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Tran, Vanessa, Weckman, Andrea M, Crowley, Valerie M, Cahill, Lindsay S, Zhong, Kathleen, Cabrera, Ana, Elphinstone, Robyn E, Pearce, Victoria, Madanitsa, Mwayiwawo, Kalilani-Phiri, Linda, Mwapasa, Victor, Khairallah, Carole, Conroy, Andrea L, terKuile, Feiko 
ORCID: https://orcid.org/0000-0003-3663-5617, Sled, John G and Kain, Kevin C
(2021)
'The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy'. EBioMedicine, Vol 73, p. 103683.
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Abstract
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.
| Item Type: | Article |
|---|---|
| Subjects: | WA Public Health > Health Problems of Special Population Groups > WA 310 Maternal welfare WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WQ Obstetrics > Pregnancy Complications > WQ 256 Infectious diseases |
| Faculty: Department: | Clinical Sciences & International Health > Clinical Sciences Department |
| Digital Object Identifer (DOI): | https://doi.org/10.1016/j.ebiom.2021.103683 |
| Depositing User: | Tracy Seddon |
| Date Deposited: | 01 Dec 2021 16:56 |
| Last Modified: | 01 Dec 2021 16:56 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/19538 |
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