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 （产生促红细胞生成素的肝癌相互作用因子 B2） 是 Eph/肝配蛋白家族的关键成员，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 （MI） 后心脏淋巴管生成中的作用和潜在的分子机制仍有待证明。这项研究表明，EphrinB2 通过激活心脏淋巴管生成信号通路来防止心肌梗死后缺血性心脏重塑和功能障碍。EphrinB2 的缺失损害了心肌淋巴管生成，并加剧了 MI 后不良心脏重塑和心室功能障碍。同时，EphrinB2 的过表达刺激心脏淋巴管生成，从而促进心脏浸润巨噬细胞引流并减少缺血性心脏的炎症。EphrinB2 对改善炎症反应清除和心脏功能的有益作用在 Lyve1 敲除小鼠中被消除。从机制上讲，EphrinB2 通过激活 CDK5 和 CDK5 依赖性 ISL1 核转位来加速细胞周期和淋巴内皮细胞增殖和迁移。EphrinB2 增强了 ISL1 在 VEGFR3 （FLT4） 启动子处的转录活性，VEGFR3 抑制剂 MAZ51 显着降低了 EphrinB2 介导的淋巴管生成并恶化了缺血性心脏功能。我们发现了 EphrinB2 驱动的心脏淋巴管生成在改善 MI 后心肌重塑和功能方面的一种新机制。