Complement Activation and the Resulting Placental Vascular Insufficiency Drives Fetal Growth Restriction Associated with Placental Malaria

• Published in: Cell host & microbe Vol. 13; no. 2; pp. 215 - 226
• Main Authors: Conroy, Andrea L., Silver, Karlee L., Zhong, Kathleen, Rennie, Monique, Ward, Peter, Sarma, J. Vidya, Molyneux, Malcolm E., Sled, John, Fletcher, Joseph F., Rogerson, Stephen, Kain, Kevin C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.02.2013
• Subjects: Adolescent; Animals; Biomarkers - metabolism; Case-Control Studies; Complement Activation; Complement C5a - metabolism; Disease Models, Animal; Female; Fetal Growth Retardation - metabolism; Fetal Growth Retardation - parasitology; Fetal Growth Retardation - pathology; Gene Expression Regulation, Developmental; Gestational Age; Humans; Malaria - metabolism; Malaria - pathology; Male; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic - metabolism; Placenta - blood supply; Placenta - parasitology; Placental Insufficiency - metabolism; Placental Insufficiency - parasitology; Placental Insufficiency - pathology; Plasmodium berghei - pathogenicity; Pregnancy; Pregnancy Complications, Parasitic - pathology; Receptor, Anaphylatoxin C5a; Receptors, Complement - metabolism; Signal Transduction; Transcription, Genetic; Young Adult
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2013.01.010

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. ► Elevated C5a is associated with placental malaria (PM) and fetal growth restriction ► Altered levels of angiogenic factors are associated with fetal growth restriction ► Complement C5a is associated with altered angiogenesis in human and murine PM ► Blocking C5a-C5aR signaling in a mouse model of PM improves fetal outcome