The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy

作者：Vanessa Tran, Andrea M. Weckman, Valerie M. Crowley, Lindsay S. Cahill, Kathleen Zhong, Ana Cabrera, Robyn E. Elphinstone, Victoria Pearce, Mwayiwawo Madanitsa, Linda Kalilani‐Phiri, Victor Mwapasa, Carole Khairallah, Andrea L. Conroy, Feiko O. ter Kuile, John G. Sled, Kevin C. Kain · 发表于：EBioMedicine · 年份：2021 · DOI：10.1016/j.ebiom.2021.103683 · 被引用次数：27 · 研究领域：Malaria Research and Control、Pregnancy and preeclampsia studies、Angiogenesis and VEGF in Cancer

Background 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 heter...