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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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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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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DOI: https://doi.org/10.1038/36342
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