2. Academic Validation
  3. Endothelial USP11 drives VEGFR2 signaling and angiogenesis via PRDX2/c-MYC axis

Endothelial USP11 drives VEGFR2 signaling and angiogenesis via PRDX2/c-MYC axis

  • Angiogenesis. 2025 Apr 8;28(2):23. doi: 10.1007/s10456-025-09976-6.
Can Chen # 1 2,  Zilong Chen # 1 2,  Ruijie Luo 1 2,  Wanheng Tu 2 3,  Minwen Long 1,  Minglu Liang 2,  Min Cheng 1,  Zhaohui Wang 4 5,  Kai Huang 6 7,  Cheng Wang 8 9
Affiliations

Affiliations

  • 1 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2 Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 3 Liyuan Cardiovascular Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. wuxiaohongtian@163.com.
  • 5 Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. wuxiaohongtian@163.com.
  • 6 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. huangkai1@hust.edu.cn.
  • 7 Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. huangkai1@hust.edu.cn.
  • 8 Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. cwangunion@hust.edu.cn.
  • 9 Department of Rheumatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. cwangunion@hust.edu.cn.
  • # Contributed equally.
PMID: 40199774 DOI: 10.1007/s10456-025-09976-6
Abstract

Angiogenesis is a crucial component of various physiological and pathological processes, including embryonic development, ischemic diseases, and tumor progression. Recent studies have highlighted the importance of ubiquitinases in angiogenesis. In this study, we utilized RNA Sequencing data of the mouse retinal development model from the GEO database to identify the potential proangiogenic deubiquitinases and found USP11 was significantly upregulated. Although USP11 is known to regulate cell survival, DNA repair, and oxidative stress in cancers and ischemic conditions, its direct role in endothelial angiogenesis remains poorly understood. Here, we demonstrated that USP11 expression correlates with key pro-angiogenic genes and is significantly upregulated at both mRNA and protein levels in VEGF-treated human umbilical vein endothelial cells (HUVECs). USP11 knockout markedly inhibited angiogenesis both in vivo and in vitro, whereas USP11 overexpression promoted angiogenesis. Mechanistically, USP11 binds to PRDX2, facilitating the removal of its K63-linked polyubiquitination, which promotes its translocation into the nucleus. This facilitates the concurrent nuclear translocation of c-Myc, a PRDX2 interactor, which subsequently enhances the transcription of KDR (encoding VEGFR2) and activates the VEGFR2 signaling pathway. Our findings suggest that USP11 promotes angiogenesis by upregulating VEGFR2 expression through the PRDX2/c-Myc pathway, indicating that USP11 could serve as a potential target for clinical interventions in angiogenesis-related diseases.

Keywords

Angiogenesis; Deubiquitinase; K63-related ubiquitination; PRDX2; USP11; VEGFR2.

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