Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes
Abstract Background Ischemic diseases represent a major global health care burden. Angiogenesis is critical in recovery of blood flow and repair of injured tissue in ischemic diseases. Ten–eleven translocation protein 2 (TET2), a member of DNA demethylases, is involved in many pathological processes...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-023-00960-5 |
| _version_ | 1797945665900249088 |
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| author | Yefei Shi Bo Li Xinru Huang Wenxin Kou Ming Zhai Yanxi Zeng Shuangjie You Qing Yu Yifan Zhao Jianhui Zhuang Wenhui Peng Weixia Jian |
| author_facet | Yefei Shi Bo Li Xinru Huang Wenxin Kou Ming Zhai Yanxi Zeng Shuangjie You Qing Yu Yifan Zhao Jianhui Zhuang Wenhui Peng Weixia Jian |
| author_sort | Yefei Shi |
| collection | DOAJ |
| description | Abstract Background Ischemic diseases represent a major global health care burden. Angiogenesis is critical in recovery of blood flow and repair of injured tissue in ischemic diseases. Ten–eleven translocation protein 2 (TET2), a member of DNA demethylases, is involved in many pathological processes. However, the role of TET2 in angiogenesis is still unrevealed. Methods TET2 was screened out from three DNA demethylases involved in 5-hydroxylmethylcytosine (5-hmC) regulation, including TET1, TET2 and TET3. Knockdown by small interfering RNAs and overexpression by adenovirus were used to evaluate the role of TET2 on the function of endothelial cells. The blood flow recovery and density of capillary were analyzed in the endothelial cells-specific TET2-deficient mice. RNA sequencing was used to identify the TET2-mediated mechanisms under hypoxia. Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation-qPCR (ChIP-qPCR) and glucosylated hydroxymethyl-sensitive-qPCR (GluMS-qPCR) were further performed to reveal the interaction of TET2 and STAT3. Results TET2 was significantly downregulated in endothelial cells under hypoxia and led to a global decrease of 5-hmC level. TET2 knockdown aggravated the hypoxia‐induced dysfunction of endothelial cells, while TET2 overexpression alleviated the hypoxia‐induced dysfunction. Meanwhile, the deficiency of TET2 in endothelial cells impaired blood flow recovery and the density of capillary in the mouse model of hindlimb ischemia. Mechanistically, RNA sequencing indicated that the STAT3 signaling pathway was significantly inhibited by TET2 knockdown. Additionally, Co-IP, ChIP-qPCR and GluMS-qPCR further illustrated that STAT3 recruited and physically interacted with TET2 to activate STAT3 target genes. As expected, the effects of TET2 overexpression were completely suppressed by STAT3 silencing in vitro. Conclusions Our study suggests that the deficiency of TET2 in endothelial cells impairs angiogenesis via suppression of the STAT3 signaling pathway. These findings give solid evidence for TET2 to be a therapeutic alternative for ischemic diseases. Graphical Abstract |
| first_indexed | 2024-04-10T20:59:46Z |
| format | Article |
| id | doaj.art-4948448a344949c9b697309fc5d3b455 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-10T20:59:46Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-4948448a344949c9b697309fc5d3b4552023-01-22T12:26:19ZengBMCCell & Bioscience2045-37012023-01-0113111610.1186/s13578-023-00960-5Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genesYefei Shi0Bo Li1Xinru Huang2Wenxin Kou3Ming Zhai4Yanxi Zeng5Shuangjie You6Qing Yu7Yifan Zhao8Jianhui Zhuang9Wenhui Peng10Weixia Jian11Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of MedicineAbstract Background Ischemic diseases represent a major global health care burden. Angiogenesis is critical in recovery of blood flow and repair of injured tissue in ischemic diseases. Ten–eleven translocation protein 2 (TET2), a member of DNA demethylases, is involved in many pathological processes. However, the role of TET2 in angiogenesis is still unrevealed. Methods TET2 was screened out from three DNA demethylases involved in 5-hydroxylmethylcytosine (5-hmC) regulation, including TET1, TET2 and TET3. Knockdown by small interfering RNAs and overexpression by adenovirus were used to evaluate the role of TET2 on the function of endothelial cells. The blood flow recovery and density of capillary were analyzed in the endothelial cells-specific TET2-deficient mice. RNA sequencing was used to identify the TET2-mediated mechanisms under hypoxia. Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation-qPCR (ChIP-qPCR) and glucosylated hydroxymethyl-sensitive-qPCR (GluMS-qPCR) were further performed to reveal the interaction of TET2 and STAT3. Results TET2 was significantly downregulated in endothelial cells under hypoxia and led to a global decrease of 5-hmC level. TET2 knockdown aggravated the hypoxia‐induced dysfunction of endothelial cells, while TET2 overexpression alleviated the hypoxia‐induced dysfunction. Meanwhile, the deficiency of TET2 in endothelial cells impaired blood flow recovery and the density of capillary in the mouse model of hindlimb ischemia. Mechanistically, RNA sequencing indicated that the STAT3 signaling pathway was significantly inhibited by TET2 knockdown. Additionally, Co-IP, ChIP-qPCR and GluMS-qPCR further illustrated that STAT3 recruited and physically interacted with TET2 to activate STAT3 target genes. As expected, the effects of TET2 overexpression were completely suppressed by STAT3 silencing in vitro. Conclusions Our study suggests that the deficiency of TET2 in endothelial cells impairs angiogenesis via suppression of the STAT3 signaling pathway. These findings give solid evidence for TET2 to be a therapeutic alternative for ischemic diseases. Graphical Abstracthttps://doi.org/10.1186/s13578-023-00960-5TET25-hmCSTAT3AngiogenesisIschemic diseases |
| spellingShingle | Yefei Shi Bo Li Xinru Huang Wenxin Kou Ming Zhai Yanxi Zeng Shuangjie You Qing Yu Yifan Zhao Jianhui Zhuang Wenhui Peng Weixia Jian Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes Cell & Bioscience TET2 5-hmC STAT3 Angiogenesis Ischemic diseases |
| title | Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes |
| title_full | Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes |
| title_fullStr | Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes |
| title_full_unstemmed | Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes |
| title_short | Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes |
| title_sort | loss of tet2 impairs endothelial angiogenesis via downregulating stat3 target genes |
| topic | TET2 5-hmC STAT3 Angiogenesis Ischemic diseases |
| url | https://doi.org/10.1186/s13578-023-00960-5 |
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