title: Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages.
abstract: The persistence of proinflammatory macrophages, which are recruited to the granulation tissue, impairs the healing of diabetic wounds. Herein, we examined the role of vascular endothelial growth factor receptor type 1 (VEGFR1) signaling in streptozotocin (STZ)-induced diabetic wound healing. Angiogenesis, lymphangiogenesis, and the healing of full-thickness skin wounds were impaired in STZ-treated wild-type (WT) mice compared with vehicle-treated WT mice, with attenuated recruitment of VEGFR1-positive macrophages expressing vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D to the wound granulation tissue. These phenomena were even more prevalent in STZ-treated VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK(-/-) mice). STZ-treated WT mice, but not STZ-treated VEGFR1 TK(-/-) mice, showed accelerated wound healing when treated with placenta growth factor. Compared with that of STZ-treated WT mice, the wound granulation tissue of STZ-treated VEGFR1 TK(-/-) mice contained more VEGFR1-positive cells expressing IL-1β [a classic (M1) activated macrophage marker] and fewer VEGFR1-positive cells expressing the mannose receptor [CD206; an alternatively activated (M2) macrophage marker]. Treatment of STZ-treated VEGFR1 TK(-/-) mice with an IL-1β-neutralizing antibody restored impaired wound healing and angiogenesis/lymphangiogenesis and induced macrophages in the wound granulation tissue to switch to an M2 phenotype. Taken together, these results suggest that VEGFR1 signaling plays a role in regulating the balance between macrophage phenotypes in STZ-induced diabetic wounds, prevents impaired diabetic wound healing, and promotes angiogenesis/lymphangiogenesis.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan; Department of Endocrinology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Okizaki
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Hosono
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan; Department of Endocrinology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Oba
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hirotoki
authors.initials: H
authors.lastname: Ohkubo
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kojo
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nishizawa
authors.affiliation: Institute of Physiology and Medicine, Jobu University, Gunma, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Department of Endocrinology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shichiri
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan. Electronic address: mmajima@med.kitasato-u.ac.jp.
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000276:immunology; D042583:Lymphangiogenesis / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000276:immunology / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D040281:Vascular Endothelial Growth Factor Receptor-1