title: Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria.
abstract: Placental malaria (PM) is a major cause of fetal growth restriction, yet the underlying mechanism is unclear. Complement C5a and C5a receptor levels are increased with PM. C5a is implicated in fetal growth restriction in non-infection-based animal models. In a case-control study of 492 pregnant Malawian women, we find that elevated C5a levels are associated with an increased risk of delivering a small-for-gestational-age infant. C5a was significantly increased in PM and was negatively correlated with the angiogenic factor angiopoietin-1 and positively correlated with angiopoietin-2, soluble endoglin, and vascular endothelial growth factor. Genetic or pharmacological blockade of C5a or its receptor in a mouse model of PM resulted in greater fetoplacental vessel development, reduced placental vascular resistance, and improved fetal growth and survival. These data suggest that C5a drives fetal growth restriction in PM through dysregulation of angiogenic factors essential for placental vascular remodeling resulting in placental vascular insufficiency.
authors: Sandra Rotman Laboratories, Sandra Rotman Centre, University Health Network-Toronto General Hospital, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Andrea L
authors: AL
authors: Conroy
authors: Karlee L
authors: KL
authors: Silver
authors: Kathleen
authors: K
authors: Zhong
authors: Monique
authors: M
authors: Rennie
authors: Peter
authors: P
authors: Ward
authors: J Vidya
authors: JV
authors: Sarma
authors: Malcolm E
authors: ME
authors: Molyneux
authors: John
authors: J
authors: Sled
authors: Joseph F
authors: JF
authors: Fletcher
authors: Stephen
authors: S
authors: Rogerson
authors: Kevin C
authors: KC
authors: Kain
mesh_terms: D000293:Adolescent; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003167:Complement Activation; D015936:Complement C5a / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006801:Humans; D008288:Malaria / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010920:Placenta / Q000098:blood supply / Q000469:parasitology; D010927:Placental Insufficiency / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D010962:Plasmodium berghei / Q000472:pathogenicity; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000473:pathology*; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D015415:Biomarkers; C488033:C5AR1 protein, human; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015936:Complement C5a