Altered Bioavailability of Nitric Oxide and L-Arginine Is a Key Determinant of Endothelial Dysfunction in Preeclampsia

Abstract

Background. Preeclampsia is a major cause of maternal and neonatal morbidity and mortality in sub-Saharan Africa. Evidence indicates that endothelial dysfunction is central to the pathogenesis of preeclampsia. This study assessed the level of the components of the arginine-nitric oxide pathway to evaluate endothelial dysfunction in normotensive pregnancies and pregnancies complicated with preeclampsia. Methods. This case-control study was conducted among pregnant women who visited Comboni Hospital from January 2017 to May 2018. A total of 180 pregnant women comprising 88 preeclamptic women (PE) and 92 healthy normotensive pregnant women (NP) were recruited. Sociodemographic, clinical, and obstetric data were obtained using validated questionnaires. Blood pressure and anthropometrics were measured, and blood samples were collected for the estimation of nitric oxide (NO∙), L-arginine, asymmetric dimethylarginine (ADMA), and 3-nitrotyrosine using an enzyme-linked immunosorbent assay technique. Results. The mean NO∙ ( p = 0.010 ) and L-arginine/ADMA ratio ( p < 0.0001 ) was significantly lower in PE compared to NP while mean L-arginine ( p = 0.034 ), ADMA ( p < 0.0001 ), and 3-nitrotyrosine ( p < 0.0001 ) were significantly higher in PE than NP. ADMA showed a significant positive association with systolic blood pressure ( β = 0.454 , p = 0.036 ) in severe PE. Women with PE had significant intrauterine growth restriction ( p < 0.0001 ) and low birth weight infants ( p < 0.0001 ) when compared to NP. Conclusion. Preeclampsia is associated with reduced NO∙ bioavailability, L-arginine/ADMA ratio, and elevated levels of ADMA and 3-nitrotyrosine. Measurements of the levels of these parameters can help in the early prediction of endothelial dysfunction in preeclampsia. Exogenous therapeutic supplementation with L-arginine during pregnancy to increase the L-arginine/ADMA ratio should be considered to improve endothelial function in preeclampsia and pregnant women at risk of developing preeclampsia.

The Pivotal Role of the Placenta in Normal and Pathological Pregnancies: A Focus on Preeclampsia, Fetal Growth Restriction, and Maternal Chronic Venous Disease

“…In this sense, some studies have found an inverse correlation between NO levels and levels of sFlt-1 and sEng in women with PE, thereby suggesting that somehow anti-angiogenic factors may inhibit the production of NO [158]. The diminished NO production is also potentially related to the reduced bioavailability of its precursor, L-arginine, both being observed in women with PE [159]. These alterations may promote changes in the renal and cardiac microvasculature as well as a reduction in the number of fetal nephrons in vivo, which can possibly also occur in humans [160].…”

Role of oxidative stress in the dysfunction of the placental endothelial nitric oxide synthase in preeclampsia

“…However DDAH is also targeted and inhibited by ROS [ 179 ]. It is suggested that reduced levels of l -arginine, rather than increased ADMA levels, may play a role in PE [ [180] , [181] , [182] ].…”

Hematobiochemical variability and predictors of new-onset and persistent postpartum preeclampsia

“…Antepartum PE is largely understood as a disorder arising from an abnormal placentation. It is thought that impaired placentation leads to the release of abnormal levels of some angiogenic, anti-angiogenic and vasoactive molecules into maternal circulation, triggering maternal endothelial dysfunction, systemic inflammation, elevated blood pressure and proteinuria 7 , 8 . Altered maternal serum levels of these molecules have been suggested as potential biomarkers of antepartum PE 7 – 9 while elevated serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and decreased serum levels of placental growth factor (PlGF), as well as elevated sFlt-1: PlGF, have been validated as biomarkers of this disease 10 – 13 .…”