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Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis

Author

Listed:
  • Nan W. Hultgren

    (University of California Irvine)

  • Jennifer S. Fang

    (University of California Irvine)

  • Mary E. Ziegler

    (University of California Irvine)

  • Ricardo N. Ramirez

    (University of California Irvine)

  • Duc T. T. Phan

    (University of California Irvine)

  • Michaela M. S. Hatch

    (University of California Irvine)

  • Katrina M. Welch-Reardon

    (University of California Irvine)

  • Antonio E. Paniagua

    (University of California, Los Angeles)

  • Lin S. Kim

    (University of California Irvine)

  • Nathan N. Shon

    (University of California Irvine)

  • David S. Williams

    (University of California, Los Angeles)

  • Ali Mortazavi

    (University of California Irvine)

  • Christopher C. W. Hughes

    (University of California Irvine
    University of California Irvine
    University of California Irvine)

Abstract

Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.

Suggested Citation

  • Nan W. Hultgren & Jennifer S. Fang & Mary E. Ziegler & Ricardo N. Ramirez & Duc T. T. Phan & Michaela M. S. Hatch & Katrina M. Welch-Reardon & Antonio E. Paniagua & Lin S. Kim & Nathan N. Shon & David, 2020. "Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18633-z
    DOI: 10.1038/s41467-020-18633-z
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    Cited by:

    1. Hanlin Lu & Peidong Yuan & Xiaoping Ma & Xiuxin Jiang & Shaozhuang Liu & Chang Ma & Sjaak Philipsen & Qunye Zhang & Jianmin Yang & Feng Xu & Cheng Zhang & Yun Zhang & Wencheng Zhang, 2023. "Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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