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Patent Ductus Arteriosus and Neonatal Death in Prostaglandin Receptor EP4-Deficient Mice

https://doi.org/10.1006/bbrc.1998.8461Get rights and content

Abstract

The physiological role of the prostaglandin E2receptor EP4 subtype was investigated by generation of EP4-deficient mice by gene targeting. Loss of the EP4 receptor was not lethalin utero,but most EP4 (−/−) neonates became pale and lethargic approximately 24 h after birth and died within 72 h. Less than 5% of the EP4 (−/−) mice survived and grew normally more than a year. Histological examination revealed that the ductus arteriosus in dead neonates remained open, while it was partially closed in the survivors.In situhybridization study showed that EP4 mRNA was strongly expressed in the ductus. These results suggest that neonatal death is at least partly due to patent ductus arteriosus and that the EP4 receptor plays a role in regulation of the patency of this vessel. They also indicate that normal function of the EP4 receptor is essential in neonatal adaptation of the circulatory system.

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      Moreover, EP4 mRNA is strongly expressed in the ductus as shown in situ hybridization study, suggesting the substantial role of the EP4 receptor in the regulation of the patency of this vessel (Segi et al., 1998). These results also indicated that the EP4 receptor is required for the rapid adaptation of the neonatal circulatory system under physiological condition (Segi et al., 1998). Cardiac LOX can be significantly activated under ischemic condition, which promotes leukocytes recruitment to injured cardiac tissues with subsequent elevation of eicosanoids like 5-HETE and 12-HETE (Hughes, Gentry, McGuire, & Taylor, 1991).

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    Gilman, A. G.Goodman, L. S.Rall, T. W.Murad, F.

    1

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