Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells

Chao Cheng Huang, Hsiao Mei Kuo, Pei Chang Wu, Shih Hsuan Cheng, Tzu Ting Chang, Yi Chen Chang, Mei Lang Kung, Deng Chyang Wu, Jiin Haur Chuang, Ming Hong Tai*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

38 Scopus citations

Abstract

Aim: Delta-like 1 homolog (DLK1) is a non-canonical ligand of Notch signaling, which plays a pivotal role in vascular development and tumor angiogenesis. This study aimed to elucidate the function and mechanism of DLK1 in angiogenesis. Methods and results: By using in situ hybridization and immunohistochemical studies, expression analysis revealed a unique vascular tropism of DLK1 in vasculature of neuroblastoma and vascular tumors. Thus, it was hypothesized that DLK1 may be cleaved and then bound to endothelial cells, thereby regulating the endothelial function. To test such hypothesis, soluble DLK1 encompassing DLK1 extracellular domain (DLK1-EC) was generated and validated by its inhibitory function in adipogenesis assay. Recombinant DLK1-EC exhibited the preferential binding capability toward endothelial cells and stimulated the microvessels sprouting in aorta rings. Above all, implantation of DLK1-EC dose-dependently elicited the cornea neovascularization in rats. By using various angiogenesis assays, it was delineated that DLK1-EC stimulated the angiogenesis by promoting the proliferation, motility and tube formation of endothelial cells. By immunoblot and luciferase analysis, it was elucidated that DLK1-EC enhanced the expression and activities of Notch1/Akt/eNOS/Hes-1 signaling in dose- and time-dependent manners. Pharmaceutical blockage of Notch signaling using γ-secretase inhibitor DAPT abrogated the DLK1-EC-induced endothelial migration and Hes-1-driven luciferase activities. Furthermore, Notch1 inactivation by neutralizing antibodies or RNA interference reversed the DLK1-EC-induced angiogenesis. Conclusions: The present study unveils the pro-angiogenic function and mechanism of soluble DLK1 through activation of Notch1 signaling in endothelial cells.

Original languageEnglish
Pages (from-to)299-312
Number of pages14
JournalAngiogenesis
Volume21
Issue number2
DOIs
StatePublished - 01 05 2018

Bibliographical note

Publisher Copyright:
© 2018, Springer Science+Business Media B.V., part of Springer Nature.

Keywords

  • Angiogenesis
  • Delta-like 1 homolog (DLK1)
  • Endothelial cells
  • Notch1

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