EphrinB2-mediated CDK5/ISL1 pathway enhances cardiac lymphangiogenesis and alleviates ischemic injury by resolving post-MI inflammation

  • Signal Transduct Target Ther. 2024 Nov 18;9(1):326. doi: 10.1038/s41392-024-02019-4.
Yingnan Bai  #  1 ,  Liming Chen  #  2 ,  Fanghao Guo  #  3  4 ,  Jinghong Zhang  2 ,  Jinlin Hu  5 ,  Xuefei Tao  6 ,  Qing Lu  7 ,  Wenyi Li  8 ,  Xueying Chen  2 ,  Ting Gong  2 ,  Nan Qiu  2 ,  Yawei Jin  2 ,  Lifan Yang  2 ,  Yu Lei  9 ,  Chengchao Ruan  9 ,  Qing Jing  4 ,  John P Cooke  10 ,  Shijun Wang  11  12 ,  Yunzeng Zou  13  14 ,  Junbo Ge  15
Affiliations
  • 1. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
  • 2. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China.
  • 3. Center for Reproductive Medicine & Fertility Preservation Program, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Innovation Center for Intervention of Chronic Disease and Promotion of Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5. Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 6. Department of Geriatric Cardiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • 7. Department of Radiology, Shanghai Dongfang Hospital, Shanghai Tongji University School of Medicine, Shanghai, China.
  • 8. Department of Endocrinology, Tongren Hospital, Shanghai JiaoMo Tong University School of Medicine, Shanghai, China.
  • 9. Department of Physiology and Pathophysiology, Shanghai Key Laboratory of Bioactive Small Molecules, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 10. Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, USA.
  • 11. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
  • 12. Minhang Hospital, Fudan University, Shanghai, China. [email protected].
  • 13. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
  • 14. Institute of Advanced Medicine, Henan University, Kaifeng, Henan, China. [email protected].
  • 15. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 39557830 DOI: 10.1038/s41392-024-02019-4
Abstract

EphrinB2 (erythropoietin-producing hepatoma interactor B2) is a key Eph/ephrin family member, promoting angiogenesis, vasculogenesis, and lymphangiogenesis during embryonic development. However, the role of EphrinB2 in cardiac lymphangiogenesis following Myocardial Infarction (MI) and the potential molecular mechanism remains to be demonstrated. This study revealed that EphrinB2 prevented ischemic heart post-MI from remodeling and dysfunction by activating the cardiac lymphangiogenesis signaling pathway. Deletion of EphrinB2 impaired cardiac lymphangiogenesis and aggravated adverse cardiac remodeling and ventricular dysfunction post-MI. At the same time, overexpression of EphrinB2 stimulated cardiac lymphangiogenesis which facilitated cardiac infiltrating macrophage drainage and reduced inflammation in the ischemic heart. The beneficial effects of EphrinB2 on improving clearance of inflammatory response and cardiac function were abolished in Lyve1 knockout mice. Mechanistically, EphrinB2 accelerated cell cycling and lymphatic endothelial cell proliferation and migration by activating CDK5 and CDK5-dependent ISL1 nuclear translocation. EphrinB2 enhanced the transcriptional activity of ISL1 at the VEGFR3 (FLT4) promoter, and VEGFR3 inhibitor MAZ51 significantly diminished the EphrinB2-mediated lymphangiogenesis and deteriorated the ischemic cardiac function. We uncovered a novel mechanism of EphrinB2-driven cardiac lymphangiogenesis in improving myocardial remodeling and function after MI.