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).
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Keywords
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.
References
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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).
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Ito, S., Yokoyama, U., Saito, J., Masuda, M., Asou, T., Ishikawa, Y. (2020). Prostaglandin E-EP4-Mediated Fibulin-1 Up-regulation Plays a Role in Intimal Thickening of the Ductus Arteriosus. In: Nakanishi, T., Baldwin, H., Fineman, J., Yamagishi, H. (eds) Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension. Springer, Singapore. https://doi.org/10.1007/978-981-15-1185-1_39
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DOI: https://doi.org/10.1007/978-981-15-1185-1_39
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