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

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

Nature communications 2023 Feb 09

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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. © 2023. The Author(s).

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. Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice. Nature communications. 2023 Feb 09;14(1):731