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The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth

Nature volume 390, pages 78–81 (1997)Cite this article

Abstract

Survival of newborn placental mammals depends on closure of the ductus arteriosus (DA), an arterial connection in the fetus which directs blood away from the pulmonary circulation and towards the placenta where oxygenation occurs1. Here we show that morphological changes resulting in closure of the DA in mice are virtually identical to those observed in larger mammals, including humans2, and that maintenance of the DA in the open, or patent, state in fetal mice is dependent on prostaglandin synthesis. This requirement is absent in mice lacking the prostaglandin E2 EP4 receptor (EP4(−/−) mice). In EP4(−/−) mice of the 129 strain, remodelling of the DA fails to occur after birth, resulting in a left-to-right shunt of blood and subsequently in death. This suggests that the neonatal drop in prostaglandin E2 (refs 3,4,5,6,7) that triggers ductal closure is sensed through the EP4 receptor. In contrast, 5% of EP4(−/−) mice of mixed genetic background survive, and selective breeding of these mice leads to a 21% survival rate, suggesting that alleles at other loci can provide an alternative mechanism for ductal closure.

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Figure 1: Mouse DA morphology and expression of the EP4 receptor.
Figure 2: The ductus arteriosus.
Figure 3: Histological examination of the DA in wild-type and EP4(−/−) mice.
Figure 4: Model for closure of the DA in normal and EP4-deficient mice.

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Acknowledgements

We thank B. Anderson and L. Johnson for assistance in cloning the EP4 gene; B. Garges for animal husbandry; A. Latour for help with tissue culture; K. Burns, T. Bartologga and R. Bagnell for assistance with histology and photomicroscopy; and A. Oakely for help with manuscript preparation. This work was supported by grants from Pfizer, the US NHLBI and the NIDDK.

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Authors and Affiliations

  1. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599-7248, North Carolina, USA

    MyTrang Nguyen, Todd Camenisch, John N. Snouwaert, Elizabeth Hicks & Beverly H. Koller

  2. Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, 27710, North Carolina, USA

    Thomas M. Coffman

  3. Division of Pediatric Cardiology Duke University Medical Center, Durham, 27710, North Carolina , USA

    Page A. W. Anderson

  4. Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, 27599-7525, North Carolina, USA

    Nadia N. Malouf

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Correspondence to Beverly H. Koller.

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Nguyen, M., Camenisch, T., Snouwaert, J. et al. The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth. Nature 390, 78–81 (1997). https://doi.org/10.1038/36342

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