抄録
Prostaglandin E (PGE), a potent vasodilator, plays a primary role in the patency of the ductus arteriosus (DA), a bypass artery for fetal circulation. Genetic disruption of the PGE specific-receptor EP4, however, paradoxically results in patent DA (PDA) in mice. Here we examined the mechanisms why EP4 disruption caused PDA. We found that chronic EP4 stimulation significantly enhanced migration and hyaluronic acid (HA) production in rat DA. When HA production was inhibited, EP4-mediated migration was negated, indicating that HA is responsible for chronic EP4-mediated migration. Interestingly, acute stimulation of EPAC, another effector of cAMP, promoted DA smooth muscle cell (SMC) migration and organization of actin stress fibers. Using immature rat DA explants, we found that ICF was promoted by both PKA and EPAC stimuli. Furthermore, adenovirus-mediated HAS2 gene transfer was sufficient to induce ICF in EP4-disrupted DA explants where ICF was not developed. Accordingly, EP4-cAMP signals have two essential roles in DA development, vascular dilation and ICF. Activation of PKA pathway increased transcription of the HAS2 genes and thus HA production. The PKA-mediated HA accumulation promoted DA SMC migration, resulting in promoting neointimal cushion formation. On the other hand, EPAC acutely promoted DA SMC migration and thus ICF in rat DA. Herein, cAMP-downstream targets, PKA and EPAC, synergistically promote ICF in DA. Our results imply that selective stimulation of cAMP-dependent signal pathway serves as an alternative therapeutic strategy for PDA to the current one, i.e. inhibition of PGE signaling by cyclooxygenase inhibitors. [J Physiol Sci. 2008;58 Suppl:S44]