Tran, VanessaWeckman, Andrea M.Crowley, Valerie M.Cahill, Lindsay S.Zhong, KathleenCabrera, AnaElphinstone, Robyn E.Pearce, VictoriaMadanitsa, MwayiwawoKalilani-Phiri, LindaMwapasa, VictorKhairallah, CaroleConroy, Andrea L.ter Kuile, Feiko O.Sled, John G.Kain, Kevin C.2023-04-042023-04-042021-11Tran V, Weckman AM, Crowley VM, et al. The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy. EBioMedicine. 2021;73:103683. doi:10.1016/j.ebiom.2021.103683https://hdl.handle.net/1805/32202Background: Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes. Methods: Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1+/- mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes. Findings: Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1+/-), to worsen birth outcomes by impeding vascular remodeling required for placental function. Interpretation: Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalMalariaAngiopoietin-1Angiopoietin-Tie2Placental vasculaturePregnancyArticle