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Lymphatic vessels are necessary for cardiac function and inflammation resolution in sepsis-induced cardiomyopathy
Cheng-Hua Wu1, Meng-Qi Guan2, Wei-Hua Lu2
1Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College); Anhui Province Clinical Research Center for Critical Respiratory Medicine, Anhui 241004, China; NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Insights
Promoting lymphatic function with vascular endothelial growth factor C (VEGF-C) improves cardiac function and resolves inflammation in sepsis-induced cardiomyopathy (SICM). Lymphatic vessels are essential for recovery in SICM.
Area of Science:
- Cardiovascular Biology
- Lymphatic Physiology
- Sepsis Pathogenesis
Background:
- Sepsis-induced cardiomyopathy (SICM) is a critical complication of sepsis, characterized by reversible global cardiac dysfunction.
- Lymphatic vessels play vital roles in fluid balance and inflammation regulation, but their involvement in SICM remains unexplored.
Purpose of the Study:
- To investigate the role of cardiac lymphatic vessels in sepsis-induced cardiomyopathy.
- To evaluate the therapeutic potential of vascular endothelial growth factor C (VEGF-C) in improving SICM by targeting lymphatics.
Main Methods:
- A mouse model of SICM was established using lipopolysaccharide (LPS) challenge.
- VEGF-C treatment was administered to assess its effects on cardiac function and lymphatic vessels.
- VEGFR-3 inhibition using MAZ51 was employed to study the VEGF-C-VEGFR-3 signaling pathway's role.
Main Results:
- Sepsis induced cardiac dysfunction and reduced lymphatic vessel area.
- VEGF-C treatment improved cardiac function, enhanced lymphangiogenesis, and promoted neutrophil clearance.
- VEGFR-3 inhibition exacerbated cardiac dysfunction, and blocked the protective effects of VEGF-C, implicating the VEGF-C-VEGFR-3 pathway.
- VEGF-C was found to inhibit the MAPK signaling pathway in the septic heart.
Conclusions:
- Functional lymphatic vessels are crucial for maintaining cardiac function and resolving inflammation during SICM.
- Targeting and promoting lymphatic function presents a novel therapeutic strategy for managing sepsis-induced cardiomyopathy.
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.
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