Background: Sepsis-induced cardiomyopathy (SICM), is defined as a global but reversible dysfunction of both the left and right sides of the heart, which plays a significant role in the pathogenesis of sepsis. Lymphatic vessels are crucial for maintaining tissue fluid balance and regulating inflammatory responses. However, the role of lymphatics in SICM is still unknown.
Methods: The SICM model was established by intraperitoneal injection of lipopolysaccharide (LPS) for 12 h. To evaluate the effects of VEGF-C on LPS-induced SICM, the mice were treated with VEGFC-156S (0.1 mg/kg) via tail vein injection 6 h after LPS challenged and sacrificed 6 h after being treated with VEGFC. To evaluate the effects of the VEGF-C-VEGFR-3 signaling pathway in SICM. MAZ51, a specific inhibitor of VEGFR-3, was given intraperitoneally once daily for a total of 30 days before challenge with LPS.
Results: We found that cardiac function was impaired in SICM, along with a significant reduction in the area of lymphatic vessels. Then, we revealed that stimulation of cardiac lymphangiogenesis with vascular endothelial growth factor C (VEGFC) effectively improved cardiac function and promoted neutrophil clearance. Meanwhile, lymphatic inhibition by MAZ51, a specific inhibitor of VEGFR3, could further exacerbate cardiac dysfunction during SICM. Furthermore, the protective effect of VEGFC on SICM could be blocked by MAZ51. Finally, combined with transcriptomics sequencing, we found that VEGFC effectively inhibited the mitogen-activated protein kinase (MAPK) signaling pathway to protect the septic heart.
Conclusions: Our data show that effective lymphatic vessels are necessary for cardiac function and inflammation resolution in SICM. Our findings offer a novel therapeutic approach to SICM by promoting lymphatic function.
Keywords: Cardiac injury; Lymphatic; Sepsis; VEGFC; VEGFR3.
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