title: Dysregulation of angiopoietins is associated with placental malaria and low birth weight.
abstract: BACKGROUND
  Placental 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: McLaughlin-Rotman Centre for Global Health, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Karlee L
authors.initials: KL
authors.lastname: Silver
authors.forename: Kathleen
authors.initials: K
authors.lastname: Zhong
authors.forename: Rose G F
authors.initials: RG
authors.lastname: Leke
authors.forename: Diane Wallace
authors.initials: DW
authors.lastname: Taylor
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D042683:Angiopoietin-1 / Q000097:blood / Q000235:genetics*; D042702:Angiopoietin-2 / Q000097:blood / Q000235:genetics*; D000818:Animals; D001724:Birth Weight; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D008288:Malaria / Q000378:metabolism* / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010920:Placenta / Q000378:metabolism* / Q000469:parasitology; D010962:Plasmodium berghei / Q000378:metabolism; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000276:immunology / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2