Research ArticleMalaria

Malaria in pregnancy alters l-arginine bioavailability and placental vascular development

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Science Translational Medicine  07 Mar 2018:
Vol. 10, Issue 431, eaan6007
DOI: 10.1126/scitranslmed.aan6007

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Malaria relief, one amino acid at a time

Malaria infection during pregnancy can disrupt placental vasculature and cause complications during the pregnancy and delivery. Nitric oxide plays a key role in placental vascular function, and its synthesis requires l-arginine. Knowing that l-arginine and nitric oxide are both depleted during malaria-induced hemolysis and that many people in malaria-endemic areas lack sufficient l-arginine in their diets, McDonald et al. examined the effects of dietary l-arginine supplementation. The authors first studied a cohort of pregnant women in Malawi and showed that the blood of patients with malaria had less l-arginine and that this was associated with worse pregnancy outcomes. Conversely, l-arginine supplementation in a mouse model of malaria in pregnancy improved fetal weight and viability, indicating the potential value of this intervention.

Abstract

Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. l-Arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that l-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of l-arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, l-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance l-arginine bioavailability as strategies to improve birth outcomes.

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