Macrophage-derived VEGF-C reduces cardiac inflammation and prevents heart dysfunction in CVB3-induced viral myocarditis via remodeling cardiac lymphatic vessels.

Background: Cardiac lymphatic vessels are important channels for cardiac fluid circulation and immune regulation. In myocardial infarction and chronic heart failure, promoting cardiac lymphangiogenesis is beneficial in reducing cardiac edema and inflammation. However, the specific involvement of cardiac lymphangiogenesis in viral myocarditis (VMC) has not been studied. Despite the recognized participation of macrophages in lymphangiogenesis, the contribution of macrophages to cardiac lymphangiogenesis in VMC is still unclear.

Methods: The male Balb/c mice with VMC were grouped according to the time to explore changes in inflammation, cardiac function and lymphangiogenesis. Adeno-associated virus (AAV) was used to determine the effect of cardiac lymphangiogenesis in VMC. Macrophage depletion and VEGF-C treatment were used to investigate the connection between macrophages and cardiac lymphangiogenesis.

Results: Cardiac inflammation and lymphatic vessel density were both upregulated, peaking on day 7 following CVB3 infection. After treatment with AAV-sVEGFR3, lymphangiogenesis was inhibited, leading to worsened cardiac dysfunction and aggravated inflammation. However, these effects were reversed by AAV-VEGF-C treatment. Furthermore, macrophages infiltrated the inflamed myocardium and secreted VEGF-C. In vitro, VEGF-C was upregulated when RAW264.7 cells were co-cultured with CVB3. Macrophage depletion in mice with VMC inhibited lymphangiogenesis, while supplementation with VEGF-C depressed it.

Conclusion: Collectively, these results indicate that activation of the VEGF-C/VEGFR3 axis exerts a protective effect in CVB3-induced VMC by resolving inflammation and alleviating cardiac dysfunction through increased lymphatic vasculature density, with macrophage-derived VEGF-C partially contributing to this effect.