Maternal hypoxia and caffeine exposure depress fetal cardiovascular function during primary organogenesis

Authors

  • Nobuo Momoi,

    1. Cardiovascular Development Research Program, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center
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    • Department of Pediatrics, Fukushima Medical University (current affiliation).

  • Joseph P. Tinney,

    1. Cardiovascular Innovation Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky, USA
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  • Bradley B. Keller,

    1. Cardiovascular Innovation Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky, USA
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  • Kimimasa Tobita

    Corresponding author
    1. Cardiovascular Development Research Program, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center
    2. Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Dr Kimimasa Tobita, Cardiovascular Development Research Program, Children's Hospital of UMPC, Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA. Email: kit3@pitt.edu

Abstract

Aims:  Hypoxia is known to influence cardiovascular (CV) function, in part, through adenosine receptor activation. We have shown in a mouse model that during primary cardiac morphogenesis, acute maternal hypoxia negatively affects fetal heart rate, and recurrent maternal caffeine exposure reduces fetal cardiac output (CO) and downregulates fetal adenosine A2A receptor gene expression. In the present study, we investigated whether maternal caffeine dosing exacerbates the fetal CV response to acute maternal hypoxia during the primary morphogenesis period.

Material and Methods:  Gestational-day-11.5 pregnant mice were exposed to hypoxia (45 s duration followed by 10 min of recovery and repeated 3 times) while simultaneously monitoring maternal and fetal CO using high-resolution echocardiography.

Results:  Following maternal hypoxia exposure, maternal CO transiently decreased and then returned to pre-hypoxia baseline values. In contrast to a uniform maternal cardiac response to each exposure to hypoxia, the fetal CO recovery time to the baseline decreased, and CO rebounded above baseline following the second and third episodes of maternal hypoxia. Maternal caffeine treatment inhibited the fetal CO recovery to maternal hypoxia by lengthening the time to CO recovery and eliminating the CO rebound post-recovery. Selective treatment with an adenosine A2A receptor antagonist, but not an adenosine A1 receptor antagonist, reproduced the altered fetal CO response to maternal hypoxia created by caffeine exposure.

Conclusions:  Results suggest an additive negative effect of maternal caffeine on the fetal CV response to acute maternal hypoxia, potentially mediated via adenosine A2A receptor inhibition during primary cardiovascular morphogenesis.

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