**2.2.1 Cyclooxygenase (COX): The generator of PGE2**

The cyclooxygenases COX1 and COX2 catalyze the synthesis of prostaglandin H, a precursor of biologically active prostaglandins including PGE2, from arachidonic acid. Therefore COX inhibitors such as indomethacin are often used for treatment of PDA to induce vasoconstriction of the DA by attenuating the synthesis of PGE2. Exposure *in utero* to indomethacin induces premature closure of the DA. Interestingly, it has been reported that infants of mothers who received indomethacin tocolysis are susceptible to symptomatic PDA. These contradictory observations suggest that a relatively complex mechanism underlies the role of COX1 and COX2 in the DA. Furthermore, genetic disruption of COX1 and COX2 results in postnatal PDA (Loftin, 2001). As seen in COX-deleted mice, COX2 plays a primary role in DA closure after birth, and its effect is attenuated in cases of preterm gestation. In addition to COX2, COX1 also contributes to DA closure in a gene dosagedependent manner (Loftin, 2001; Loftin, 2002). Although it is not apparent from the literature why COX deletion causes PDA in mice, we assume that the same mechanism should work as described below in mice harboring deletion of the EP4 gene, a predominant PGE2 receptor in the DA. Trivedi et al. have demonstrated that COX2 expression is attenuated in EP4-deleted mice (Trivedi,. 2006), suggesting the existence of a positive feedback loop in COX-PGE2 cascades.
