Effect of PGE2 on DA tone by EP4 modulating Kv channels with different oxygen tension between preterm and term

Objective: To investigate common downstream mechanism of PGE2 and O2-sensitive voltage-dependent potassium (Kv) channels in preterm and term DA tone regulations, for suggesting respective prescriptions for preterm and term PDA. Study design: The expressions of Kv1.2, 1.5 and 2.1 were compared between preterm and term in rabbit and human DAs at mRNA and protein levels; DA contracting responses caused by O2, Kv channels blocker 4-AP, EP4 antagonist GW627368X, and PGE2 reduce using vessels rings and Whole-Cell Patch-Clamp were explored. Results: Kv 1.2 and 2.1 expressions were developed with pregnant age in preterm DA and decreased after birth with oxygen stimulation in term DA. GW627368X led significant DA constriction and DASMC IK current decrease in preterm, which was slimier to 4-AP effects, but just slightly influenced on DA tension and DASMC IK current at term. In addition, PGE2 led great DA dilation and IK current increase of DASMC in preterm but not in term. These DA tension and IK current changes were in line with Kv channel expressions. Conclusion: Higher levels of PGE2 binds with GPCR EP4, which activates G-protein to couple with O2-sensitive Kv channels and to open them, leading to DA vasorelaxation in the fetus. It indicates that EP4 inhibitors, instead of PGE2 or its analogue PGE1, may be a selectable strategy for preterm PDA.