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

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.