Lymphangiogenesis and accumulation of reparative macrophages contribute to liver repair after hepatic ischemia–reperfusion injury

Hepatic tissue repair plays a critical role in determining the outcome of hepatic ischemia–reperfusion (I/R) injury. Hepatic lymphatics participate in the clearance of dead tissues and contribute to the reparative process after acute hepatic injury; however, it remains unknown whether lymphangiogene...

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Bibliographic Details
Published in:Angiogenesis (London) 2020-08, Vol.23 (3), p.395-410
Main Authors: Nakamoto, Shuji, Ito, Yoshiya, Nishizawa, Nobuyuki, Goto, Takuya, Kojo, Ken, Kumamoto, Yusuke, Watanabe, Masahiko, Majima, Masataka
Format: Article
Language:English
Subjects:
Accumulation
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cardiology
Cell Biology
Gene expression
Genes
Growth factors
Injuries
Ischemia
Liver
Lymphatic system
Macrophages
Oncology
Ophthalmology
Original Paper
Phenotypes
Repair
Reperfusion
Structure-function relationships
Therapeutic applications
Vascular endothelial growth factor
Vascular endothelial growth factor receptors
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Summary:Hepatic tissue repair plays a critical role in determining the outcome of hepatic ischemia–reperfusion (I/R) injury. Hepatic lymphatics participate in the clearance of dead tissues and contribute to the reparative process after acute hepatic injury; however, it remains unknown whether lymphangiogenesis in response to hepatic inflammation is involved in liver repair. Herein, we determined if hepatic lymphangiogenesis improves liver repair after hepatic I/R injury. Using a mouse model of hepatic I/R injury, we investigated hepatic lymphatic structure, growth, and function in injured murine livers. Hepatic I/R injury enhanced lymphangiogenesis around the portal tract and this was associated with increased expression of pro-lymphangiogenic growth factors including vascular endothelial growth factor (VEGF)-C and VEGF-D. Recombinant VEGF-D treatment facilitated liver repair in association with the expansion of lymphatic vessels and increased expression of genes related to the reparative macrophage phenotype. Treatment with a VEGF receptor 3 (VEGFR3) inhibitor suppressed liver repair, lymphangiogenesis, drainage function, and accumulation of VEGFR3-expressing reparative macrophages. VEGF-C and VEGF-D upregulated expression of genes related to lymphangiogenic factors and the reparative macrophage phenotype in cultured macrophages. These results suggest that activation of VEGFR3 signaling increases lymphangiogenesis and the number of reparative macrophages, both of which play roles in liver repair. Expanded lymphatics and induction of reparative macrophage accumulation may be therapeutic targets to enhance liver repair after hepatic injury.
ISSN:0969-6970
1573-7209
DOI:10.1007/s10456-020-09718-w