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Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice

Author

Listed:
  • Hanlin Lu

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Peidong Yuan

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Xiaoping Ma

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine
    LiaoCheng People’s Hospital)

  • Xiuxin Jiang

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Shaozhuang Liu

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Chang Ma

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Sjaak Philipsen

    (Erasmus MC)

  • Qunye Zhang

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Jianmin Yang

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Feng Xu

    (Qilu Hospital of Shandong University)

  • Cheng Zhang

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Yun Zhang

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

  • Wencheng Zhang

    (Qilu Hospital of Shandong University, Cheeloo College of Medicine)

Abstract

Angiogenesis is a critical pathophysiological process involved in organ growth and various diseases. Transcription factors Sp1/Sp3 are necessary for fetal development and tumor growth. Sp1/Sp3 proteins were downregulated in the capillaries of the gastrocnemius in patients with critical limb ischemia samples. Endothelial-specific Sp1/Sp3 knockout reduces angiogenesis in retinal, pathological, and tumor models and induced activation of the Notch1 pathway. Further, the inactivation of VEGFR2 signaling by Notch1 contributes to the delayed angiogenesis phenotype. Mechanistically, endothelial Sp1 binds to the promoter of Notch1 and inhibits its transcription, which is enhanced by Sp3. The proangiogenic effect of ACEI is abolished in Sp1/Sp3-deletion male mice. We identify USP7 as an ACEI-activated deubiquitinating enzyme that translocated into the nucleus binding to Sp1/Sp3, which are deacetylated by HDAC1. Our findings demonstrate a central role for endothelial USP7-Sp1/Sp3-Notch1 signaling in pathophysiological angiogenesis in response to ACEI treatment.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36409-z
    DOI: 10.1038/s41467-023-36409-z
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    References listed on IDEAS

    as
    1. Arndt F. Siekmann & Nathan D. Lawson, 2007. "Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries," Nature, Nature, vol. 445(7129), pages 781-784, February.
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    3. John Ridgway & Gu Zhang & Yan Wu & Scott Stawicki & Wei-Ching Liang & Yvan Chanthery & Joe Kowalski & Ryan J. Watts & Christopher Callahan & Ian Kasman & Mallika Singh & May Chien & Christine Tan & Jo, 2006. "Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis," Nature, Nature, vol. 444(7122), pages 1083-1087, December.
    4. Muyang Li & Delin Chen & Ariel Shiloh & Jianyuan Luo & Anatoly Y. Nikolaev & Jun Qin & Wei Gu, 2002. "Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization," Nature, Nature, vol. 416(6881), pages 648-653, April.
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    Cited by:

    1. Hanlin Lu & Xiuxin Jiang & Lifan He & Xuyang Ji & Xinyun Li & Shaozhuang Liu & Yuanyuan Sun & Xiaoteng Qin & Xiwen Xiong & Sjaak Philipsen & Bo Xi & Meng Zhang & Jianmin Yang & Cheng Zhang & Yun Zhang, 2023. "Endothelial Sp1/Sp3 are essential to the effect of captopril on blood pressure in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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