VEGF-C-mediated Cardiac Lymphangiogenesis Promotes Inflammation Resolution in Autoimmune Acute Myocarditis in Mice

BACKGROUND Acute myocarditis is an immune-mediated inflammatory disease characterized by myocardial inflammation and edema. Cardiac lymphatic vessels are essential for fluid clearance and immune regulation; however, their role in modulating inflammation in autoimmune myocarditis remains largely unclear. METHODS We investigated the impact of cardiac lymphangiogenesis using a murine model of experimental autoimmune myocarditis induced by cardiac myosin peptide immunization. Human autopsy samples were analyzed for lymphatic expansion. Mice were treated with VEGF-C C156S, a VEGFR3-specific agonist, beginning one week after immunization. Cardiac lymphangiogenesis, myocardial edema, inflammatory infiltration, fibrosis, and cardiac function were evaluated by immunohistochemistry, echocardiography, gene expression analysis, and water content measurements. RESULTS The VEGF-C treatment accelerated cardiac lymphangiogenesis, enhanced lymphatic drainage, reduced myocardial edema, and attenuated inflammatory cell infiltration and fibrosis. Echocardiography showed the preservation of left ventricular function. VEGF-C selectively decreased the accumulation of iNOS⁺ inflammatory macrophages without broadly suppressing T cells or reparative macrophages. Bulk RNA sequencing confirmed the down-regulation of inflammatory gene signatures associated with macrophage activation. CONCLUSIONS The early stimulation of cardiac lymphangiogenesis by VEGF-C promotes the resolution of inflammation, reduces myocardial injury, and preserves cardiac function in autoimmune myocarditis. Targeting the cardiac lymphatic system may represent a promising therapeutic strategy for acute myocarditis.