title: Induction of Angiogenesis by a Type III Phosphodiesterase Inhibitor, Cilostazol, Through Activation of Peroxisome Proliferator-Activated Receptor-γ and cAMP Pathways in Vascular Cells.
abstract: OBJECTIVE
  Peripheral arterial disease is highly prevalent in the elderly and in the subjects with cardiovascular risk factors such as diabetes. Approximately 2% to 4% of those affected with peripheral arterial disease commonly complain of intermittent claudication. Cilostazol, a type III phosphodiesterase inhibitor, is the only Food and Drug Administration-approved drug for the treatment of intermittent claudication. Cilostazol has been shown to be beneficial for the improvement of pain-free walking distance in patients with intermittent claudication in a series of randomized clinical trials. However, the underlying mechanism how cilostazol improved intermittent claudication symptoms is still unclear.
  
  
  RESULTS
  In this study, the effect of cilostazol on ischemic leg was investigated in mouse ischemic hindlimb model. Administration of cilostazol significantly increased the expression of hepatocyte growth factor (HGF), vascular endothelial growth factor, angiopoietin-1, and peroxisome proliferator-activated receptor-γ in vasculature. The capillary density in ischemic leg was also significantly increased in cilostazol treatment group when compared with control and aspirin treatment group. However, an increase in capillary density and the expression of growth factors was almost completely abolished by coadministration of HGF-neutralizing antibody, suggesting that cilostazol enhanced angiogenesis mainly through HGF. In vitro experiment revealed that cilostazol treatment increased HGF production in vascular smooth muscle cells via 2 major pathways: peroxisome proliferator-activated receptor-γ and cAMP pathways.
  
  
  CONCLUSIONS
  Our data suggest that the favorable effects of cilostazol on ischemic leg might be through the angiogenesis through the induction of HGF via peroxisome proliferator-activated receptor-γ and cAMP pathways.
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kanbara
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan. taniyama@cgt.med.osaka-u.ac.jp morishit@cgt.med.osaka-u.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Otsu
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Miguel
authors.initials: M
authors.lastname: Carracedo
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ikeda-Iwabu
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Muratsu
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.affiliation: From the Departments of Clinical Gene Therapy (F.S., Y.K., Y.T., R.O., M.C., Y.I.-I., J.M., R.M.) and Geriatric and General Medicine (Y.T., J.M., K.S., K.Y., H.R.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan. taniyama@cgt.med.osaka-u.ac.jp morishit@cgt.med.osaka-u.ac.jp.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D002478:Cells, Cultured; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D007511:Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D051381:Rats; D015290:Second Messenger Systems; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; C553307:HGF protein, mouse; D047495:PPAR gamma; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D017228:Hepatocyte Growth Factor; D000242:Cyclic AMP; D000077407:Cilostazol
keywords: angiogenesis effect; cilostazol; hepatocyte growth factor; intermittent claudication; muscle development; peripheral arterial disease