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Prostaglandin E-EP4-Mediated Fibulin-1 Up-regulation Plays a Role in Intimal Thickening of the Ductus Arteriosus

  • Satoko Ito
  • Utako YokoyamaEmail author
  • Junichi Saito
  • Munetaka Masuda
  • Toshihide Asou
  • Yoshihiro Ishikawa
Open Access
Conference paper
  • 383 Downloads

Abstract

The normal closure of the ductus arteriosus (DA) consists of two steps: vasoconstriction and intimal thickening (IT). We have revealed that prostaglandin E2 (PGE2)-EP4 signaling plays a critical role in IT formation via smooth muscle cell (SMC) migration through hyaluronic acid [1]. In this study, we found that fibulin-1 was the most significantly up-regulated gene by EP4 stimulation in DA smooth muscle cells (SMCs).

Keywords

Ductus arteriosus Cell migration Intimal thickening 

The normal closure of the ductus arteriosus (DA) consists of two steps: vasoconstriction and intimal thickening (IT). We have revealed that prostaglandin E2 (PGE2)-EP4 signaling plays a critical role in IT formation via smooth muscle cell (SMC) migration through hyaluronic acid [1]. In this study, we found that fibulin-1 was the most significantly up-regulated gene by EP4 stimulation in DA smooth muscle cells (SMCs).

It has been reported that fibulin-1 has binding domains for ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motif type 1) and versican [2, 3], which participates in cell migration, and this fibulin-1-binding protease ADAMTS-1 promotes versican fragmentation [4, 5]. Furthermore, coupling of fragmented versican and hyaluronic acid promotes cell migration [6]. We speculated that fibulin-1 promotes DASMC migration and induces IT of the DA with ADAMTS-1 and versican. We aimed to examine the role of PGE2-EP4-signaling-mediated fibulin-1in IT of the DA.

Based on the microarray analysis showing that fibulin-1 was the most increased gene by EP4 stimulation in DASMCs, we performed RT-PCR and confirmed similar findings. EP4 stimulation did not increase fibulin-1 in aortic SMCs. Protein expression of fibulin-1 was markedly increased by EP4 stimulation in DASMCs. Immunohistochemistry of rat DA tissues showed that fibulin-1, ADAMTS-1, and fragmented versican were co-localized in the area of IT. VersicanV1 mRNA expression was significantly higher in endothelial cells than in DASMCs, and ADAMTS-1 was expressed in both endothelial cells and DASMCs. EP4 stimulation significantly increased binding of hyaluronic acid to fragmented versicanV1 protein in DASMCs. A Scratch assay showed that EP4 promoted DASMC migration, which was attenuated by fibulin-1-targeted siRNA and ADAMTS-1-targeted siRNA.

In conclusion, PGE2-EP4-mediated fibulin-1 integrates extracellular matrices such as ADAMTS-1, versican V1, and hyaluronic acid to promote SMC migration of the DA.

Notes

Acknowledgment

This study was funded by MEXT/JSPS KAKENHI (SI, 43008732; U.Y., 16H05358, 15H05761; J.S., 16H07107; Y.I., H1605300, 16K15205), Yokohama Foundation for Advancement of Medical Science (J.S.), and the Japan Agency for Medical Research and Development (AMED) (Y.I., 66890011, 66890023, 17ek0109240h0001, A261TS).

References

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© The Author(s) 2020

Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

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Authors and Affiliations

  • Satoko Ito
    • 1
  • Utako Yokoyama
    • 1
    Email author
  • Junichi Saito
    • 1
  • Munetaka Masuda
    • 2
  • Toshihide Asou
    • 3
  • Yoshihiro Ishikawa
    • 1
  1. 1.Cardiovascular Research InstituteYokohama City UniversityYokohamaJapan
  2. 2.Department of SurgeryYokohama City UniversityYokohamaJapan
  3. 3.Department of Cardiovascular SurgeryKanagawa Children’s Medical CenterYokohamaJapan

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