title: VEGFR1-positive macrophages facilitate liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion injury.
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.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Hirotoki
authors.initials: H
authors.lastname: Ohkubo
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Minamino
authors.affiliation: Department of Immunology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Eshima
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kojo
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Okizaki
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Gakubunkan Institute of Physiology and Medicine, Jobu University, Takasaki, Gunma, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency / Q000235:genetics*
chemical_list: D004815:Epidermal Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1