title: The VEGF-C/VEGFR3 signaling pathway contributes to resolving chronic skin inflammation by activating lymphatic vessel function.
abstract: BACKGROUND
  The functions of lymphatic vessels are to drain the protein-rich lymph from the extracellular space, to maintain normal tissue pressure, and to mediate the immune response, particularly in inflammatory conditions.
  
  
  OBJECTIVE
  To evaluate the function of the vascular endothelial growth factor (VEGF)-C/VEGF receptor (VEGFR)-3 signaling pathway in chronic skin inflammation.
  
  
  METHODS
  We used adenovirus-mediated VEGF-C or VEGFR3-immunoglobulin (Ig) production and investigated the effects of VEGF-C/VEGFR3 signaling on the resolution of inflammation using the experimental chronic contact hypersensitivity (CHS) reaction mouse model.
  
  
  RESULTS
  VEGF-C gene transfer promoted significant reduction of ear swelling and ear weight in CHS reaction-induced skin inflammation. Although, there was no significant difference in the number of lymphatic vessels, the number of infiltrating CD11b-positive inflammatory cells was significantly reduced in the VEGF-C group, which suggested that VEGF-C upregulated the drainage of interstitial fluid and inflammatory cells via lymphatic vessels. Furthermore, blockade of VEGFR3 expression resulted in a significant delay in the recovery from CHS reaction-induced skin inflammation. Lymphatic vessel size was enlarged and a significant increase of infiltrating CD11b inflammatory cells was observed in mice with VEGFR3-Ig gene transfer compared to control mice. These results suggested that blockade of VEGFR3 inhibited the drainage function of the lymphatic system.
  
  
  CONCLUSIONS
  This study provides evidence that VEGF-C/VEGFR3 signaling plays an important role in the resolution of skin inflammation; the regulation of lymphatic function may have a great therapeutic potential in inflammatory skin diseases.
authors.affiliation: Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Hagura
authors.affiliation: Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address: jasai@koto.kpu-m.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Asai
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Takenaka
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kinoshita
authors.affiliation: Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Norito
authors.initials: N
authors.lastname: Katoh
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000628:therapy*; D042583:Lymphangiogenesis / Q000502:physiology; D042601:Lymphatic Vessels / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D012871:Skin Diseases / Q000378:metabolism / Q000628:therapy; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D042582:Vascular Endothelial Growth Factor C; D049452:Green Fluorescent Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Chronic delayed-type hypersensitivity reaction; Lymphatic vessels; VEGF-C; VEGFR3