2. Academic Validation
  3. Endothelial β-catenin upregulation and Y142 phosphorylation drive diabetic angiogenesis via upregulating KDR/HDAC9

Endothelial β-catenin upregulation and Y142 phosphorylation drive diabetic angiogenesis via upregulating KDR/HDAC9

  • Cell Commun Signal. 2024 Mar 15;22(1):182. doi: 10.1186/s12964-024-01566-1.
Zhenfeng Chen # 1,  Bingqi Lin # 1,  Xiaodan Yao 1,  Jie Weng 1,  Jinlian Liu 1,  Qi He 1,  Ke Song 1,  Chuyu Zhou 1,  Zirui Zuo 1,  Xiaoxia Huang 1,  Zhuanhua Liu 1,  Qiaobing Huang 1,  Qiulin Xu 2,  Xiaohua Guo 3 4
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Department of Intensive Care Unit, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Science, Southern Medical University, Guangzhou, 510515, China. xuqiulin@gdph.org.cn.
  • 3 Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. lanblue@smu.edu.cn.
  • 4 National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. lanblue@smu.edu.cn.
  • # Contributed equally.
PMID: 38491522 DOI: 10.1186/s12964-024-01566-1
Abstract

Background: Diabetic angiogenesis is closely associated with disabilities and death caused by diabetic microvascular complications. Advanced glycation end products (AGEs) are abnormally accumulated in diabetic patients and are a key pathogenic factor for diabetic angiogenesis. The present study focuses on understanding the mechanisms underlying diabetic angiogenesis and identifying therapeutic targets based on these mechanisms.

Methods: In this study, AGE-induced angiogenesis serves as a model to investigate the mechanisms underlying diabetic angiogensis. Mouse aortic rings, matrigel plugs, and HUVECs or 293T cells were employed as research objects to explore this pathological process by using transcriptomics, gene promoter reporter assays, virtual screening and so on.

Results: Here, we found that AGEs activated Wnt/β-catenin signaling pathway and enhanced the β-catenin protein level by affecting the expression of β-catenin degradation-related genes, such as FZDs (Frizzled receptors), LRPs (LDL Receptor Related Proteins), and AXIN1. AGEs could also mediate β-catenin Y142 phosphorylation through VEGFR1/Flt-1 isoform5. These dual effects of AGEs elevated the nuclear translocation of β-catenin and sequentially induced the expression of VEGFR2/KDR/Flk-1 (Kinase Insert Domain Receptor) and HDAC9 (Histone Deacetylase 9) by POU5F1 and NANOG, respectively, thus mediating angiogenesis. Finally, through virtual screening, Bioymifi, an inhibitor that blocks VEGFR1/Flt-1 isoform5-β-catenin complex interaction and alleviates AGE-induced angiogenesis, was identified.

Conclusion: Collectively, this study offers insight into the pathophysiological functions of β-catenin in diabetic angiogenesis.

Keywords

HDAC9; KDR; Advanced glycation end products; Bioymifi; Diabetic angiogenesis; Phosphorylation; VEGFR1 isoform5; β-catenin.

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