Abstract
Liver repair after acute liver injury is characterized by hepatocyte proliferation, removal of necrotic tissue, and restoration of hepatocellular and hepatic microvascular architecture. Macrophage recruitment is essential for liver tissue repair and recovery from injury; however, the underlying mechanisms are unclear. Signaling through vascular endothelial growth factor receptor 1 (VEGFR1) is suggested to play a role in macrophage migration and angiogenesis. The aim of the present study was to examine the role of VEGFR1 in liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion (I/R). VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK-/- mice) and wild-type (WT) mice were subjected to hepatic warm I/R, and the processes of liver repair and sinusoidal reconstruction were examined. Compared with WT mice, VEGFR1 TK-/- mice exhibited delayed liver repair after hepatic I/R. VEGFR1-expressing macrophages recruited to the injured liver showed reduced expression of epidermal growth factor (EGF). VEGFR1 TK-/- mice also showed evidence of sustained sinusoidal functional and structural damage, and reduced expression of pro-angiogenic factors. Treatment of VEGFR1 TK-/- mice with EGF attenuated hepatoceullar and sinusoidal injury during hepatic I/R. VEGFR1 TK-/- bone marrow (BM) chimeric mice showed impaired liver repair and sinusoidal reconstruction, and reduced recruitment of VEGFR1-expressing macrophages to the injured liver. VEGFR1-macrophages recruited to the liver during hepatic I/R contribute to liver repair and sinusoidal reconstruction. VEGFR1 activation is a potential therapeutic strategy for promoting liver repair and sinusoidal restoration after acute liver injury.
Highlights
Ischemia/reperfusion (I/R) injury to the liver is a major complication of hemorrhagic shock, liver resection, and transplantation
Vascular endothelial growth factor (VEGF) receptor-1 (VEGFR1) signaling promotes liver repair after hepatic I/R To investigate the involvement of VEGFR1 in liver repair after hepatic I/R, we determined the expression of VEGF-A/ VEGFR1
Because bone marrow (BM)-derived macrophages contribute to liver repair after acute liver injury [30,31], we examined whether recruited VEGFR1-positive cells were derived from the BM
Summary
Ischemia/reperfusion (I/R) injury to the liver is a major complication of hemorrhagic shock, liver resection, and transplantation. Hepatocytes are most susceptible, liver sinusoidal endothelial cells (LSEC) are injured during hepatic I/R [1,2,3]. Hepatic I/R elicits tissue repair, a process of healing in the liver, which is characterized by the proliferation of hepatocytes, removal of necrotic tissue, and restoration of the hepatocellular and hepatic microvascular architecture. Hepatic tissue repair plays a critical role in determining the final outcome of hepatic I/R injury because a delay in liver repair and regeneration is associated with increased morbidity and mortality. The mechanisms underlying hepatocellular regeneration and sinusoidal restoration from hepatic I/R injury are unclear [4,5]. Vascular endothelial growth factor (VEGF)-A is a major regulator of both vascular development and physiological and pathological angiogenesis during tumorigenesis, inflammation, and wound healing [6,7]. VEGFR1 is expressed on monocytes/ macrophages [11] and plays an important role in macrophage recruitment to inflamed and cancerous tissues [12,13]
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