A study for functions of prostaglandin E receptor EP4 subtype by analysing knockout mice

The physiological role of the prostaglandin (PG) E-2 receptor EP4 subtype was investigated by the generation of EP4-deficient mice by gene targeting. Loss of the EP4 receptor was not lethal in utero, bur 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. Marked congestion in the pulmonary capillaries were observed before death, suggesting that EP4 (-/-) neonates had left-sided heart failure. Histological examination revealed that the ductus arteriosus in dead neonates remained open, while it was partially closed in the survivors. In situ hybridization study showed that EP4 mRNA was strongly expressed in the ductus. The treatment of indomethacin, an inhibitor of PG synthesis, on wild-type fetus induced constriction of ductus arteriosus, while the ductus in EP4 (-/-) fetus was insensitive to indomethacin. These results suggest that neonatal death is at least partly due to patent ductus arteriosus, and that the EP4 receptor plays a role in the regulation of the patency of this vessel. They also indicate that the normal function of the EP4 receptor is essential in neonatal adaptation of the circulatory system.