Chen Can, Chen Zilong, Luo Ruijie, Tu Wanheng, Long Minwen, Liang Minglu, Cheng Min, Wang Zhaohui, Huang Kai, Wang Cheng
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Angiogenesis. 2025 Apr 8;28(2):23. doi: 10.1007/s10456-025-09976-6.
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.
血管生成是包括胚胎发育、缺血性疾病和肿瘤进展在内的各种生理和病理过程的关键组成部分。最近的研究强调了泛素酶在血管生成中的重要性。在本研究中，我们利用来自GEO数据库的小鼠视网膜发育模型的RNA测序数据来鉴定潜在的促血管生成去泛素酶，发现USP11显著上调。尽管已知USP11在癌症和缺血条件下调节细胞存活、DNA修复和氧化应激，但其在内皮血管生成中的直接作用仍知之甚少。在这里，我们证明了USP11的表达与关键的促血管生成基因相关，并且在VEGF处理的人脐静脉内皮细胞（HUVECs）中，其mRNA和蛋白质水平均显著上调。USP11基因敲除在体内和体外均显著抑制血管生成，而USP11过表达则促进血管生成。机制上，USP11与PRDX2结合，促进其K63连接的多聚泛素化的去除，从而促进其转运到细胞核中。这促进了PRDX2相互作用蛋白c-MYC同时转运到细胞核中，随后增强了KDR（编码VEGFR2）的转录并激活了VEGFR2信号通路。我们的研究结果表明，USP11通过PRDX2/c-MYC途径上调VEGFR2表达来促进血管生成，这表明USP11可能作为血管生成相关疾病临床干预的潜在靶点。
