Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria.

Andrea L Conroy, Karlee L Silver, Kathleen Zhong, Monique Rennie, Peter Ward, J Vidya Sarma, Malcolm E Molyneux, John Sled, Joseph F Fletcher, Stephen Rogerson, Kevin C Kain

Sandra Rotman Laboratories, Sandra Rotman Centre, University Health Network-Toronto General Hospital, University of Toronto, Toronto, ON M5G 1L7, Canada.

Cell host & microbe 2013 Feb 13

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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. Copyright © 2013 Elsevier Inc. All rights reserved.

Citation

Andrea L Conroy, Karlee L Silver, Kathleen Zhong, Monique Rennie, Peter Ward, J Vidya Sarma, Malcolm E Molyneux, John Sled, Joseph F Fletcher, Stephen Rogerson, Kevin C Kain. Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria. Cell host & microbe. 2013 Feb 13;13(2):215-26