez DJ, Martinez Martinez CM, Cruz C,Maldonado PD, Pedraza Chaverri J. S allylcysteine ameliorates ischemia andreperfusion induced renal damage. Phytother Res2008;22:836840.
30. Ashafaq M, Khan MM, Shadab Raza S, Ahmad A, Khuwaja G, Javed H, Khan A, et al.S allyl cysteine mitigates oxidative damage and improves neurologic deficit in a ratmodel of focal cerebral ischemia. Nutr Res2012;32:133143.
1. Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J2012;33:829837,837a837d.
2. Alkaitis MS, Crabtree MJ. Recoupling the cardiac nitric oxide synthases:tetrahydrobiopterin synthesis and recycling. Curr Heart Fail Rep2012;9:200210.
3. Guzik TJ, Harrison DG. Vascular NADPH oxidases as drug targets for novel antioxidantstrategies. Drug Discov Today2006;11:524533.
4. Kumar S, Sun X, Wedgwood S, Black SM. Hydrogen peroxide decreases endothelialnitric oxide synthase promoter activity through the inhibition of AP1activity. Am JPhysiol Lung Cell Mol Physiol2008;295:L370377.
5. Hrabarova E, Juranek I, Soltes L. Pro oxidative effect of peroxynitrite regardingbiological systems: a special focus on high molar mass hyaluronan degradation. GenPhysiol Biophys2011;30:223238.
6. Forstermann U, Li H. Therapeutic effect of enhancing endothelial nitric oxide synthase(eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol2011;164:213223.
7. Martinez MC, Andriantsitohaina R. Reactive nitrogen species: molecular mechanismsand potential significance in health and disease. Antioxid Redox Signal2009;11:669702.
8. van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim Shapiro DB, KozlovAV, et al. Nitrite as regulator of hypoxic signaling in mammalian physiology. Med ResRev2009;29:683741.
9. Broniowska KA, Hogg N. The chemical biology of S nitrosothiols. Antioxid RedoxSignal2012;17:969980.
10. Scatena R, Bottoni P, Pontoglio A, Giardina B. Pharmacological modulation of nitricoxide release: new pharmacological perspectives, potential benefits and risks. Curr MedChem2010;17:6173.
11. Serafim RA, Primi MC, Trossini GH, Ferreira EI. Nitric oxide: state of the art in drugdesign. Curr Med Chem2012;19:386405.
12. Chuah SC, Moore PK, Zhu YZ. S allylcysteine mediates cardioprotection in an acutemyocardial infarction rat model via a hydrogen sulfide mediated pathway. Am J PhysiolHeart Circ Physiol2007;293:H26932701.
13. Pinto JT, Krasnikov BF, Cooper AJ. Redox sensitive proteins are potential targets ofgarlic derived mercaptocysteine derivatives. J Nutr2006;136:835S841S.
14. Ried K, Frank OR, Stocks NP. Aged garlic extract lowers blood pressure in patientswith treated but uncontrolled hypertension: a randomised controlled trial. Maturitas2010;67:144150.
1. Eiland E, Nzerue C, Faulkner M. Preeclampsia2012. J Pregnancy2012;2012:586578.
2. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternalendothelium: the role of antiangiogenic factors and implications for later cardiovasculardisease. Circulation2011;123:28562869.
3. Bates DO. An unexpected tail of VEGF and PlGF in pre eclampsia. Biochem Soc Trans2011;39:15761582.
4. Wu FT, Stefanini MO, Mac Gabhann F, Kontos CD, Annex BH, Popel AS. A systemsbiology perspective on sVEGFR1: its biological function, pathogenic role andtherapeutic use. J Cell Mol Med2010;14:528552.
5. Nagai A, Sado T, Naruse K, Noguchi T, Haruta S, Yoshida S, Tanase Y, et al.Antiangiogenic induced hypertension: the molecular basis of signaling network.Gynecol Obstet Invest2012;73:8998.
6. Hay N. Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta2011;1813:19651970.
7. Cindrova Davies T, Sanders DA, Burton GJ, Charnock Jones DS. Soluble FLT1sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGFreceptor mediated signalling. Cardiovasc Res2011;89:671679.
8. Cudmore MJ, Ahmad S, Sissaoui S, Ramma W, Ma B, Fujisawa T, Al Ani B, et al. Lossof Akt activity increases circulating soluble endoglin release in preeclampsia:identification of inter dependency between Akt1and heme oxygenase1. Eur Heart J2012;33:11501158.
9. Kokkinos MI, Murthi P, Wafai R, Thompson EW, Newgreen DF. Cadherins in thehuman placenta epithelial mesenchymal transition (EMT) and placental development.Placenta2010;31:747755.
10. Stahmann N, Woods A, Spengler K, Heslegrave A, Bauer R, Krause S, Viollet B, et al.Activation of AMP activated protein kinase by vascular endothelial growth factormediates endothelial angiogenesis independently of nitric oxide synthase. J Biol Chem2010;285:1063810652.
11. Schweighofer B, Schultes J, Pomyje J, Hofer E. Signals and genes induced byangiogenic growth factors in comparison to inflammatory cytokines in endothelial cells.Clin Hemorheol Microcirc2007;37:5762.
12. Henao DE, Cadavid AP, Saleem MA. Exogenous vascular endothelial growth factorsupplementation can restore the podocyte barrier forming capacity disrupted by sera ofpreeclamptic women. J Obstet Gynaecol Res2013;39:4652.
13. Chedraui P, Solis EJ, Bocci G, Gopal S, Russo E, Escobar GS, Hidalgo L, et al.Feto placental nitric oxide, asymmetric dimethylarginine and vascular endothelialgrowth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia. JMatern Fetal Neonatal Med2013;26:226232.
14. Govender L, Mackraj I, Gathiram P, Moodley J. The role of angiogenic, anti angiogenicand vasoactive factors in pre eclamptic African women: early versus late onsetpre eclampsia. Cardiovasc J Afr2012;23:153159.
15. Shibuya M. Vascular endothelial growth factor and its receptor system: physiologicalfunctions in angiogenesis and pathological roles in various diseases. J Biochem2013;153:1319.
16. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved inangiogenesis versus lymphangiogenesis. Curr Opin Cell Biol2009;21:154165.
17. Leanos Miranda A, Campos Galicia I, Isordia Salas I, Rivera Leanos R, Romero ArauzJF, Ayala Mendez JA, Ulloa Aguirre A. Changes in circulating concentrations ofsoluble fms like tyrosine kinase1and placental growth factor measured by automatedelectrochemiluminescence immunoassays methods are predictors of preeclampsia. JHypertens2012;30:21732181.
18. Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, et al.eNOS deficiency acts through endothelin to aggravate sFlt1inducedpre eclampsia like phenotype. J Am Soc Nephrol2012;23:652660.
19. Suzuki H, Ohkuchi A, Matsubara S, Takei Y, Murakami M, Shibuya M, Suzuki M, et al.Effect of recombinant placental growth factor2on hypertension induced by full lengthmouse soluble fms like tyrosine kinase1adenoviral vector in pregnant mice.Hypertension2009;54:11291135.
20. Fox KA, Longo M, Tamayo E, Kechichian T, Bytautiene E, Hankins GD, Saade GR, etal. Effects of pravastatin on mediators of vascular function in a mouse model of solubleFms like tyrosine kinase1induced preeclampsia. Am J Obstet Gynecol2011;205:366e361365.
21. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, et al. Excessplacental soluble fms like tyrosine kinase1(sFlt1) may contribute to endothelialdysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest2003;111:649658.
22. Facemire CS, Nixon AB, Griffiths R, Hurwitz H, Coffman TM. Vascular endothelialgrowth factor receptor2controls blood pressure by regulating nitric oxide synthaseexpression. Hypertension2009;54:652658.
23. Gilbert JS, Verzwyvelt J, Colson D, Arany M, Karumanchi SA, Granger JP.Recombinant vascular endothelial growth factor121infusion lowers blood pressure andimproves renal function in rats with placentalischemia induced hypertension.Hypertension2010;55:380385.
24. Bergmann A, Ahmad S, Cudmore M, Gruber AD, Wittschen P, Lindenmaier W,Christofori G, et al. Reduction of circulating soluble Flt1alleviates preeclampsia likesymptoms in a mouse model. J Cell Mol Med2010;14:18571867.
25. Vignon Zellweger N, Heiden S, Miyauchi T, Emoto N. Endothelin and endothelinreceptors in the renal and cardiovascular systems. Life Sci2012;91:490500.
26. Mazzuca MQ, Khalil RA. Vascular endothelin receptor type B: structure, function anddysregulation in vascular disease. Biochem Pharmacol2012;84:147162.
27. Jain A. Endothelin1: a key pathological factor in pre eclampsia? Reprod BiomedOnline2012;25:443449.
28. Bernardi F, Constantino L, Machado R, Petronilho F, Dal Pizzol F. Plasma nitric oxide,endothelin1, arginase and superoxide dismutase in pre eclamptic women. J ObstetGynaecol Res2008;34:957963.
29. LaMarca BB, Cockrell K, Sullivan E, Bennett W, Granger JP. Role of endothelin inmediating tumor necrosis factor induced hypertension in pregnant rats. Hypertension2005;46:8286.
30. Tam Tam KB, George E, Cockrell K, Arany M, Speed J, Martin JN, Jr., Lamarca B, etal. Endothelin type A receptor antagonist attenuates placental ischemia inducedhypertension and uterine vascular resistance. Am J Obstet Gynecol2011;204:330e331334.
31. Chen DD, Dong YG, Yuan H, Chen AF. Endothelin1activation of endothelin Areceptor/NADPH oxidase pathway and diminished antioxidants critically contribute toendothelial progenitor cell reduction and dysfunction in salt sensitive hypertension.Hypertension2012;59:10371043.
32. Fiore G, Florio P, Micheli L, Nencini C, Rossi M, Cerretani D, Ambrosini G, et al.Endothelin1triggers placental oxidative stress pathways: putative role in preeclampsia.J Clin Endocrinol Metab2005;90:42054210.
33. Kingman M, Ruggiero R, Torres F. Ambrisentan, an endothelin receptor typeA selective endothelin receptor antagonist, for the treatment of pulmonary arterialhypertension. Expert Opin Pharmacother2009;10:18471858.
34. Gao Y. The multiple actions of NO. Pflugers Arch2010;459:829839.
35. Huang LT, Hsieh CS, Chang KA, Tain YL. Roles of nitric oxide and asymmetricdimethylarginine in pregnancy and fetal programming. Int J Mol Sci2012;13:1460614622.
36. Boeldt DS, Yi FX, Bird IM. eNOS activation and NO function: pregnancy adaptiveprogramming of capacitative entry responses alters nitric oxide (NO) output in vascularendothelium new insights into eNOS regulation through adaptive cell signaling. JEndocrinol2011;210:243258.
37. Tortladze M, Kintraia N, Sanikidze T. The EPR study of nitric oxide in placenta duringpreeclampsia. Georgian Med News2012:5559.
38. Dai B, Liu T, Zhang B, Zhang X, Wang Z. The polymorphism for endothelial nitricoxide synthase gene, the level of nitric oxide and the risk for pre eclampsia: Ameta analysis. Gene2013.
39. Kalidindi M, Velauthar L, Khan K, Aquilina J. The role of nitrates in the prevention ofpreeclampsia: an update. Curr Opin Obstet Gynecol2012;24:361367.
40. Korokin MV, Pokrovsky MV, Novikov OO, Gureev VV, Denisyuk TA, Korokina LV,Polyanskaya OS, et al. Effect of L arginine, vitamin B6and folic acid on parameters ofendothelial dysfunction and microcirculation in the placenta in modeling ofL NAME induced NO deficiency. Bull Exp Biol Med2011;152:7072.
41. Turgut NH, Temiz TK, Bagcivan I, Turgut B, Gulturk S, Karadas B. The effect ofsildenafil on the altered thoracic aorta smooth muscle responses in rat pre eclampsiamodel. Eur J Pharmacol2008;589:180187.
42. Wareing M, Myers JE, O'Hara M, Kenny LC, Warren AY, Taggart MJ, Skillern L, et al.Effects of a phosphodiesterase5(PDE5) inhibitor on endothelium dependent relaxationof myometrial small arteries. Am J Obstet Gynecol2004;190:12831290.
43. Evora PR, Evora PM, Celotto AC, Rodrigues AJ, Joviliano EE. Cardiovasculartherapeutics targets on the NO sGC cGMP signaling pathway: a critical overview. CurrDrug Targets2012;13:12071214.
1. Bates DO. An unexpected tail of VEGF and PlGF in pre eclampsia. Biochem Soc Trans2011;39:15761582.
2. Shibuya M. Vascular endothelial growth factor and its receptor system: physiologicalfunctions in angiogenesis and pathological roles in various diseases. J Biochem2013;153:1319.
3. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved inangiogenesis versus lymphangiogenesis. Curr Opin Cell Biol2009;21:154165.
4. Chedraui P, Solis EJ, Bocci G, Gopal S, Russo E, Escobar GS, Hidalgo L, et al.Feto placental nitric oxide, asymmetric dimethylarginine and vascular endothelialgrowth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia. JMatern Fetal Neonatal Med2013;26:226232.
5. Cao Y. Positive and negative modulation of angiogenesis by VEGFR1ligands. SciSignal2009;2:re1.
6. De Falco S. The discovery of placenta growth factor and its biological activity. Exp MolMed2012;44:19.
7. Jacobs M, Nassar N, Roberts CL, Hadfield R, Morris JM, Ashton AW. Levels of solublefms like tyrosine kinase one in first trimester and outcomes of pregnancy: a systematicreview. Reprod Biol Endocrinol2011;9:77.
8. Leanos Miranda A, Campos Galicia I, Isordia Salas I, Rivera Leanos R, Romero ArauzJF, Ayala Mendez JA, Ulloa Aguirre A. Changes in circulating concentrations ofsoluble fms like tyrosine kinase1and placental growth factor measured by automatedelectrochemiluminescence immunoassays methods are predictors of preeclampsia. JHypertens2012;30:21732181.
9. Rohra DK, Zeb A, Qureishi RN, Azam SI, Khan NB, Zuberi HS, Sikandar R. Predictionof pre eclampsia during early pregnancy in primiparas with soluble fms like tyrosinekinase1and placental growth factor. Natl Med J India2012;25:6873.
10. Gomez Arriaga P, Herraiz I, Lopez Jimenez E, Gomez Montes E, Denk B, Galindo A.Uterine artery Doppler and sFlt1/PlGF ratio: usefulness in the diagnosis ofpre eclampsia. Ultrasound Obstet Gynecol2013.
11. Nachtigal P, Zemankova Vecerova L, Rathouska J, Strasky Z. The role of endoglin inatherosclerosis. Atherosclerosis2012;224:411.
12. Santibanez JF, Letamendia A, Perez Barriocanal F, Silvestri C, Saura M, Vary CP,Lopez Novoa JM, et al. Endoglin increases eNOS expression by modulating Smad2protein levels and Smad2dependent TGF beta signaling. J Cell Physiol2007;210:456468.
13. Park S, Dimaio TA, Liu W, Wang S, Sorenson CM, Sheibani N. Endoglin Regulates theActivation and Quiescence of Endothelium by Participating in Canonical andNon Canonical TGF beta Signaling Pathways. J Cell Sci2013.
14. Mano Y, Kotani T, Shibata K, Matsumura H, Tsuda H, Sumigama S, Yamamoto E, et al.The loss of endoglin promotes the invasion of extravillous trophoblasts. Endocrinology2011;152:43864394.
15. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, et al.Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med2006;12:642649.
16. Leanos Miranda A, Campos Galicia I, Ramirez Valenzuela KL, Chinolla Arellano ZL,Isordia Salas I. Circulating Angiogenic Factors and Urinary Prolactin as Predictors ofAdverse Outcomes in Women With Preeclampsia. Hypertension2013.
17. Elhawary TM, El Bendary AS, Demerdash H. Maternal serum endoglin as an earlymarker of pre eclampsia in high risk patients. Int J Womens Health2012;4:521525.
18. Lai J, Syngelaki A, Poon LC, Nucci M, Nicolaides KH. Maternal Serum SolubleEndoglin at3033Weeks in the Prediction of Preeclampsia. Fetal Diagn Ther2012.
19. Foidart JM, Munaut C, Chantraine F, Akolekar R, Nicolaides KH. Maternal plasmasoluble endoglin at1113weeks' gestation in pre eclampsia. Ultrasound Obstet Gynecol2010;35:680687.
20. Mignini LE, Latthe PM, Villar J, Kilby MD, Carroli G, Khan KS. Mapping the theoriesof preeclampsia: the role of homocysteine. Obstet Gynecol2005;105:411425.
21. Mujawar SA, Patil VW, Daver RG. Study of serum homocysteine, folic Acid andvitamin b(12) in patients with preeclampsia. Indian J Clin Biochem2011;26:257260.
22. Murphy MM, Fernandez Ballart JD. Homocysteine in pregnancy. Adv Clin Chem2011;53:105137.
23. Castelao JE, Gago Dominguez M. Risk factors for cardiovascular disease in women:relationship to lipid peroxidation and oxidative stress. Med Hypotheses2008;71:3944.
24. Singh U, Gupta HP, Singh RK, Shukla M, Singh R, Mehrotra SS, Prasad S. A study ofchanges in homocysteine levels during normal pregnancy and pre eclampsia. J IndianMed Assoc2008;106:503505.
25. Walker MC, Smith GN, Perkins SL, Keely EJ, Garner PR. Changes in homocysteinelevels during normal pregnancy. Am J Obstet Gynecol1999;180:660664.
26. Acilmis YG, Dikensoy E, Kutlar AI, Balat O, Cebesoy FB, Ozturk E, Cicek H, et al.Homocysteine, folic acid and vitamin B12levels in maternal and umbilical cord plasmaand homocysteine levels in placenta in pregnant women with pre eclampsia. J ObstetGynaecol Res2011;37:4550.
27. Khosrowbeygi A, Ahmadvand H. Circulating levels of homocysteine in preeclampticwomen. Bangladesh Med Res Counc Bull2011;37:106109.
28. Shenoy V, Kanasaki K, Kalluri R. Pre eclampsia: connecting angiogenic and metabolicpathways. Trends Endocrinol Metab2010;21:529536.
29. Shiraishi M, Haruna M, Matsuzaki M, Ota E, Murayama R, Watanabe E, Sasaki S, et al.Association between oxidized LDL and folate during pregnancy. Biol Res Nurs2013;15:213218.
30. Usluer H, Turker G, Gokalp AS. Value of homocysteine levels, troponin I, and score forneonatal acute physiology and perinatal extension II as early predictors of morbidity.Pediatr Int2012;54:104110.
31. D'Anna R, Baviera G, Corrado F, Ientile R, Granese D, Stella NC. Plasma homocysteinein early and late pregnancies complicated with preeclampsia and isolated intrauterinegrowth restriction. Acta Obstet Gynecol Scand2004;83:155158.
32. Bouras G, Deftereos S, Tousoulis D, Giannopoulos G, Chatzis G, Tsounis D, ClemanMW, et al. Asymmetric dimethylarginine (ADMA): a promising biomarker forcardiovascular disease? Curr Top Med Chem2013.
33. Poniedzialek Czajkowska E, Marciniak B, Kimber Trojnar Z, Leszczynska Gorzelak B,Oleszczuk J. Nitric oxide in normal and preeclamptic pregnancy. Curr PharmBiotechnol2011;12:743749.
34. Sibal L, Agarwal SC, Home PD, Boger RH. The Role of Asymmetric Dimethylarginine(ADMA) in Endothelial Dysfunction and Cardiovascular Disease. Curr Cardiol Rev2010;6:8290.
35. Rizos D, Eleftheriades M, Batakis E, Rizou M, Haliassos A, Hassiakos D, Botsis D.Levels of asymmetric dimethylarginine throughout normal pregnancy and inpregnancies complicated with preeclampsia or had a small for gestational age baby. JMatern Fetal Neonatal Med2012;25:13111315.
36. Demir B, Demir S, Pasa S, Guven S, Atamer Y, Atamer A, Kocyigit Y. The role ofhomocysteine, asymmetric dimethylarginine and nitric oxide in pre eclampsia. J ObstetGynaecol2012;32:525528.
37. Laskowska M, Laskowska K, Oleszczuk J. Differences in the association betweenmaternal serum homocysteine and ADMA levels in women with pregnanciescomplicated by preeclampsia and/or intrauterine growth restriction. HypertensPregnancy2013;32:8393.
38. Anderssohn M, Maass LM, Diemert A, Luneburg N, Atzler D, Hecher K, Boger RH.Severely decreased activity of placental dimethylarginine dimethylaminohydrolase inpre eclampsia. Eur J Obstet Gynecol Reprod Biol2012;161:152156.
39. Ahima RS, Flier JS. Leptin. Annu Rev Physiol2000;62:413437.
40. Miehle K, Stepan H, Fasshauer M. Leptin, adiponectin and other adipokines ingestational diabetes mellitus and pre eclampsia. Clin Endocrinol (Oxf)2012;76:211.
41. Elhawary TM, Demerdash HD, Sweilam MA. Relationship between Interleukin10Polymorphism and Maternal Serum Leptin Level in Preeclampsia. Clin Exp Hypertens2012.
42. Samolis S, Papastefanou I, Panagopoulos P, Galazios G, Kouskoukis A, Maroulis G.Relation between first trimester maternal serum leptin levels and body mass index innormotensive and pre eclamptic pregnancies role of leptin as a marker ofpre eclampsia: a prospective case control study. Gynecol Endocrinol2010;26:338343.
43. Sitras V, Paulssen RH, Gronaas H, Leirvik J, Hanssen TA, Vartun A, Acharya G.Differential placental gene expression in severe preeclampsia. Placenta2009;30:424433.
44. Basak S, Duttaroy AK. Leptin induces tube formation in first trimester extravilloustrophoblast cells. Eur J Obstet Gynecol Reprod Biol2012;164:2429.
45. Maymo JL, Perez AP, Gambino Y, Calvo JC, Sanchez Margalet V, Varone CL. Review:Leptin gene expression in the placenta regulation of a key hormone in trophoblastproliferation and survival. Placenta2011;32Suppl2:S146153.
46. Jansson N, Greenwood SL, Johansson BR, Powell TL, Jansson T. Leptin stimulates theactivity of the system A amino acid transporter in human placental villous fragments. JClin Endocrinol Metab2003;88:12051211.
47. Klaffenbach D, Meissner U, Raake M, Fahlbusch F, Alejandre Alcazar MA, Allabauer I,Kratzsch J, et al. Upregulation of leptin receptor in placental cells by hypoxia. RegulPept2011;167:156162.
48. Molvarec A, Szarka A, Walentin S, Beko G, Karadi I, Prohaszka Z, Rigo J, Jr. Serumleptin levels in relation to circulating cytokines, chemokines, adhesion molecules andangiogenic factors in normal pregnancy and preeclampsia. Reprod Biol Endocrinol2011;9:124.
49. Dalamaga M, Srinivas SK, Elovitz MA, Chamberland J, Mantzoros CS. Serumadiponectin and leptin in relation to risk for preeclampsia: results from a largecase control study. Metabolism2011;60:15391544.
50. Gaidamauskas E, Gyrup C, Boldt HB, Schack VR, Overgaard MT, Laursen LS, OxvigC. IGF dependent modulation of IGF binding protein (IGFBP) proteolysis bypregnancy associated plasma protein A (PAPP A): Multiple PAPP A IGFBP interactionsites. Biochim Biophys Acta2012.
51. Handschuh K, Guibourdenche J, Guesnon M, Laurendeau I, Evain Brion D, Fournier T.Modulation of PAPP A expression by PPARgamma in human first trimester trophoblast.Placenta2006;27Suppl A:S127134.
52. She BQ, Chen SC, Lee FK, Cheong ML, Tsai MS. Low maternal serum levels ofpregnancy associated plasma protein A during the first trimester are associated withsubsequent preterm delivery with preterm premature rupture of membranes. Taiwan JObstet Gynecol2007;46:242247.
53. Goetzinger KR, Singla A, Gerkowicz S, Dicke JM, Gray DL, Odibo AO. Predicting therisk of pre eclampsia between11and13weeks' gestation by combining maternalcharacteristics and serum analytes, PAPP A and free beta hCG. Prenat Diagn2010;30:11381142.
54. Bestwick JP, George LM, Wu T, Morris JK, Wald NJ. The value of early secondtrimester PAPP A and ADAM12in screening for pre eclampsia. J Med Screen2012;19:5154.
55. Atis A, Tandogan T, Aydin Y, Sen C, Turgay F, Eren N, Goker N. Late pregnancyassociated plasma protein A levels decrease in preterm labor. J Matern Fetal NeonatalMed2011;24:923927.
56. Huppertz B, Meiri H, Gizurarson S, Osol G, Sammar M. Placental protein13(PP13): anew biological target shifting individualized risk assessment to personalized drugdesign combating pre eclampsia. Hum Reprod Update2013.
57. Than NG, Pick E, Bellyei S, Szigeti A, Burger O, Berente Z, Janaky T, et al. Functionalanalyses of placental protein13/galectin13. Eur J Biochem2004;271:10651078.
58. Kliman HJ, Sammar M, Grimpel YI, Lynch SK, Milano KM, Pick E, Bejar J, et al.Placental protein13and decidual zones of necrosis: an immunologic diversion that maybe linked to preeclampsia. Reprod Sci2012;19:1630.
59. El Sherbiny WS, Soliman A, Nasr AS. Placental protein13as an early predictor inEgyptian patients with preeclampsia, correlation to risk, and association with outcome.J Investig Med2012;60:818822.
60. Than NG, Abdul Rahman O, Magenheim R, Nagy B, Fule T, Hargitai B, Sammar M, etal. Placental protein13(galectin13) has decreased placental expression but increasedshedding and maternal serum concentrations in patients presenting with pretermpre eclampsia and HELLP syndrome. Virchows Arch2008;453:387400.
61. Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H, Harrington K. First trimestermarkers for the prediction of pre eclampsia in women with a priori high risk.Ultrasound Obstet Gynecol2010;35:671679.
62. Odibo AO, Zhong Y, Goetzinger KR, Odibo L, Bick JL, Bower CR, Nelson DM.First trimester placental protein13, PAPP A, uterine artery Doppler and maternalcharacteristics in the prediction of pre eclampsia. Placenta2011;32:598602.
63. Romero R, Kusanovic JP, Than NG, Erez O, Gotsch F, Espinoza J, Edwin S, et al.First trimester maternal serum PP13in the risk assessment for preeclampsia. Am JObstet Gynecol2008;199:122e121122e111.
64. Centlow M, Carninci P, Nemeth K, Mezey E, Brownstein M, Hansson SR. Placentalexpression profiling in preeclampsia: local overproduction of hemoglobin may drivepathological changes. Fertil Steril2008;90:18341843.
65. Balla J, Vercellotti GM, Jeney V, Yachie A, Varga Z, Eaton JW, Balla G. Heme, hemeoxygenase and ferritin in vascular endothelial cell injury. Mol Nutr Food Res2005;49:10301043.
66. Ascenzi P, Bocedi A, Visca P, Altruda F, Tolosano E, Beringhelli T, Fasano M.Hemoglobin and heme scavenging. IUBMB Life2005;57:749759.
67. May K, Rosenlof L, Olsson MG, Centlow M, Morgelin M, Larsson I, Cederlund M, etal. Perfusion of human placenta with hemoglobin introduces preeclampsia like injuriesthat are prevented by alpha1microglobulin. Placenta2011;32:323332.
68. Anderson UD, Olsson MG, Rutardottir S, Centlow M, Kristensen KH, Isberg PE,Thilaganathan B, et al. Fetal hemoglobin and alpha1microglobulin as first and earlysecond trimester predictive biomarkers for preeclampsia. Am J Obstet Gynecol2011;204:520e521525.
69. Olsson MG, Centlow M, Rutardottir S, Stenfors I, Larsson J, Hosseini Maaf B, OlssonML, et al. Increased levels of cell free hemoglobin, oxidation markers, and theantioxidative heme scavenger alpha(1) microglobulin in preeclampsia. Free Radic BiolMed2010;48:284291.
2. Myatt L. Review: Reactive oxygen and nitrogen species and functional adaptation ofthe placenta. Placenta2010;31Suppl:S6669.
3. Pollheimer J, Knofler M. The role of the invasive, placental trophoblast in humanpregnancy. Wien Med Wochenschr2012;162:187190.
4. Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. JSoc Gynecol Investig2004;11:342352.
5. Pijnenborg R, Vercruysse L, Carter AM. Deep trophoblast invasion and spiral arteryremodelling in the placental bed of the lowland gorilla. Placenta2011;32:586591.
6. Mandala M, Osol G. Physiological remodelling of the maternal uterine circulationduring pregnancy. Basic Clin Pharmacol Toxicol2012;110:1218.
7. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre eclampsia. Lancet2010;376:631644.
8. Chen JZ, Sheehan PM, Brennecke SP, Keogh RJ. Vessel remodelling, pregnancyhormones and extravillous trophoblast function. Mol Cell Endocrinol2012;349:138144.
9. Friebe A, Koesling D. The function of NO sensitive guanylyl cyclase: what we canlearn from genetic mouse models. Nitric Oxide2009;21:149156.
10. Boger RH, Diemert A, Schwedhelm E, Luneburg N, Maas R, Hecher K. The role ofnitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiologyof preeclampsia. Gynecol Obstet Invest2010;69:113.
11. Gao Y. The multiple actions of NO. Pflugers Arch2010;459:829839.
12. Valdes G, Corthorn J. Review: The angiogenic and vasodilatory utero placentalnetwork. Placenta2011;32Suppl2:S170175.
13. Krause BJ, Hanson MA, Casanello P. Role of nitric oxide in placental vasculardevelopment and function. Placenta2011;32:797805.
14. Groesch KA, Torry RJ, Wilber AC, Abrams R, Bieniarz A, Guilbert LJ, Torry DS.Nitric oxide generation affects pro and anti angiogenic growth factor expression inprimary human trophoblast. Placenta2011;32:926931.
15. Boeldt DS, Yi FX, Bird IM. eNOS activation and NO function: pregnancy adaptiveprogramming of capacitative entry responses alters nitric oxide (NO) output in vascularendothelium new insights into eNOS regulation through adaptive cell signaling. JEndocrinol2011;210:243258.
16. Ehsanipoor RM, Fortson W, Fitzmaurice LE, Liao WX, Wing DA, Chen DB, Chan K.Nitric Oxide and Carbon Monoxide Production and Metabolism in Preeclampsia.Reprod Sci2012.
17. Demir B, Demir S, Pasa S, Guven S, Atamer Y, Atamer A, Kocyigit Y. The role ofhomocysteine, asymmetric dimethylarginine and nitric oxide in pre eclampsia. J ObstetGynaecol2012;32:525528.
18. Ramesar SV, Drewes SE, Gathiram P, Moodley J, Mackraj I. The effect ofKraussianone2(Kr2), a natural pyrano isoflavone from Eriosema kraussianum, in anL NAME induced pre eclamptic rat model. Phytother Res2012;26:13751380.
19. Murphy SR, LaMarca B, Cockrell K, Arany M, Granger JP. L arginine supplementationabolishes the blood pressure and endothelin response to chronic increases in plasmasFlt1in pregnant rats. Am J Physiol Regul Integr Comp Physiol2012;302:R259263.
20. Howlader MZ, Parveen S, Tamanna S, Khan TA, Begum F. Oxidative stress andantioxidant status in neonates born to pre eclamptic mother. J Trop Pediatr2009;55:363367.
21. Clerici G, Slavescu C, Fiengo S, Kanninen TT, Romanelli M, Biondi R, Di Renzo GC.Oxidative stress in pathological pregnancies. J Obstet Gynaecol2012;32:124127.
22. Gohil JT, Patel PK, Gupta P. Evaluation of oxidative stress and antioxidant defence insubjects of preeclampsia. J Obstet Gynaecol India2011;61:638640.
23. Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol2011;25:287299.
24. Siddiqui IA, Jaleel A, Tamimi W, Al Kadri HM. Role of oxidative stress in thepathogenesis of preeclampsia. Arch Gynecol Obstet2010;282:469474.
25. Aris A, Benali S, Ouellet A, Moutquin JM, Leblanc S. Potential biomarkers ofpreeclampsia: inverse correlation between hydrogen peroxide and nitric oxide early inmaternal circulation and at term in placenta of women with preeclampsia. Placenta2009;30:342347.
26. Farrow KN, Lakshminrusimha S, Reda WJ, Wedgwood S, Czech L, Gugino SF, DavisJM, et al. Superoxide dismutase restores eNOS expression and function in resistancepulmonary arteries from neonatal lambs with persistent pulmonary hypertension. Am JPhysiol Lung Cell Mol Physiol2008;295:L979987.
27. Poniedzialek Czajkowska E, Marciniak B, Kimber Trojnar Z, Leszczynska Gorzelak B,Oleszczuk J. Nitric oxide in normal and preeclamptic pregnancy. Curr PharmBiotechnol2011;12:743749.
28. Duley L, Gulmezoglu AM, Henderson Smart DJ, Chou D. Magnesium sulphate andother anticonvulsants for women with pre eclampsia. Cochrane Database Syst Rev2010:CD000025.
29. Magee LA, Abalos E, von Dadelszen P, Sibai B, Easterling T, Walkinshaw S. How tomanage hypertension in pregnancy effectively. Br J Clin Pharmacol2011;72:394401.
30. Mert I, Oruc AS, Yuksel S, Cakar ES, Buyukkagnici U, Karaer A, Danisman N. Role ofoxidative stress in preeclampsia and intrauterine growth restriction. J Obstet GynaecolRes2012;38:658664.
31. Rahman K. Studies on free radicals, antioxidants, and co factors. Clin Interv Aging2007;2:219236.
32. Wibowo N, Purwosunu Y, Sekizawa A, Farina A, Idriansyah L, Fitriana I. Antioxidantsupplementation in pregnant women with low antioxidant status. J Obstet GynaecolRes2012;38:11521161.
33. Chen Q, Jones D, Stone P, Ching LM, Chamley L. Vitamin C enhances phagocytosis ofnecrotic trophoblasts by endothelial cells and protects the phagocytosing endothelialcells from activation. Placenta2009;30:163168.
34. Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, et al.eNOS deficiency acts through endothelin to aggravate sFlt1inducedpre eclampsia like phenotype. J Am Soc Nephrol2012;23:652660.
35. Gui S, Jia J, Niu X, Bai Y, Zou H, Deng J, Zhou R. Arginine supplementation forimproving maternal and neonatal outcomes in hypertensive disorder of pregnancy: Asystematic review. J Renin Angiotensin Aldosterone Syst2013.
36. Vadillo Ortega F, Perichart Perera O, Espino S, Avila Vergara MA, Ibarra I, Ahued R,Godines M, et al. Effect of supplementation during pregnancy with L arginine andantioxidant vitamins in medical food on pre eclampsia in high risk population:randomised controlled trial. BMJ2011;342:d2901.
37. Korokin MV, Pokrovsky MV, Novikov OO, Gureev VV, Denisyuk TA, Korokina LV,Polyanskaya OS, et al. Effect of L arginine, vitamin B6and folic acid on parameters ofendothelial dysfunction and microcirculation in the placenta in modeling ofL NAME induced NO deficiency. Bull Exp Biol Med2011;152:7072.
38. Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy.Oxid Med Cell Longev2011;2011:841749.
39. Reinhart KM, Coleman CI, Teevan C, Vachhani P, White CM. Effects of garlic onblood pressure in patients with and without systolic hypertension: a meta analysis. AnnPharmacother2008;42:17661771.
40. Ried K, Frank OR, Stocks NP, Fakler P, Sullivan T. Effect of garlic on blood pressure: asystematic review and meta analysis. BMC Cardiovasc Disord2008;8:13.
41. McInnes GT. Lowering blood pressure for cardiovascular risk reduction. J HypertensSuppl2005;23:S38.
42. Lawson LD, Gardner CD. Composition, stability, and bioavailability of garlic productsused in a clinical trial. J Agric Food Chem2005;53:62546261.
43. Ried K, Frank OR, Stocks NP. Aged garlic extract lowers blood pressure in patientswith treated but uncontrolled hypertension: a randomised controlled trial. Maturitas2010;67:144150.
44. Asdaq SM, Inamdar MN. Potential of garlic and its active constituent, S allyl cysteine,as antihypertensive and cardioprotective in presence of captopril. Phytomedicine2010;17:10161026.
45. Al Qattan KK, Thomson M, Al Mutawa'a S, Al Hajeri D, Drobiova H, Ali M. Nitricoxide mediates the blood pressure lowering effect of garlic in the rat two kidney,one clip model of hypertension. J Nutr2006;136:774S776S.
46. Kim KM, Chun SB, Koo MS, Choi WJ, Kim TW, Kwon YG, Chung HT, et al.Differential regulation of NO availability from macrophages and endothelial cells bythe garlic component S allyl cysteine. Free Radic Biol Med2001;30:747756.
47. Maldonado PD, Alvarez Idaboy JR, Aguilar Gonzalez A, Lira Rocha A, Jung Cook H,Medina Campos ON, Pedraza Chaverri J, et al. Role of allyl group in the hydroxyl andperoxyl radical scavenging activity of S allylcysteine. J Phys Chem B2011;115:1340813417.
48. Padmanabhan M, Prince PS. Preventive effect of S allylcysteine on lipid peroxides andantioxidants in normal and isoproterenol induced cardiotoxicity in rats: ahistopathological study. Toxicology2006;224:128137.
49. Saravanan G, Ponmurugan P. Beneficial effect of S allylcysteine (SAC) on bloodglucose and pancreatic antioxidant system in streptozotocin diabetic rats. Plant FoodsHum Nutr2010;65:374378.
50. Atif F, Yousuf S, Agrawal SK. S allyl L cysteine diminishes cerebral ischemia inducedmitochondrial dysfunctions in hippocampus. Brain Res2009;1265:128137.
51. Segoviano Murillo S, Sanchez Gonzalez DJ, Martinez Martinez CM, Cruz C,Maldonado PD, Pedraza Chaverri J. S allylcysteine ameliorates ischemia andreperfusion induced renal damage. Phytother Res2008;22:836840.
1. Drose S, Brandt U. Molecular mechanisms of superoxide production by themitochondrial respiratory chain. Adv Exp Med Biol2012;748:145169.
2. Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol2011;25:287299.
3. Demir B, Demir S, Atamer Y, Guven S, Atamer A, Kocyigit Y, Hekimoglu A, et al.Serum levels of lipids, lipoproteins and paraoxonase activity in pre eclampsia. J IntMed Res2011;39:14271431.
4. Mihu D, Sabau L, Costin N, Ciortea R, Malutan A, Mihu CM. Implications of maternalsystemic oxidative stress in normal pregnancy and in pregnancy complicated bypreeclampsia. J Matern Fetal Neonatal Med2012;25:944951.
5. Boij R, Svensson J, Nilsson Ekdahl K, Sandholm K, Lindahl TL, Palonek E, Garle M,et al. Biomarkers of coagulation, inflammation, and angiogenesis are independentlyassociated with preeclampsia. Am J Reprod Immunol2012;68:258270.
6. Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced inflammatory andregulatory cytokines in pregnancy and the etiology of preeclampsia. SeminImmunopathol2007;29:151162.
7. Lamarca B. The role of immune activation in contributing to vascular dysfunction andthe pathophysiology of hypertension during preeclampsia. Minerva Ginecol2010;62:105120.
8. Ong SS, Baker PN, Mayhew TM, Dunn WR. Remodeling of myometrial radial arteriesin preeclampsia. Am J Obstet Gynecol2005;192:572579.
9. Hung TH, Skepper JN, Burton GJ. In vitro ischemia reperfusion injury in term humanplacenta as a model for oxidative stress in pathological pregnancies. Am J Pathol2001;159:10311043.
10. Redman CW, Sargent IL. Placental stress and pre eclampsia: a revised view. Placenta2009;30Suppl A:S3842.
11. Lee SM, Romero R, Lee YJ, Park IS, Park CW, Yoon BH. Systemic inflammatorystimulation by microparticles derived from hypoxic trophoblast as a model forinflammatory response in preeclampsia. Am J Obstet Gynecol2012;207:337e331338.
12. Zavalza Gomez AB. Obesity and oxidative stress: a direct link to preeclampsia? ArchGynecol Obstet2011;283:415422.
13. Aris A, Benali S, Ouellet A, Moutquin JM, Leblanc S. Potential biomarkers ofpreeclampsia: inverse correlation between hydrogen peroxide and nitric oxide early inmaternal circulation and at term in placenta of women with preeclampsia. Placenta2009;30:342347.
14. Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy.Oxid Med Cell Longev2011;2011:841749.
15. Kodera Y, Suzuki A, Imada O, Kasuga S, Sumioka I, Kanezawa A, Taru N, et al.Physical, chemical, and biological properties of s allylcysteine, an amino acid derivedfrom garlic. J Agric Food Chem2002;50:622632.
16. Amagase H, Petesch BL, Matsuura H, Kasuga S, Itakura Y. Intake of garlic and itsbioactive components. J Nutr2001;131:955S962S.
17. Medina Campos ON, Barrera D, Segoviano Murillo S, Rocha D, Maldonado PD,Mendoza Patino N, Pedraza Chaverri J. S allylcysteine scavenges singlet oxygen andhypochlorous acid and protects LLC PK(1) cells of potassium dichromate inducedtoxicity. Food Chem Toxicol2007;45:20302039.
18. Chung LY. The antioxidant properties of garlic compounds: allyl cysteine, alliin, allicin,and allyl disulfide. J Med Food2006;9:205213.
19. Kim JM, Lee JC, Chang N, Chun HS, Kim WK. S Allyl L cysteine attenuates cerebralischemic injury by scavenging peroxynitrite and inhibiting the activity of extracellularsignal regulated kinase. Free Radic Res2006;40:827835.
20. Maldonado PD, Alvarez Idaboy JR, Aguilar Gonzalez A, Lira Rocha A, Jung Cook H,Medina Campos ON, Pedraza Chaverri J, et al. Role of allyl group in the hydroxyl andperoxyl radical scavenging activity of S allylcysteine. J Phys Chem B2011;115:1340813417.
21. Ho SE, Ide N, Lau BH. S allyl cysteine reduces oxidant load in cells involved in theatherogenic process. Phytomedicine2001;8:3946.
22. Kalayarasan S, Sriram N, Sureshkumar A, Sudhandiran G. Chromium (VI) inducedoxidative stress and apoptosis is reduced by garlic and its derivative S allylcysteinethrough the activation of Nrf2in the hepatocytes of Wistar rats. J Appl Toxicol2008;28:908919.
23. Cindrova Davies T, Spasic Boskovic O, Jauniaux E, Charnock Jones DS, Burton GJ.Nuclear factor kappa B, p38, and stress activated protein kinase mitogen activatedprotein kinase signaling pathways regulate proinflammatory cytokines and apoptosis inhuman placental explants in response to oxidative stress: effects of antioxidant vitamins.Am J Pathol2007;170:15111520.
24. Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM. Periconceptional multivitaminuse reduces the risk of preeclampsia. Am J Epidemiol2006;164:470477.
25. Catov JM, Nohr EA, Bodnar LM, Knudson VK, Olsen SF, Olsen J. Association ofpericonceptional multivitamin use with reduced risk of preeclampsia amongnormal weight women in the Danish National Birth Cohort. Am J Epidemiol2009;169:13041311.
26. Klemmensen A, Tabor A, Osterdal ML, Knudsen VK, Halldorsson TI, Mikkelsen TB,Olsen SF. Intake of vitamin C and E in pregnancy and risk of pre eclampsia:prospective study among57346women. BJOG2009;116:964974.
1. Hall CN, Garthwaite J. What is the real physiological NO concentration in vivo? NitricOxide2009;21:92103.
2. Gao Y. The multiple actions of NO. Pflugers Arch2010;459:829839.
3. Hofmann F, Bernhard D, Lukowski R, Weinmeister P. cGMP regulated protein kinases(cGK). Handb Exp Pharmacol2009:137162.
4. Fleissner F, Thum T. Critical role of the nitric oxide/reactive oxygen species balance inendothelial progenitor dysfunction. Antioxid Redox Signal2011;15:933948.
5. Bian K, Doursout MF, Murad F. Vascular system: role of nitric oxide in cardiovasculardiseases. J Clin Hypertens (Greenwich)2008;10:304310.
6. van Hinsbergh VW. Endothelium role in regulation of coagulation and inflammation.Semin Immunopathol2012;34:93106.
7. Popolo A, Autore G, Pinto A, Marzocco S. Oxidative stress in cardiovascular diseaseand chronic renal failure. Free Radic Res2013.
8. Jezek P, Hlavata L. Mitochondria in homeostasis of reactive oxygen species in cell,tissues, and organism. Int J Biochem Cell Biol2005;37:24782503.
9. Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in thepathogenesis of hypertension: focus on nitric oxide, endothelial derived hyperpolarizingfactors, and prostaglandins. J Clin Hypertens (Greenwich)2012;14:198205.
10. Poniedzialek Czajkowska E, Marciniak B, Kimber Trojnar Z, Leszczynska Gorzelak B,Oleszczuk J. Nitric oxide in normal and preeclamptic pregnancy. Curr PharmBiotechnol2011;12:743749.
11. Ehsanipoor RM, Fortson W, Fitzmaurice LE, Liao WX, Wing DA, Chen DB, Chan K.Nitric Oxide and Carbon Monoxide Production and Metabolism in Preeclampsia.Reprod Sci2012.
12. Dai B, Liu T, Zhang B, Zhang X, Wang Z. The polymorphism for endothelial nitricoxide synthase gene, the level of nitric oxide and the risk for pre eclampsia: Ameta analysis. Gene2013.
13. Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, et al.eNOS deficiency acts through endothelin to aggravate sFlt1inducedpre eclampsia like phenotype. J Am Soc Nephrol2012;23:652660.
14. Murphy SR, LaMarca B, Cockrell K, Arany M, Granger JP. L arginine supplementationabolishes the blood pressure and endothelin response to chronic increases in plasmasFlt1in pregnant rats. Am J Physiol Regul Integr Comp Physiol2012;302:R259263.
15. Groesch KA, Torry RJ, Wilber AC, Abrams R, Bieniarz A, Guilbert LJ, Torry DS. Nitricoxide generation affects pro and anti angiogenic growth factor expression in primaryhuman trophoblast. Placenta2011;32:926931.
16. Bamberger AM, Koglin M, Kempfert J, Loning T, Scholz H, Behrends S. Expressionand tissue localization of soluble guanylyl cyclase in the human placenta using novelantibodies directed against the alpha(2) subunit. J Clin Endocrinol Metab2001;86:909912.
17. Ayling LJ, Whitley GS, Aplin JD, Cartwright JE. Dimethylargininedimethylaminohydrolase (DDAH) regulates trophoblast invasion and motility througheffects on nitric oxide. Hum Reprod2006;21:25302537.
18.Novaro V, Colman Lerner A, Ortega FV, Jawerbaum A, Paz D, Lo Nostro F, Pustovrh C,et al. Regulation of metalloproteinases by nitric oxide in human trophoblast cells inculture. Reprod Fertil Dev2001;13:411420.
19. Tsukimori K, Komatsu H, Fukushima K, Kaku T, Nakano H, Wake N. Inhibition ofnitric oxide synthetase at mid gestation in rats is associated with increases in arterialpressure, serum tumor necrosis factor alpha, and placental apoptosis. Am J Hypertens2008;21:477481.
20. Chang CC, Chang TY, Yu CH, Tsai ML. Induction of VE cadherin in rat placentaltrophoblasts by VEGF through a NO dependent pathway. Placenta2005;26:234241.
21. Bir SC, Xiong Y, Kevil CG, Luo J. Emerging role of PKA/eNOS pathway in therapeuticangiogenesis for ischaemic tissue diseases. Cardiovasc Res2012;95:718.
22. Nagarajan S, Rajendran S, Saran U, Priya MK, Swaminathan A, Siamwala JH, Sinha S,et al. Nitric oxide protects endothelium from cadmium mediated leakiness. Cell Biol Int2013.
23. de Pace V, Chiossi G, Facchinetti F. Clinical use of nitric oxide donors and L arginine inobstetrics. J Matern Fetal Neonatal Med2007;20:569579.
24. Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy.Oxid Med Cell Longev2011;2011:841749.
25. Matsubara K, Matsubara Y, Hyodo S, Katayama T, Ito M. Role of nitric oxide andreactive oxygen species in the pathogenesis of preeclampsia. J Obstet Gynaecol Res2010;36:239247.
26. Kim KM, Chun SB, Koo MS, Choi WJ, Kim TW, Kwon YG, Chung HT, et al.Differential regulation of NO availability from macrophages and endothelial cells bythe garlic component S allyl cysteine. Free Radic Biol Med2001;30:747756.
27. Asdaq SM, Inamdar MN. Potential of garlic and its active constituent, S allyl cysteine,as antihypertensive and cardioprotective in presence of captopril. Phytomedicine2010;17:10161026.
28. Hwang YP, Kim HG, Choi JH, Do MT, Chung YC, Jeong TC, Jeong HG. S Allylcysteine attenuates free fatty acid induced lipogenesis in human HepG2cells throughactivation of the AMP activated protein kinase dependent pathway. J Nutr Biochem2013.
29. Segoviano Murillo S, Sanchez Gonzalez DJ, Martinez Martinez CM, Cruz C,Maldonado PD, Pedraza Chaverri J. S allylcysteine ameliorates ischemia andreperfusion induced renal damage. Phytother Res2008;22:836840.
30. Ashafaq M, Khan MM, Shadab Raza S, Ahmad A, Khuwaja G, Javed H, Khan A, et al.S allyl cysteine mitigates oxidative damage and improves neurologic deficit in a ratmodel of focal cerebral ischemia. Nutr Res2012;32:133143.
1. Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J2012;33:829837,837a837d.
2. Alkaitis MS, Crabtree MJ. Recoupling the cardiac nitric oxide synthases:tetrahydrobiopterin synthesis and recycling. Curr Heart Fail Rep2012;9:200210.
3. Guzik TJ, Harrison DG. Vascular NADPH oxidases as drug targets for novel antioxidantstrategies. Drug Discov Today2006;11:524533.
4. Kumar S, Sun X, Wedgwood S, Black SM. Hydrogen peroxide decreases endothelialnitric oxide synthase promoter activity through the inhibition of AP1activity. Am JPhysiol Lung Cell Mol Physiol2008;295:L370377.
5. Hrabarova E, Juranek I, Soltes L. Pro oxidative effect of peroxynitrite regardingbiological systems: a special focus on high molar mass hyaluronan degradation. GenPhysiol Biophys2011;30:223238.
6. Forstermann U, Li H. Therapeutic effect of enhancing endothelial nitric oxide synthase(eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol2011;164:213223.
7. Martinez MC, Andriantsitohaina R. Reactive nitrogen species: molecular mechanismsand potential significance in health and disease. Antioxid Redox Signal2009;11:669702.
8. van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim Shapiro DB, KozlovAV, et al. Nitrite as regulator of hypoxic signaling in mammalian physiology. Med ResRev2009;29:683741.
9. Broniowska KA, Hogg N. The chemical biology of S nitrosothiols. Antioxid RedoxSignal2012;17:969980.
10. Scatena R, Bottoni P, Pontoglio A, Giardina B. Pharmacological modulation of nitricoxide release: new pharmacological perspectives, potential benefits and risks. Curr MedChem2010;17:6173.
11. Serafim RA, Primi MC, Trossini GH, Ferreira EI. Nitric oxide: state of the art in drugdesign. Curr Med Chem2012;19:386405.
12. Chuah SC, Moore PK, Zhu YZ. S allylcysteine mediates cardioprotection in an acutemyocardial infarction rat model via a hydrogen sulfide mediated pathway. Am J PhysiolHeart Circ Physiol2007;293:H26932701.
13. Pinto JT, Krasnikov BF, Cooper AJ. Redox sensitive proteins are potential targets ofgarlic derived mercaptocysteine derivatives. J Nutr2006;136:835S841S.
14. Ried K, Frank OR, Stocks NP. Aged garlic extract lowers blood pressure in patientswith treated but uncontrolled hypertension: a randomised controlled trial. Maturitas2010;67:144150.
1. Eiland E, Nzerue C, Faulkner M. Preeclampsia2012. J Pregnancy2012;2012:586578.
2. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternalendothelium: the role of antiangiogenic factors and implications for later cardiovasculardisease. Circulation2011;123:28562869.
3. Bates DO. An unexpected tail of VEGF and PlGF in pre eclampsia. Biochem Soc Trans2011;39:15761582.
4. Wu FT, Stefanini MO, Mac Gabhann F, Kontos CD, Annex BH, Popel AS. A systemsbiology perspective on sVEGFR1: its biological function, pathogenic role andtherapeutic use. J Cell Mol Med2010;14:528552.
5. Nagai A, Sado T, Naruse K, Noguchi T, Haruta S, Yoshida S, Tanase Y, et al.Antiangiogenic induced hypertension: the molecular basis of signaling network.Gynecol Obstet Invest2012;73:8998.
6. Hay N. Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta2011;1813:19651970.
7. Cindrova Davies T, Sanders DA, Burton GJ, Charnock Jones DS. Soluble FLT1sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGFreceptor mediated signalling. Cardiovasc Res2011;89:671679.
8. Cudmore MJ, Ahmad S, Sissaoui S, Ramma W, Ma B, Fujisawa T, Al Ani B, et al. Lossof Akt activity increases circulating soluble endoglin release in preeclampsia:identification of inter dependency between Akt1and heme oxygenase1. Eur Heart J2012;33:11501158.
9. Kokkinos MI, Murthi P, Wafai R, Thompson EW, Newgreen DF. Cadherins in thehuman placenta epithelial mesenchymal transition (EMT) and placental development.Placenta2010;31:747755.
10. Stahmann N, Woods A, Spengler K, Heslegrave A, Bauer R, Krause S, Viollet B, et al.Activation of AMP activated protein kinase by vascular endothelial growth factormediates endothelial angiogenesis independently of nitric oxide synthase. J Biol Chem2010;285:1063810652.
11. Schweighofer B, Schultes J, Pomyje J, Hofer E. Signals and genes induced byangiogenic growth factors in comparison to inflammatory cytokines in endothelial cells.Clin Hemorheol Microcirc2007;37:5762.
12. Henao DE, Cadavid AP, Saleem MA. Exogenous vascular endothelial growth factorsupplementation can restore the podocyte barrier forming capacity disrupted by sera ofpreeclamptic women. J Obstet Gynaecol Res2013;39:4652.
13. Chedraui P, Solis EJ, Bocci G, Gopal S, Russo E, Escobar GS, Hidalgo L, et al.Feto placental nitric oxide, asymmetric dimethylarginine and vascular endothelialgrowth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia. JMatern Fetal Neonatal Med2013;26:226232.
14. Govender L, Mackraj I, Gathiram P, Moodley J. The role of angiogenic, anti angiogenicand vasoactive factors in pre eclamptic African women: early versus late onsetpre eclampsia. Cardiovasc J Afr2012;23:153159.
15. Shibuya M. Vascular endothelial growth factor and its receptor system: physiologicalfunctions in angiogenesis and pathological roles in various diseases. J Biochem2013;153:1319.
16. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved inangiogenesis versus lymphangiogenesis. Curr Opin Cell Biol2009;21:154165.
17. Leanos Miranda A, Campos Galicia I, Isordia Salas I, Rivera Leanos R, Romero ArauzJF, Ayala Mendez JA, Ulloa Aguirre A. Changes in circulating concentrations ofsoluble fms like tyrosine kinase1and placental growth factor measured by automatedelectrochemiluminescence immunoassays methods are predictors of preeclampsia. JHypertens2012;30:21732181.
18. Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, et al.eNOS deficiency acts through endothelin to aggravate sFlt1inducedpre eclampsia like phenotype. J Am Soc Nephrol2012;23:652660.
19. Suzuki H, Ohkuchi A, Matsubara S, Takei Y, Murakami M, Shibuya M, Suzuki M, et al.Effect of recombinant placental growth factor2on hypertension induced by full lengthmouse soluble fms like tyrosine kinase1adenoviral vector in pregnant mice.Hypertension2009;54:11291135.
20. Fox KA, Longo M, Tamayo E, Kechichian T, Bytautiene E, Hankins GD, Saade GR, etal. Effects of pravastatin on mediators of vascular function in a mouse model of solubleFms like tyrosine kinase1induced preeclampsia. Am J Obstet Gynecol2011;205:366e361365.
21. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, et al. Excessplacental soluble fms like tyrosine kinase1(sFlt1) may contribute to endothelialdysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest2003;111:649658.
22. Facemire CS, Nixon AB, Griffiths R, Hurwitz H, Coffman TM. Vascular endothelialgrowth factor receptor2controls blood pressure by regulating nitric oxide synthaseexpression. Hypertension2009;54:652658.
23. Gilbert JS, Verzwyvelt J, Colson D, Arany M, Karumanchi SA, Granger JP.Recombinant vascular endothelial growth factor121infusion lowers blood pressure andimproves renal function in rats with placentalischemia induced hypertension.Hypertension2010;55:380385.
24. Bergmann A, Ahmad S, Cudmore M, Gruber AD, Wittschen P, Lindenmaier W,Christofori G, et al. Reduction of circulating soluble Flt1alleviates preeclampsia likesymptoms in a mouse model. J Cell Mol Med2010;14:18571867.
25. Vignon Zellweger N, Heiden S, Miyauchi T, Emoto N. Endothelin and endothelinreceptors in the renal and cardiovascular systems. Life Sci2012;91:490500.
26. Mazzuca MQ, Khalil RA. Vascular endothelin receptor type B: structure, function anddysregulation in vascular disease. Biochem Pharmacol2012;84:147162.
27. Jain A. Endothelin1: a key pathological factor in pre eclampsia? Reprod BiomedOnline2012;25:443449.
28. Bernardi F, Constantino L, Machado R, Petronilho F, Dal Pizzol F. Plasma nitric oxide,endothelin1, arginase and superoxide dismutase in pre eclamptic women. J ObstetGynaecol Res2008;34:957963.
29. LaMarca BB, Cockrell K, Sullivan E, Bennett W, Granger JP. Role of endothelin inmediating tumor necrosis factor induced hypertension in pregnant rats. Hypertension2005;46:8286.
30. Tam Tam KB, George E, Cockrell K, Arany M, Speed J, Martin JN, Jr., Lamarca B, etal. Endothelin type A receptor antagonist attenuates placental ischemia inducedhypertension and uterine vascular resistance. Am J Obstet Gynecol2011;204:330e331334.
31. Chen DD, Dong YG, Yuan H, Chen AF. Endothelin1activation of endothelin Areceptor/NADPH oxidase pathway and diminished antioxidants critically contribute toendothelial progenitor cell reduction and dysfunction in salt sensitive hypertension.Hypertension2012;59:10371043.
32. Fiore G, Florio P, Micheli L, Nencini C, Rossi M, Cerretani D, Ambrosini G, et al.Endothelin1triggers placental oxidative stress pathways: putative role in preeclampsia.J Clin Endocrinol Metab2005;90:42054210.
33. Kingman M, Ruggiero R, Torres F. Ambrisentan, an endothelin receptor typeA selective endothelin receptor antagonist, for the treatment of pulmonary arterialhypertension. Expert Opin Pharmacother2009;10:18471858.
34. Gao Y. The multiple actions of NO. Pflugers Arch2010;459:829839.
35. Huang LT, Hsieh CS, Chang KA, Tain YL. Roles of nitric oxide and asymmetricdimethylarginine in pregnancy and fetal programming. Int J Mol Sci2012;13:1460614622.
36. Boeldt DS, Yi FX, Bird IM. eNOS activation and NO function: pregnancy adaptiveprogramming of capacitative entry responses alters nitric oxide (NO) output in vascularendothelium new insights into eNOS regulation through adaptive cell signaling. JEndocrinol2011;210:243258.
37. Tortladze M, Kintraia N, Sanikidze T. The EPR study of nitric oxide in placenta duringpreeclampsia. Georgian Med News2012:5559.
38. Dai B, Liu T, Zhang B, Zhang X, Wang Z. The polymorphism for endothelial nitricoxide synthase gene, the level of nitric oxide and the risk for pre eclampsia: Ameta analysis. Gene2013.
39. Kalidindi M, Velauthar L, Khan K, Aquilina J. The role of nitrates in the prevention ofpreeclampsia: an update. Curr Opin Obstet Gynecol2012;24:361367.
40. Korokin MV, Pokrovsky MV, Novikov OO, Gureev VV, Denisyuk TA, Korokina LV,Polyanskaya OS, et al. Effect of L arginine, vitamin B6and folic acid on parameters ofendothelial dysfunction and microcirculation in the placenta in modeling ofL NAME induced NO deficiency. Bull Exp Biol Med2011;152:7072.
41. Turgut NH, Temiz TK, Bagcivan I, Turgut B, Gulturk S, Karadas B. The effect ofsildenafil on the altered thoracic aorta smooth muscle responses in rat pre eclampsiamodel. Eur J Pharmacol2008;589:180187.
42. Wareing M, Myers JE, O'Hara M, Kenny LC, Warren AY, Taggart MJ, Skillern L, et al.Effects of a phosphodiesterase5(PDE5) inhibitor on endothelium dependent relaxationof myometrial small arteries. Am J Obstet Gynecol2004;190:12831290.
43. Evora PR, Evora PM, Celotto AC, Rodrigues AJ, Joviliano EE. Cardiovasculartherapeutics targets on the NO sGC cGMP signaling pathway: a critical overview. CurrDrug Targets2012;13:12071214.
1. Bates DO. An unexpected tail of VEGF and PlGF in pre eclampsia. Biochem Soc Trans2011;39:15761582.
2. Shibuya M. Vascular endothelial growth factor and its receptor system: physiologicalfunctions in angiogenesis and pathological roles in various diseases. J Biochem2013;153:1319.
3. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved inangiogenesis versus lymphangiogenesis. Curr Opin Cell Biol2009;21:154165.
4. Chedraui P, Solis EJ, Bocci G, Gopal S, Russo E, Escobar GS, Hidalgo L, et al.Feto placental nitric oxide, asymmetric dimethylarginine and vascular endothelialgrowth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia. JMatern Fetal Neonatal Med2013;26:226232.
5. Cao Y. Positive and negative modulation of angiogenesis by VEGFR1ligands. SciSignal2009;2:re1.
6. De Falco S. The discovery of placenta growth factor and its biological activity. Exp MolMed2012;44:19.
7. Jacobs M, Nassar N, Roberts CL, Hadfield R, Morris JM, Ashton AW. Levels of solublefms like tyrosine kinase one in first trimester and outcomes of pregnancy: a systematicreview. Reprod Biol Endocrinol2011;9:77.
8. Leanos Miranda A, Campos Galicia I, Isordia Salas I, Rivera Leanos R, Romero ArauzJF, Ayala Mendez JA, Ulloa Aguirre A. Changes in circulating concentrations ofsoluble fms like tyrosine kinase1and placental growth factor measured by automatedelectrochemiluminescence immunoassays methods are predictors of preeclampsia. JHypertens2012;30:21732181.
9. Rohra DK, Zeb A, Qureishi RN, Azam SI, Khan NB, Zuberi HS, Sikandar R. Predictionof pre eclampsia during early pregnancy in primiparas with soluble fms like tyrosinekinase1and placental growth factor. Natl Med J India2012;25:6873.
10. Gomez Arriaga P, Herraiz I, Lopez Jimenez E, Gomez Montes E, Denk B, Galindo A.Uterine artery Doppler and sFlt1/PlGF ratio: usefulness in the diagnosis ofpre eclampsia. Ultrasound Obstet Gynecol2013.
11. Nachtigal P, Zemankova Vecerova L, Rathouska J, Strasky Z. The role of endoglin inatherosclerosis. Atherosclerosis2012;224:411.
12. Santibanez JF, Letamendia A, Perez Barriocanal F, Silvestri C, Saura M, Vary CP,Lopez Novoa JM, et al. Endoglin increases eNOS expression by modulating Smad2protein levels and Smad2dependent TGF beta signaling. J Cell Physiol2007;210:456468.
13. Park S, Dimaio TA, Liu W, Wang S, Sorenson CM, Sheibani N. Endoglin Regulates theActivation and Quiescence of Endothelium by Participating in Canonical andNon Canonical TGF beta Signaling Pathways. J Cell Sci2013.
14. Mano Y, Kotani T, Shibata K, Matsumura H, Tsuda H, Sumigama S, Yamamoto E, et al.The loss of endoglin promotes the invasion of extravillous trophoblasts. Endocrinology2011;152:43864394.
15. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, et al.Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med2006;12:642649.
16. Leanos Miranda A, Campos Galicia I, Ramirez Valenzuela KL, Chinolla Arellano ZL,Isordia Salas I. Circulating Angiogenic Factors and Urinary Prolactin as Predictors ofAdverse Outcomes in Women With Preeclampsia. Hypertension2013.
17. Elhawary TM, El Bendary AS, Demerdash H. Maternal serum endoglin as an earlymarker of pre eclampsia in high risk patients. Int J Womens Health2012;4:521525.
18. Lai J, Syngelaki A, Poon LC, Nucci M, Nicolaides KH. Maternal Serum SolubleEndoglin at3033Weeks in the Prediction of Preeclampsia. Fetal Diagn Ther2012.
19. Foidart JM, Munaut C, Chantraine F, Akolekar R, Nicolaides KH. Maternal plasmasoluble endoglin at1113weeks' gestation in pre eclampsia. Ultrasound Obstet Gynecol2010;35:680687.
20. Mignini LE, Latthe PM, Villar J, Kilby MD, Carroli G, Khan KS. Mapping the theoriesof preeclampsia: the role of homocysteine. Obstet Gynecol2005;105:411425.
21. Mujawar SA, Patil VW, Daver RG. Study of serum homocysteine, folic Acid andvitamin b(12) in patients with preeclampsia. Indian J Clin Biochem2011;26:257260.
22. Murphy MM, Fernandez Ballart JD. Homocysteine in pregnancy. Adv Clin Chem2011;53:105137.
23. Castelao JE, Gago Dominguez M. Risk factors for cardiovascular disease in women:relationship to lipid peroxidation and oxidative stress. Med Hypotheses2008;71:3944.
24. Singh U, Gupta HP, Singh RK, Shukla M, Singh R, Mehrotra SS, Prasad S. A study ofchanges in homocysteine levels during normal pregnancy and pre eclampsia. J IndianMed Assoc2008;106:503505.
25. Walker MC, Smith GN, Perkins SL, Keely EJ, Garner PR. Changes in homocysteinelevels during normal pregnancy. Am J Obstet Gynecol1999;180:660664.
26. Acilmis YG, Dikensoy E, Kutlar AI, Balat O, Cebesoy FB, Ozturk E, Cicek H, et al.Homocysteine, folic acid and vitamin B12levels in maternal and umbilical cord plasmaand homocysteine levels in placenta in pregnant women with pre eclampsia. J ObstetGynaecol Res2011;37:4550.
27. Khosrowbeygi A, Ahmadvand H. Circulating levels of homocysteine in preeclampticwomen. Bangladesh Med Res Counc Bull2011;37:106109.
28. Shenoy V, Kanasaki K, Kalluri R. Pre eclampsia: connecting angiogenic and metabolicpathways. Trends Endocrinol Metab2010;21:529536.
29. Shiraishi M, Haruna M, Matsuzaki M, Ota E, Murayama R, Watanabe E, Sasaki S, et al.Association between oxidized LDL and folate during pregnancy. Biol Res Nurs2013;15:213218.
30. Usluer H, Turker G, Gokalp AS. Value of homocysteine levels, troponin I, and score forneonatal acute physiology and perinatal extension II as early predictors of morbidity.Pediatr Int2012;54:104110.
31. D'Anna R, Baviera G, Corrado F, Ientile R, Granese D, Stella NC. Plasma homocysteinein early and late pregnancies complicated with preeclampsia and isolated intrauterinegrowth restriction. Acta Obstet Gynecol Scand2004;83:155158.
32. Bouras G, Deftereos S, Tousoulis D, Giannopoulos G, Chatzis G, Tsounis D, ClemanMW, et al. Asymmetric dimethylarginine (ADMA): a promising biomarker forcardiovascular disease? Curr Top Med Chem2013.
33. Poniedzialek Czajkowska E, Marciniak B, Kimber Trojnar Z, Leszczynska Gorzelak B,Oleszczuk J. Nitric oxide in normal and preeclamptic pregnancy. Curr PharmBiotechnol2011;12:743749.
34. Sibal L, Agarwal SC, Home PD, Boger RH. The Role of Asymmetric Dimethylarginine(ADMA) in Endothelial Dysfunction and Cardiovascular Disease. Curr Cardiol Rev2010;6:8290.
35. Rizos D, Eleftheriades M, Batakis E, Rizou M, Haliassos A, Hassiakos D, Botsis D.Levels of asymmetric dimethylarginine throughout normal pregnancy and inpregnancies complicated with preeclampsia or had a small for gestational age baby. JMatern Fetal Neonatal Med2012;25:13111315.
36. Demir B, Demir S, Pasa S, Guven S, Atamer Y, Atamer A, Kocyigit Y. The role ofhomocysteine, asymmetric dimethylarginine and nitric oxide in pre eclampsia. J ObstetGynaecol2012;32:525528.
37. Laskowska M, Laskowska K, Oleszczuk J. Differences in the association betweenmaternal serum homocysteine and ADMA levels in women with pregnanciescomplicated by preeclampsia and/or intrauterine growth restriction. HypertensPregnancy2013;32:8393.
38. Anderssohn M, Maass LM, Diemert A, Luneburg N, Atzler D, Hecher K, Boger RH.Severely decreased activity of placental dimethylarginine dimethylaminohydrolase inpre eclampsia. Eur J Obstet Gynecol Reprod Biol2012;161:152156.
39. Ahima RS, Flier JS. Leptin. Annu Rev Physiol2000;62:413437.
40. Miehle K, Stepan H, Fasshauer M. Leptin, adiponectin and other adipokines ingestational diabetes mellitus and pre eclampsia. Clin Endocrinol (Oxf)2012;76:211.
41. Elhawary TM, Demerdash HD, Sweilam MA. Relationship between Interleukin10Polymorphism and Maternal Serum Leptin Level in Preeclampsia. Clin Exp Hypertens2012.
42. Samolis S, Papastefanou I, Panagopoulos P, Galazios G, Kouskoukis A, Maroulis G.Relation between first trimester maternal serum leptin levels and body mass index innormotensive and pre eclamptic pregnancies role of leptin as a marker ofpre eclampsia: a prospective case control study. Gynecol Endocrinol2010;26:338343.
43. Sitras V, Paulssen RH, Gronaas H, Leirvik J, Hanssen TA, Vartun A, Acharya G.Differential placental gene expression in severe preeclampsia. Placenta2009;30:424433.
44. Basak S, Duttaroy AK. Leptin induces tube formation in first trimester extravilloustrophoblast cells. Eur J Obstet Gynecol Reprod Biol2012;164:2429.
45. Maymo JL, Perez AP, Gambino Y, Calvo JC, Sanchez Margalet V, Varone CL. Review:Leptin gene expression in the placenta regulation of a key hormone in trophoblastproliferation and survival. Placenta2011;32Suppl2:S146153.
46. Jansson N, Greenwood SL, Johansson BR, Powell TL, Jansson T. Leptin stimulates theactivity of the system A amino acid transporter in human placental villous fragments. JClin Endocrinol Metab2003;88:12051211.
47. Klaffenbach D, Meissner U, Raake M, Fahlbusch F, Alejandre Alcazar MA, Allabauer I,Kratzsch J, et al. Upregulation of leptin receptor in placental cells by hypoxia. RegulPept2011;167:156162.
48. Molvarec A, Szarka A, Walentin S, Beko G, Karadi I, Prohaszka Z, Rigo J, Jr. Serumleptin levels in relation to circulating cytokines, chemokines, adhesion molecules andangiogenic factors in normal pregnancy and preeclampsia. Reprod Biol Endocrinol2011;9:124.
49. Dalamaga M, Srinivas SK, Elovitz MA, Chamberland J, Mantzoros CS. Serumadiponectin and leptin in relation to risk for preeclampsia: results from a largecase control study. Metabolism2011;60:15391544.
50. Gaidamauskas E, Gyrup C, Boldt HB, Schack VR, Overgaard MT, Laursen LS, OxvigC. IGF dependent modulation of IGF binding protein (IGFBP) proteolysis bypregnancy associated plasma protein A (PAPP A): Multiple PAPP A IGFBP interactionsites. Biochim Biophys Acta2012.
51. Handschuh K, Guibourdenche J, Guesnon M, Laurendeau I, Evain Brion D, Fournier T.Modulation of PAPP A expression by PPARgamma in human first trimester trophoblast.Placenta2006;27Suppl A:S127134.
52. She BQ, Chen SC, Lee FK, Cheong ML, Tsai MS. Low maternal serum levels ofpregnancy associated plasma protein A during the first trimester are associated withsubsequent preterm delivery with preterm premature rupture of membranes. Taiwan JObstet Gynecol2007;46:242247.
53. Goetzinger KR, Singla A, Gerkowicz S, Dicke JM, Gray DL, Odibo AO. Predicting therisk of pre eclampsia between11and13weeks' gestation by combining maternalcharacteristics and serum analytes, PAPP A and free beta hCG. Prenat Diagn2010;30:11381142.
54. Bestwick JP, George LM, Wu T, Morris JK, Wald NJ. The value of early secondtrimester PAPP A and ADAM12in screening for pre eclampsia. J Med Screen2012;19:5154.
55. Atis A, Tandogan T, Aydin Y, Sen C, Turgay F, Eren N, Goker N. Late pregnancyassociated plasma protein A levels decrease in preterm labor. J Matern Fetal NeonatalMed2011;24:923927.
56. Huppertz B, Meiri H, Gizurarson S, Osol G, Sammar M. Placental protein13(PP13): anew biological target shifting individualized risk assessment to personalized drugdesign combating pre eclampsia. Hum Reprod Update2013.
57. Than NG, Pick E, Bellyei S, Szigeti A, Burger O, Berente Z, Janaky T, et al. Functionalanalyses of placental protein13/galectin13. Eur J Biochem2004;271:10651078.
58. Kliman HJ, Sammar M, Grimpel YI, Lynch SK, Milano KM, Pick E, Bejar J, et al.Placental protein13and decidual zones of necrosis: an immunologic diversion that maybe linked to preeclampsia. Reprod Sci2012;19:1630.
59. El Sherbiny WS, Soliman A, Nasr AS. Placental protein13as an early predictor inEgyptian patients with preeclampsia, correlation to risk, and association with outcome.J Investig Med2012;60:818822.
60. Than NG, Abdul Rahman O, Magenheim R, Nagy B, Fule T, Hargitai B, Sammar M, etal. Placental protein13(galectin13) has decreased placental expression but increasedshedding and maternal serum concentrations in patients presenting with pretermpre eclampsia and HELLP syndrome. Virchows Arch2008;453:387400.
61. Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H, Harrington K. First trimestermarkers for the prediction of pre eclampsia in women with a priori high risk.Ultrasound Obstet Gynecol2010;35:671679.
62. Odibo AO, Zhong Y, Goetzinger KR, Odibo L, Bick JL, Bower CR, Nelson DM.First trimester placental protein13, PAPP A, uterine artery Doppler and maternalcharacteristics in the prediction of pre eclampsia. Placenta2011;32:598602.
63. Romero R, Kusanovic JP, Than NG, Erez O, Gotsch F, Espinoza J, Edwin S, et al.First trimester maternal serum PP13in the risk assessment for preeclampsia. Am JObstet Gynecol2008;199:122e121122e111.
64. Centlow M, Carninci P, Nemeth K, Mezey E, Brownstein M, Hansson SR. Placentalexpression profiling in preeclampsia: local overproduction of hemoglobin may drivepathological changes. Fertil Steril2008;90:18341843.
65. Balla J, Vercellotti GM, Jeney V, Yachie A, Varga Z, Eaton JW, Balla G. Heme, hemeoxygenase and ferritin in vascular endothelial cell injury. Mol Nutr Food Res2005;49:10301043.
66. Ascenzi P, Bocedi A, Visca P, Altruda F, Tolosano E, Beringhelli T, Fasano M.Hemoglobin and heme scavenging. IUBMB Life2005;57:749759.
67. May K, Rosenlof L, Olsson MG, Centlow M, Morgelin M, Larsson I, Cederlund M, etal. Perfusion of human placenta with hemoglobin introduces preeclampsia like injuriesthat are prevented by alpha1microglobulin. Placenta2011;32:323332.
68. Anderson UD, Olsson MG, Rutardottir S, Centlow M, Kristensen KH, Isberg PE,Thilaganathan B, et al. Fetal hemoglobin and alpha1microglobulin as first and earlysecond trimester predictive biomarkers for preeclampsia. Am J Obstet Gynecol2011;204:520e521525.
69. Olsson MG, Centlow M, Rutardottir S, Stenfors I, Larsson J, Hosseini Maaf B, OlssonML, et al. Increased levels of cell free hemoglobin, oxidation markers, and theantioxidative heme scavenger alpha(1) microglobulin in preeclampsia. Free Radic BiolMed2010;48:284291.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |