title: Prostaglandin E2 inhibits elastogenesis in the ductus arteriosus via EP4 signaling.
abstract: BACKGROUND
  Elastic fiber formation begins in mid-gestation and increases dramatically during the last trimester in the great arteries, providing elasticity and thus preventing vascular wall structure collapse. However, the ductus arteriosus (DA), a fetal bypass artery between the aorta and pulmonary artery, exhibits lower levels of elastic fiber formation, which promotes vascular collapse and subsequent closure of the DA after birth. The molecular mechanisms for this inhibited elastogenesis in the DA, which is necessary for the establishment of adult circulation, remain largely unknown.
  
  
  RESULTS
  Stimulation of the prostaglandin E₂ (PGE₂) receptor EP4 significantly inhibited elastogenesis and decreased lysyl oxidase (LOX) protein, which catalyzes elastin cross-links in DA smooth muscle cells (SMCs), but not in aortic SMCs. Aortic SMCs expressed much less EP4 than DASMCs. Adenovirus-mediated overexpression of LOX restored the EP4-mediated inhibition of elastogenesis in DASMCs. In EP4-knockout mice, electron microscopic examination showed that the DA acquired an elastic phenotype that was similar to the neighboring aorta. More importantly, human DA and aorta tissues from 7 patients showed a negative correlation between elastic fiber formation and EP4 expression, as well as between EP4 and LOX expression. The PGE₂-EP4-c-Src-phospholipase C (PLC)γ-signaling pathway most likely promoted the lysosomal degradation of LOX.
  
  
  CONCLUSIONS
  Our data suggest that PGE₂ signaling inhibits elastogenesis in the DA, but not in the aorta, through degrading LOX protein. Elastogenesis is spatially regulated by PGE₂-EP4 signaling in the DA.
authors.affiliation: Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan (U.Y., S.M., A.S., R.I., M.-H.J., Y.I.); the Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, Tokyo, Japan (S.M., R.I.); the Department of Cell Physiology, Jikei University School of Medicine, Tokyo, Japan (S.M.); the Department of Surgery, Yokohama City University, Yokohama, Japan (M.M.); the Department of Cardiovascular Surgery, Kanagawa Children's Medical Center, Yokohama, Japan (T.A.); the Department of Pharmaceutical Biochemistry, Kumamoto University, Kumamoto, Japan (Y.S.); Cardiovascular Research Institute, Kurume University, Kurume, Japan (H.A.); and the Department of Pharmacology, Kansai Medical University, Osaka, Japan (T.N.).
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.forename: Susumu
authors.initials: S
authors.lastname: Minamisawa
authors.forename: Aki
authors.initials: A
authors.lastname: Shioda
authors.forename: Ryo
authors.initials: R
authors.lastname: Ishiwata
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Jin
authors.forename: Munetaka
authors.initials: M
authors.lastname: Masuda
authors.forename: Toshihide
authors.initials: T
authors.lastname: Asou
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aoki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D015232:Dinoprostone / Q000502:physiology*; D004373:Ductus Arteriosus / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D004547:Elastic Tissue / Q000502:physiology* / Q000648:ultrastructure; D004548:Elasticity / Q000502:physiology*; D004549:Elastin / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D010641:Phenotype; D051966:Phospholipase C gamma / Q000502:physiology; D008249:Protein-Lysine 6-Oxidase / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D058309:Receptors, Prostaglandin E, EP4 Subtype; D004549:Elastin; D008249:Protein-Lysine 6-Oxidase; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051966:Phospholipase C gamma; D015232:Dinoprostone
keywords: elasticity; muscle, smooth; pediatrics; prostaglandins; signal transduction