Serum/glucocorticoid-regulated kinase 1 as a novel transcriptional target of bone morphogenetic protein-ALK1 receptor signaling in vascular endothelial cells (original) (raw)

Abstract

Bone morphogenetic protein 9 (BMP9)/BMP10-ALK1 receptor signaling is essential for endothelial differentiation and vascular morphogenesis. Mutations in ALK1/ACVRL1 and other signal-related genes are implicated in human vascular diseases, and the Alk1/Acvrl1 deletion in mice causes severe impairment of vascular formation and embryonic lethality. In the microarray screen to search for novel downstream genes of ALK1 signaling, we found that the mRNA and protein expression of serum/glucocorticoid-regulated kinase 1 (SGK1) was rapidly up-regulated by the BMP9 stimulation of cultured human endothelial cells. The increase in SGK1 mRNA was completely blocked by the transcriptional inhibitor actinomycin D and significantly suppressed by the siRNA treatment against the co-SMAD transcription factor SMAD4. Upon the BMP9 treatment of endothelial cells, phosphorylated SMAD1/5/9 bound to a consensus site upstream of the SGK1 gene, which was necessary for BMP9-dependent increment of the luciferase reporter activity driven by the SGK1 proximal enhancer. The Sgk1 mRNA expression in mouse embryos was enriched in vascular endothelial cells at embryonic day 9.0–9.5, at which Sgk1 null mice showed embryonic lethality due to abnormal vascular formation, and its mRNA as well as protein expression was clearly reduced in Alk1/Acvrl1 null embryos. These results indicate that SGK1 is a novel target gene of BMP9/BMP10-ALK1 signaling in endothelial cells and further suggest a possibility that down-regulation of the Sgk1 expression may be involved in the mechanisms of vascular defects by the ALK1 signaling deficiency.

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Acknowledgements

The authors thank T. Tsujiuchi and N. Kurumatani for general instruction, K. Miyazono, T. Watabe, F. Itoh, M. Okada, S. Nada and T. Akagi for information and reagents, T. Ioka, M. Sakabe, T. Uemoto, H. Kawakami, N. Yoshida, M. Suzuki and K. Endo for technical instruction and assistance. This work was supported in part by the grants from the Ministry of Education, Culture, Sports, Science and Technology, Takeda Science Foundation, SENSIN Medical Research Foundation, The Smoking Research Foundation and Miyata Cardiac Research Promotion Foundation, the Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center, and Nara Medical University Grant-in-Aid for Collaborative Research Projects.

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Authors and Affiliations

  1. Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan
    Mutsumi Araki, Takashi Hisamitsu, Yumi Kinugasa-Katayama, Toru Tanaka, Yukihiro Harada, Shu Nakao, Shuhei Ishii, Masahide Fujita, Yusuke Watanabe & Osamu Nakagawa
  2. Graduate School of Medical Sciences, Nara Medical University, Kashihara, Nara, Japan
    Mutsumi Araki, Shuhei Ishii, Yoshihiko Saito, Yusuke Watanabe & Osamu Nakagawa
  3. Laboratory for Cardiovascular System Research, Nara Medical University Advanced Medical Research Center, Kashihara, Nara, Japan
    Mutsumi Araki, Masahide Fujita & Osamu Nakagawa
  4. Laboratory of Stem Cell and Regenerative Medicine, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
    Yukihiro Harada, Shu Nakao & Teruhisa Kawamura
  5. The First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    Yoshihiko Saito
  6. International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
    Sanshiro Hanada & Koichi Nishiyama

Authors

  1. Mutsumi Araki
  2. Takashi Hisamitsu
  3. Yumi Kinugasa-Katayama
  4. Toru Tanaka
  5. Yukihiro Harada
  6. Shu Nakao
  7. Sanshiro Hanada
  8. Shuhei Ishii
  9. Masahide Fujita
  10. Teruhisa Kawamura
  11. Yoshihiko Saito
  12. Koichi Nishiyama
  13. Yusuke Watanabe
  14. Osamu Nakagawa

Corresponding author

Correspondence toOsamu Nakagawa.

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Araki, M., Hisamitsu, T., Kinugasa-Katayama, Y. et al. Serum/glucocorticoid-regulated kinase 1 as a novel transcriptional target of bone morphogenetic protein-ALK1 receptor signaling in vascular endothelial cells.Angiogenesis 21, 415–423 (2018). https://doi.org/10.1007/s10456-018-9605-x

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