Browsing by Subject "Angiopoietin-1"

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    The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy
    (Elsevier, 2021-11) 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.; ter Kuile, Feiko O.; Sled, John G.; Kain, Kevin C.; Pediatrics, School of Medicine
    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.
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    Cytomegalovirus reactivation and acute and chronic complications in children with cerebral malaria: a prospective cohort study
    (Springer Nature, 2025-02-17) Mayhew, Jonathan A.; Witten, Andrew J.; Bond, Caitlin A.; Opoka, Robert O.; Bangirana, Paul; Conroy, Andrea L.; Hernandez‑Alvarado, Nelmary; Schleiss, Mark R.; John, Chandy C.; Pediatrics, School of Medicine
    Background: Virus co-infection or reactivation may modify the host response during cerebral malaria. Cytomegalovirus (CMV) DNAemia has been associated with increased morbidity and mortality in adults with sepsis; however, the impact of CMV DNAemia on adverse outcomes in children with cerebral malaria is unknown. Methods: Clinical, physiological, and neurocognitive outcomes were compared in children aged 18 months to 12 years with cerebral malaria (N = 242) based on the presence or absence of CMV DNAemia 24 h after admission. The primary study outcome was subsequent in-hospital mortality. Secondary outcomes included the presence of acute kidney injury, neurocognitive impairment over a 2-year follow-up, and chronic kidney disease at the 1-year follow-up. Markers of platelet and endothelial cell activation and oxidative and nitrosative stress were measured to characterize the mechanisms by which CMV DNAemia might contribute to pathogenesis. Results: CMV DNAemia was present in 33 children with cerebral malaria (13.6%) 24 h after admission. CMV DNAemia was not significantly associated with mortality in this study. Children with CMV-DNAemia had a higher prevalence of acute kidney injury than those without CMV-DNAemia (59.4% vs. 38.6%, p = 0.03). There was no difference in the prevalence of chronic kidney disease or long-term neurocognitive impairment based on the presence of DNAemia. CMV DNAemia was associated with elevated plasma levels of P-selectin, angiopoietin-1, asymmetric dimethylarginine, and platelet counts. Conclusions: In children with cerebral malaria, CMV DNAemia is associated with acute kidney injury but not in-hospital mortality, chronic kidney disease, or long-term neurocognitive impairment.