title: Cilostazol improves lymphatic function by inducing proliferation and stabilization of lymphatic endothelial cells.
abstract: BACKGROUND
  Cilostazol, an inhibitor of phosphodiesterase type III, is an antiplatelet agent and vasodilator. Some clinical reports have suggested that this drug can improve progressive and refractory lymphedema.
  
  
  OBJECTIVE
  In this study, we investigated whether cilostazol has the potential to proliferate lymphatic vessels and to improve lymphatic function using human lymphatic endothelial cells (LECs) and mouse lymphedema models.
  
  
  METHODS
  Human LECs were counted at several time points while they were cultured in the presence of cilostazol and/or protein kinase A inhibitor. After receiving a diet including 0.1% cilostazol or control diet, skin tissue and lymphatic function of k-cyclin transgenic (kCYC(+/-)) mice, which have pernicious lymphatic dysfunction, was analyzed. A different lymphedema model was generated in wild type mice by excising circumferential tail skin to remove the superficial lymphatics. After oral administration of cilostazol, tail lymphedema was examined in this mouse model.
  
  
  RESULTS
  Proliferation of LECs was promoted in a dose-dependent manner, which was partially inhibited by a protein kinase A inhibitor. Lymphatic vessel count increased in the cilostazol-treated kCYC(+/-) mice over that in the non-treated mice. Lymph flow improved in cilostazol-fed kCYC(+/-) mice as assessed by subcutaneous injection of Evans blue dye into the footpad. Oral administration of cilostazol also decreased lymphedema in a tail of wild type mice.
  
  
  CONCLUSIONS
  Cilostazol promoted growth of human LECs and improved lymph flow and lymphedema in two different mouse lymphedema models. These results suggest that cilostazol would be a promising agent for the treatment of lymphedema.
authors: Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Department of Dermatology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Takayuki
authors: T
authors: Kimura
authors: Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. Electronic address: hamazaki@ri.ncgm.go.jp.
authors: Tatsuo S
authors: TS
authors: Hamazaki
authors: Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Department of Dermatology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Makoto
authors: M
authors: Sugaya
authors: Department of Cardiovascular Surgery, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Shoji
authors: S
authors: Fukuda
authors: Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Techuan
authors: T
authors: Chan
authors: EM Support Unit, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Miwa
authors: M
authors: Tamura-Nakano
authors: Department of Dermatology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Shinichi
authors: S
authors: Sato
authors: Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Hitoshi
authors: H
authors: Okochi
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000077407:Cilostazol; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects; D004729:Endothelium, Lymphatic / Q000187:drug effects*; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects*; D008209:Lymphedema / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol
keywords: Cilostazol; Lymphatic endothelial cells; Lymphedema