title: Cilostazol promotes angiogenesis after peripheral ischemia through a VEGF-dependent mechanism.
abstract: OBJECTIVE
  Cilostazol has been found to be effective for the treatment of intermittent claudication (IC). This compound has several beneficial effects on platelet aggregation, serum lipids and endothelial cells, but how these might relate to improvements in walking is not entirely understood. The aim of this work was to investigate the effects of cilostazol on angiogenic response in a murine model of peripheral ischemia and to clarify the underlying molecular mechanisms of that response.
  
  
  METHODS
  We studied ischemia-induced neovascularization in the ischemic hindlimb of cilostazol-treated and untreated control mice.
  
  
  RESULTS
  We found that the perfusion recovery was significantly improved in treated compared with control mice. Interestingly, there was a higher level of circulating endothelial progenitor cells (EPCs) in mice treated with cilostazol than in untreated mice. Furthermore, cilostazol administration resulted in upregulation of granulocyte colony-stimulating factor (G-CSF) and vascular endothelial growth factor (VEGF) in the ischemic muscle of treated mice. Finally, inhibiting VEGF activity significantly reduced cilostazol-induced angiogenesis.
  
  
  CONCLUSIONS
  The results of this study show that cilostazol administration enhances collateral blood flow in the ischemic hindlimbs of mice through a VEGF-dependent mechanism. These data may help to explain the beneficial effects that this drug has on patients with peripheral arterial disease (PAD) and IC.
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, A Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy. f.biscetti@gmail.com
authors.forename: Federico
authors.initials: F
authors.lastname: Biscetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pecorini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Straface
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.forename: Egidio
authors.initials: E
authors.lastname: Stigliano
authors.forename: Sergio
authors.initials: S
authors.lastname: Rutella
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Flavia
authors.initials: F
authors.lastname: Angelini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ghirlanda
authors.forename: Andrea
authors.initials: A
authors.lastname: Flex
mesh_terms: D000818:Animals; D000077407:Cilostazol; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; C467480:vascular endothelial growth factor A, mouse; D000077407:Cilostazol