Dysregulation of Angiopoietins Is Associated with Placental Malaria and Low Birth Weight

Abstract

BackgroundPlacental malaria (PM) is associated with adverse pregnancy outcomes including low birth weight (LBW). However, the precise mechanisms by which PM induces LBW are poorly defined. Based on the essential role of angiopoietin (ANG)-1 and -2 in normal placental vascular development, we hypothesized that PM may result in the dysregulation of angiopoietins and thereby contribute to LBW outcomes.Methods and FindingsIn a mouse model of PM, we show that Plasmodium berghei ANKA infection of pregnant mice resulted in dysregulated angiopoietin levels and fetal growth restriction. PM lead to decreased ANG-1, increased ANG-2, and an elevated ratio of ANG-2/ANG-1 in the placenta and the serum. These observations were extended to malaria-exposed pregnant women: In a study of primigravid women prospectively followed over the course of pregnancy, Plasmodium falciparum infection was associated with a decrease in maternal plasma ANG-1 levels (P = 0.031) and an increase in the ANG-2:ANG-1 ratio (P = 0.048). ANG-1 levels recovered with successful treatment of peripheral parasitemia (P = 0.010). In a cross-sectional study of primigravidae at delivery, angiopoietin dysregulation was associated with PM (P = 0.002) and LBW (P = 0.041). Women with PM who delivered LBW infants had increased ANG-2:ANG-1 ratios (P = 0.002) compared to uninfected women delivering normal birth weight infants.ConclusionsThese data support the hypothesis that dysregulation of angiopoietins is associated with PM and LBW outcomes, and suggest that ANG-1 and ANG-2 levels may be clinically informative biomarkers to identify P. falciparum-infected mothers at risk of LBW deliveries.

Biomarkers of endothelial activation/dysfunction in infectious diseases

“…Subsequent studies, however, have all identified Ang-1 as a more consistent diagnostic biomarker in malaria, discriminating between cerebral malaria and uncomplicated malaria in Thai adults and Ugandan children, between cerebral, severe, and uncomplicated malaria in Thai adults, and between cerebral malaria with retinopathy and febrile, non-malarial causes of decreased level of consciousness in Malawian children 28 - 30 . Furthermore, decreased Ang-1 was associated with P. falciparum malaria in pregnancy, while an increased Ang-2:Ang-1 ratio was associated with both placental malaria and low birth weight infants 31 . As a prognostic marker, the plasma Ang-2 concentration at admission to hospital has been shown to correlate with mortality in children with cerebral malaria in two separate studies 32 , 33 …”

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

“…Animal protocols were approved by the Toronto University Health Network Animal Care Committee and performed in accordance with the Canadian Council on Animal Care Guidelines. We used a previously validated mouse model of PM that replicates key pathogenic features of human PM, including placental parasite sequestration, placental inflammation, spontaneous abortion, and fetal growth restriction (Silver et al, 2010). Eight-to ten-week-old Balb/c female mice were obtained from The Jackson Laboratories Inc. (Bar Harbor, ME) and maintained on a 12-hour light/dark cycle with ad libitum access to standard rodent chow and water.…”

“…Females were mated and checked for the presence of a vaginal plug (GD1). Cryopreserved PbA strain malaria (MR4; American Type Culture Collection, Manassas, VA) was passaged through a male Balb/c mouse as previously described (Silver et al, 2010). On GD13, dams were inoculated with 10 6 PbA-infected erythrocytes in RPMI (Sigma-Aldrich, Oakville, ON, Canada) via tail vein injection.…”

The role of Vitamin D in malaria

“…Plasma levels of Ang-2 and ratio of Ang-2/Ang-1 are clinical biomarkers that can predict fatal cerebral malaria [57][58][59]. Dysregulation of Angs is associated with placental malaria and low birth weight [60]. The association of increased Ang-2 and decreased nitric oxide are poor outcomes in severe P. falciparum [61][62].…”