VEGF-C-mediated cardiac lymphangiogenesis promotes inflammation resolution in autoimmune acute myocarditis in mice

AIMS: Acute myocarditis is an immune-mediated inflammatory disease characterized by myocardial inflammation and oedema. Although cardiac lymphatic vessels are essential for fluid clearance and immune regulation, their role in modulating autoimmune cardiac inflammation remains largely undefined. We aimed to determine whether promoting lymphangiogenesis could mitigate inflammation and preserve cardiac function in autoimmune myocarditis. METHODS AND RESULTS: We used a murine model of experimental autoimmune myocarditis (EAM) induced by cardiac myosin peptide immunization and examined human autopsy hearts for lymphatic expansion. Mice received VEGF-C C156S, a VEGFR3-selective agonist, starting one week after immunization. We assessed lymphangiogenesis, oedema, immune infiltration, fibrosis, and cardiac function using immunohistochemistry, echocardiography, qPCR, and RNA sequencing. VEGF-C treatment enhanced lymphatic sprouting and function, reduced myocardial water content, and attenuated immune cell infiltration and interstitial fibrosis. Cardiac function was preserved, as measured by echocardiography. Notably, VEGF-C selectively decreased the accumulation of iNOS+ inflammatory macrophages without broadly suppressing T cells or reparative macrophage subsets. Transcriptomic profiling confirmed down-regulation of inflammatory gene programmes associated with macrophage activation. CONCLUSION: Early stimulation of cardiac lymphangiogenesis by VEGF-C promotes inflammation resolution, limits myocardial injury, and preserves cardiac function in autoimmune myocarditis. Targeting the cardiac lymphatic system may represent a novel therapeutic strategy for inflammatory heart disease.