PGE, a potent vasodilator, plays a primary role in maintaining the patency of the ductus arteriosus (DA). Genetic disruption of the PGE-specific receptor EP4, however, paradoxically results in fatal patent DA (PDA) in mice. Here we demonstrate that EP4-mediated signals promote DA closure by hyaluronic acid-mediated (HA-mediated) intimal cushion formation (ICF). Chronic EP4 stimulation by ONO-AE1-329, a selective EP4 agonist, significantly enhanced migration and HA production in rat DA smooth muscle cells. When HA production was inhibited, EP4-mediated migration was negated. Activation of EP4, adenylyl cyclase, and PKA all increased HA production and the level of HA synthase 2 (HAS2) transcripts. In immature rat DA explants, ICF was promoted by EP4/PKA stimuli. Furthermore, adenovirus-mediated Has2 gene transfer was sufficient to induce ICF in EP4-disrupted DA explants in which the intimal cushion had not formed. Accordingly, signals through EP4 have 2 essential roles in DA development, namely, vascular dilation and ICF. The latter would lead to luminal narrowing, helping adhesive occlusion and permanent closure of the vascular lumen. Our results imply that HA induction serves as an alternative therapeutic strategy for the treatment of PDA to the current one, i.e., inhibition of PGE signaling by cyclooxygenase inhibitors, which might delay PGE-mediated ICF in immature infants.

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The process of rearranging lamella crystal structures in isotactic polypropylene (iPP) and butene randomly copolymerized iPP (bPP) spherulites during hot drawing was investigated by in-situ microbeam smallangle X-ray scattering (SAXS)-wide-angle X-ray scattering (WAXS)-polarized optical microscopy (POM) simultaneous measurements. We subjected a fixed position in an upper quadrant of a spherulite, which is stretched in the horizontal direction, to microbeam X-ray irradiation, and observed local structural changes, such as those in ordered crystal size and orientation, and a lamella stacking structure. We successfully obtained the structural information on parent and daughter lamellae in various orientations. In iPP, the long period of perpendicular parent lamellae increased, and then the disordering of crystal packing structures along the a-axis started. When necking started, the long periods of parent and daughter lamellae drastically started to decrease with the alignment of the c-axis in the stretching direction. The ease of crystal fragmentation and c-axis alignment strongly depended on the type of lamella, indicating the order of stress concentration during drawing. In bPP, it was found that the alignments of all the lamellae occur almost simultaneously and that parent and daughter lamellae independently rotate until necking.