Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China.
Center for Reproductive Medicine & Fertility Preservation Program, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Signal Transduct Target Ther. 2024 Nov 18;9(1):326. doi: 10.1038/s41392-024-02019-4.
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.
EphrinB2（促红细胞生成素产生肝癌相互作用因子 B2）是 Eph/ephrin 家族的关键成员，在胚胎发育过程中促进血管生成、血管生成和淋巴管生成。然而，EphrinB2 在心肌梗死后心脏淋巴管生成中的作用及其潜在的分子机制仍有待证明。本研究揭示 EphrinB2 通过激活心脏淋巴管生成信号通路，防止心肌梗死后缺血性心脏重构和功能障碍。EphrinB2 的缺失会损害心脏淋巴管生成，并加重心肌梗死后的不良心脏重构和心室功能障碍。同时，EphrinB2 的过表达刺激心脏淋巴管生成，促进心脏浸润性巨噬细胞引流，并减少缺血心脏的炎症。在 Lyve1 敲除小鼠中，EphrinB2 改善炎症反应清除和心脏功能的有益作用被消除。在机制上，EphrinB2 通过激活 CDK5 和 CDK5 依赖性 ISL1 核转位加速细胞周期和淋巴管内皮细胞增殖和迁移。EphrinB2 增强了 VEGFR3（FLT4）启动子上 ISL1 的转录活性，VEGFR3 抑制剂 MAZ51 显著减弱 EphrinB2 介导的淋巴管生成，并恶化缺血性心脏功能。我们揭示了 EphrinB2 驱动的心脏淋巴管生成在改善心肌梗死后心肌重构和功能中的新机制。
