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The brain-placental axis: Therapeutic and pharmacological relevancy to pregnancy.

ABSTRACT: The placenta plays a critical role in mammalian reproduction. Although it is a transient organ, its function is indispensable to communication between the mother and fetus, and supply of nutrients and oxygen to the growing fetus. During pregnancy, the placenta is vulnerable to various intrinsic and extrinsic conditions which can result in increased risk of fetal neurodevelopmental disorders as well as fetal death. The placenta controls the neuroendocrine secretion in the brain as a means of adaptive processes to safeguard the fetus from adverse programs, to optimize fetal development and other physiological changes necessary for reproductive success. Although a wealth of information is available on neuroendocrine functions in pregnancy, they are largely limited to the regulation of hypothalamus-pituitary-adrenal/gonad (HPA/ HPG) axis, particularly the oxytocin and prolactin system. There is a major gap in knowledge on systems-level functional interaction between the brain and placenta. In this review, we aim to outline the current state of knowledge about the brain-placental axis with description of the functional interactions between the placenta and the maternal and fetal brain. While describing the brain-placental interactions, a special emphasis has been given on the therapeutics and pharmacology of the placental receptors to neuroligands expressed in the brain during gestation. As a key feature of this review, we outline the prospects of integrated pharmacogenomics, single-cell sequencing and organ-on-chip systems to foster priority areas in this field of research. Finally, we remark on the application of precision genomics approaches to study the brain-placental axis in order to accelerate personalized medicine and therapeutics to treat placental and fetal brain disorders.

SUBMITTER: Behura SK

PROVIDER: S-EPMC6944055 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The brain-placental axis: Therapeutic and pharmacological relevancy to pregnancy.

Behura Susanta K SK Dhakal Pramod P Kelleher Andrew M AM Balboula Ahmed A Patterson Amanda A Spencer Thomas E TE

Pharmacological research 20191007

The placenta plays a critical role in mammalian reproduction. Although it is a transient organ, its function is indispensable to communication between the mother and fetus, and supply of nutrients and oxygen to the growing fetus. During pregnancy, the placenta is vulnerable to various intrinsic and extrinsic conditions which can result in increased risk of fetal neurodevelopmental disorders as well as fetal death. The placenta controls the neuroendocrine secretion in the brain as a means of adap ...[more]

PMID: 31600597

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Project description:BackgroundMalaria 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.MethodsUsing 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.FindingsDecreased 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.InterpretationCollectively, 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.FundingThis 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.

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The brain-placental axis: Therapeutic and pharmacological relevancy to pregnancy.

Publications

The brain-placental axis: Therapeutic and pharmacological relevancy to pregnancy.

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