Lack of nitric oxide bioavailability in early pregnancy predisposes to dyslipidemia and surges preeclampsia and fetal growth retardation

Aida A. Korish


Background: Hyperlipidemia has been reported in preeclampsia (PrE) and is linked to poor pregnancy outcome and long-term cardiovascular complications. This study aimed to elucidate the relationship between nitric oxide (NO) and blood lipids levels during normal pregnancy and in NG-nitro-l-arginine methyl ester (L-NAME) - induced preeclampsia before and after magnesium sulphate (MgSO4) therapy and its effect on the pregnancy outcome.

Methods: Forty female Wistar rats were divided into four groups: non pregnant (NP) group - non pregnant healthy rats receiving no treatment, control pregnant (Con-P) group - control pregnant rats receiving no treatment, pregnant (PE) group - pregnant animals with untreated PrE, and the pregnant MgSO4 (PE-Mg) group - pregnant animals with PrE- treated with MgSO4. The nitric oxide synthase inhibitor L-NAME was used to induce experimental model of PrE in the PE and the PE-Mg groups. The changes in total NO production, total cholesterol (TC), triglycerides (TG), low density lipoproteins (LDL-C), high density lipoproteins (HDL), LDL-C/HDL-C ratio, soluble vascular endothelial growth factor receptor-1 (sVEGFR1) also known as sFlt-1, blood pressure, kidney functions, body weight, and pregnancy outcome were assessed.

Results: Decreased NO production in the PE group was associated with elevated TC, TG, LDL-C/HDL-C ratio, hypertension, proteinuria, increased urea, creatinine, and sFlt-1 levels, and poor pregnancy outcome demonstrated by high pup mortality rate and low birth weight. Increased NO production in the PE-Mg group treated with MgSO4 therapy was associated with decreased signs of preeclampsia and hypolipidemia and increased pup viability and birth weight.

Conclusions: NO bioavailability is crucial for the homeostasis of the lipid profile in normal pregnancy and the prevention of preeclampsia. Routine periodic assessments of the blood lipid profile and the NO production in the pregnant females may be a helpful tool in early prediction of preeclampsia.


Preeclampsia, Nitric oxide, Hyperlipidemia, Low birth weight, Endothelial dysfunction, Magnesium sulphate

Full Text:



Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;170(1):1-7.

Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. InSeminars in perinatology. 2012;36(1):56-9.

Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circulation research. 2019;124(7):1094-112.

M Reslan O, A Khalil R. Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia. Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Cardiovascular & Hematological Agents). 2010;8(4):204-26.

Boeldt DS, Bird IM. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. The Journal of endocrinology. 2017;232(1):27.

Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: An endothelial cell disorder. International Journal of Gynecology & Obstetrics. 1990;32(3):299.

Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of hypertension during preeclampsia linking placental ischemia with endothelial dysfunction. Hypertension. 2001;38(3):718-22.

Roberts JM, Escudero C. The placenta in preeclampsia. Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 2012;2(2):72-83.

Vikse BE. Pre-eclampsia and the risk of kidney disease. Lancet. 2013;382(9887):104-6.

Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta- analysis. BMJ. 2007;335(7627):974.

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. Revista Espanola De Cardiologia (English ed). 2016;69(10):939.

Charlton F, Tooher J, Rye KA, Hennessy A. Cardiovascular risk, lipids and pregnancy: preeclampsia and the risk of later life cardiovascular disease. Heart, Lung and Circulation. 2014;23(3):203-312.

Cabral CE, Klein MR. Phytosterols in the treatment of hypercholesterolemia and prevention of cardiovascular diseases. Arquivos brasileiros de cardiologia. 2017;109(5):475-82.

Hadden DR, McLaughlin C. Normal and abnormal maternal metabolism during pregnancy. InSeminars in Fetal and Neonatal Medicine. 2009;14:66-71.

King JC. Physiology of pregnancy and nutrient metabolism. The American journal of clinical nutrition. 2000;71(5):1218-25.

Adank MC, Benschop L, Peterbroers KR, Gregoor AM, Kors AW, Mulder MT, Schalekamp-Timmermans S, Van Lennep JE, Steegers EA. Is maternal lipid profile in early pregnancy associated with pregnancy complications and blood pressure in pregnancy and long term postpartum? American journal of obstetrics and gynecology. 2019;221(2):150-1.

Alahakoon TI, Medbury HJ, Williams H, Lee VW. Lipid profiling in maternal and fetal circulations in preeclampsia and fetal growth restriction-a prospective case control observational study. BMC Pregnancy and Childbirth. 2020;20(1):61.

Ghodke B, Pusukuru R, Mehta V. Association of lipid profile in pregnancy with preeclampsia, gestational diabetes mellitus, and preterm delivery. Cureus. 2017;9(7).

Al-Amin A, Rolnik DL, Black C, White A, Stolarek C, Brennecke S, et al. Accuracy of second trimester prediction of preterm preeclampsia by three different screening algorithms. Aust N Z J Obstet Gynaecol. 2018;58(2):192-6.

Korish AA. Magnesium sulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis. Hypertension Research. 2012;35(10):1005-11.

Shafik AN, Khattab MA, Osman AH. Magnesium sulfate versus esomeprazole impact on the neonates of preeclamptic rats. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2018;225:236-42.

Yalamati P, Bhongir AV, Karra M, Beedu SR. Comparative analysis of urinary total proteins by bicinchoninic acid and pyrogallol red molybdate methods. Journal of clinical and diagnostic research: JCDR. 2015;9(8):BC01.

Thalineau E, Truong HN, Berger A, Fournier C, Boscari A, Wendehenne D, Jeandroz S. Cross-regulation between N metabolism and nitric oxide (NO) signaling during plant immunity. Frontiers in plant science. 2016;7:472.

Krause BJ, Hanson MA, Casanello P. Role of nitric oxide in placental vascular development and function. Placenta. 2011;32(11):797-805.

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 in primary human trophoblast. Placenta. 2011;32:926-31.

Sutton EF, Gemmel M, Powers RW. Nitric oxide signaling in pregnancy and preeclampsia. Nitric Oxide. 2020;95:55-62.

Jeyabalan A, Novak J, Danielson LA, Kerchner LJ, Opett SL, Conrad KP. Essential role for vascular gelatinase activity in relaxin-induced renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small arteries. Circulation research. 2003;93(12):1249-57.

Shaamash AH, Elsnosy ED, Makhlouf AM, Zakhari MM, Ibrahim OA, EL-dien HM. Maternal and fetal serum nitric oxide (NO) concentrations in normal pregnancy, pre-eclampsia and eclampsia. Int J Gynaecol Obstet. 2000;68:207-14.

Shah DA, Khalil RA. Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia. Biochemical pharmacology. 2015;95(4):211-26.

Ngene NC, Moodley J. Role of angiogenic factors in the pathogenesis and management of pre‐eclampsia. International Journal of Gynecology & Obstetrics. 2018;141(1):5-13.

Osol G, Ko NL, Mandalà M. Altered endothelial nitric oxide signaling as a paradigm for maternal vascular maladaptation in preeclampsia. Current hypertension reports. 2017;19(10):82.

Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. The Journal of clinical investigation. 2003;111(5):649-58.

Sandrim VC, Palei AC, Metzger IF, Gomes VA, Cavalli RC, Tanus-Santos JE. Nitric oxide formation is inversely related to serum levels of antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endogline in preeclampsia. Hypertension. 2008;52(2):402-7.

Dymara-Konopka W, Laskowska M, Błażewicz A. Angiogenic imbalance as a contributor of preeclampsia. Current pharmaceutical biotechnology. 2018;19(10):797-815.

Sharami SH, Ranjbar ZA, Alizadeh F, Kazemnejad E. The relationship of hyperlipidemia with maternal and neonatal outcomes in pregnancy: A cross-sectional study. International Journal of Reproductive BioMedicine. 2019;17(10):739.

Adegoke OA, Lyare EE, Gbenebitse SO. Fasting plasma glucose and cholesterol levels in pregnant Nigerian Women. Niger Postgrad Med J. 2003;10(1):32-6.

Ardalić D, Stefanović A, Banjac G, Cabunac P, Miljković M, Mandić-Marković V, Stanimirović S, Pažin BD, Spasić S, Spasojević-Kalimanovska V, Karadžov-Orlić N. Lipid profile and lipid oxidative modification parameters in the first trimester of high-risk pregnancies-possibilities for preeclampsia prediction. Clinical biochemistry. 2020;81:34-40.

Agarwal V, Gupta BK, Vishnu A. Association of lipid profile and uric acid with pre-eclampsia of third trimester in nullipara women. Journal of clinical and diagnostic research: JCDR. 2014;8(7):CC04.

Aluko EO, Omobowale TO, Oyagbemi AA, Adejumobi OA, Ajibade TO, Fasanmade AA. Reduction in nitric oxide bioavailability shifts serum lipid content towards atherogenic lipoprotein in rats. Biomedicine & Pharmacotherapy. 2018;101:792-7.

Ryoo S, Lemmon CA, Soucy KG, Gupta G, White AR, Nyhan D, et al. Oxidized low-density lipoprotein–dependent endothelial arginase II activation contributes to impaired nitric oxide signaling. Circulation research. 2006;99(9):951-60.

Leiva A, Salsoso R, Sáez T, Sanhueza C, Pardo F, Sobrevia L. Cross-sectional and longitudinal lipid determination studies in pregnant women reveal an association between increased maternal LDL cholesterol concentrations and reduced human umbilical vein relaxation. Placenta. 2015;36(8):895-902.

Khan TM, Malik A. Study of Magnesium Sulphate Vs Diazepam in Eclampsia. 2016. Available at: Accessed on 23 May 2021.

Okereke E, Ahonsi B, Tukur J, Ishaku SM, Oginni AB. Benefits of using magnesium sulphate (MgSO 4) for eclampsia management and maternal mortality reduction: lessons from Kano State in Northern Nigeria. BMC research notes. 2012;5(1):1-6.

Trapani A, Gonçalves LF, Trapani TF, Vieira S, Pires M, Pires MM. Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment. Obstetrics & Gynecology. 2016;128(2):253-9.

Ormesher L, Myers JE, Chmiel C, Wareing M, Greenwood SL, Tropea T, et al. Effects of dietary nitrate supplementation, from beetroot juice, on blood pressure in hypertensive pregnant women: A randomised, double-blind, placebo-controlled feasibility trial. Nitric Oxide. 2018;80:37-44.

Alexander BT, Llinas MT, Kruckeberg WC, Granger JP. L-arginine attenuates hypertension in pregnant rats with reduced uterine perfusion pressure. Hypertension. 2004;43(4):832-6.