The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy
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
Affiliations
Vanessa Tran
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada
Andrea M. Weckman
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada
Valerie M. Crowley
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada
Lindsay S. Cahill
Mouse Imaging Centre, Hospital for Sick Children, Toronto, Canada
Kathleen Zhong
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada
Ana Cabrera
Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Canada
Robyn E. Elphinstone
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada
Victoria Pearce
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada
Mwayiwawo Madanitsa
Department of Clinical Sciences, Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo, Malawi
Linda Kalilani-Phiri
College of Medicine, University of Malawi, Blantyre, Malawi
Victor Mwapasa
College of Medicine, University of Malawi, Blantyre, Malawi
Carole Khairallah
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
Andrea L. Conroy
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States
Feiko O. ter Kuile
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
John G. Sled
Mouse Imaging Centre, Hospital for Sick Children, Toronto, Canada
Kevin C. Kain
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada; Corresponding author: Dr. Kevin C. Kain, University Health Network, Toronto General Hospital, MaRS Centre, TMDT, 10th Floor 10-351, Toronto, Ontario M5G 1L7, (+1) 416 581 7704
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 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. Funding: This work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies.
