PMID- 22339730
OWN - NLM
STAT- MEDLINE
DCOM- 20120530
LR  - 20181201
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 123
IP  - 3
DP  - 2012 Aug 1
TI  - A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between 
      multiple signalling pathways including the ERK/p38 MAPK signalling transduction 
      cascade.
PG  - 147-59
LID - 10.1042/CS20110432 [doi]
AB  - Cilostazol is an anti-platelet agent with vasodilatory activity that acts by 
      increasing intracellular concentrations of cAMP. Recent reports have suggested 
      that cilostazol may promote angiogenesis. In the present study, we have 
      investigated the effect of cilostazol in promoting angiogenesis and 
      vasculogenesis in a hindlimb ischaemia model and have also examined its potential 
      mechanism of action in vitro and in vivo. We found that cilostazol treatment 
      significantly increased colony formation by human early EPCs (endothelial 
      progenitor cells) through a mechanism involving the activation of cAMP/PKA 
      (protein kinase A), PI3K (phosphoinositide 3-kinase)/Akt/eNOS (endothelial NO 
      synthase) and ERK (extracellular-signal-regulated kinase)/p38 MAPK 
      (mitogen-activated protein kinase) signalling pathways. Cilostazol also enhanced 
      proliferation, chemotaxis, NO production and vascular tube formation in HUVECs 
      (human umbilical vein endothelial cells) through activation of multiple 
      signalling pathways downstream of PI3K/Akt/eNOS. Cilostazol up-regulated VEGF 
      (vascular endothelial growth factor)-A165 expression and secretion of VEGF-A in 
      HUVECs through activation of the PI3K/Akt/eNOS pathway. In a mouse hindlimb 
      ischaemia model, recovery of blood flow ratio (ipsilateral/contralateral) 14 days 
      after surgery was significantly improved in cilostazol-treated mice (10 mg/kg of 
      body weight) compared with vehicle-treated controls (0.63+/-0.07 and 0.43+/-0.05 
      respectively, P<0.05). Circulating CD34+ cells were also increased in 
      cilostazol-treated mice (3614+/-670 compared with 2151+/-608 cells/ml, P<0.05). 
      Expression of VEGF and phosphorylation of PI3K/Akt/eNOS and ERK/p38 MAPK in 
      ischaemic muscles were significantly enhanced by cilostazol. Our data suggest 
      that cilostazol produces a vasculo-angiogenic effect by up-regulating a broad 
      signalling network that includes the ERK/p38 MAPK, VEGF-A165, PI3K/Akt/eNOS and 
      cAMP/PKA pathways.
FAU - Chao, Ting-Hsing
AU  - Chao TH
AD  - Department of Internal Medicine, National Cheng Kung University College of 
      Medicine and Hospital, Tainan, Taiwan. chaotinghsing@yahoo.com.tw
FAU - Tseng, Shih-Ya
AU  - Tseng SY
FAU - Li, Yi-Heng
AU  - Li YH
FAU - Liu, Ping-Yen
AU  - Liu PY
FAU - Cho, Chung-Lung
AU  - Cho CL
FAU - Shi, Guey-Yueh
AU  - Shi GY
FAU - Wu, Hua-Lin
AU  - Wu HL
FAU - Chen, Jyh-Hong
AU  - Chen JH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Antigens, CD34)
RN  - 0 (Drug Combinations)
RN  - 0 (Laminin)
RN  - 0 (Proteoglycans)
RN  - 0 (Tetrazoles)
RN  - 119978-18-6 (matrigel)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 9007-34-5 (Collagen)
RN  - EC 1.14.13.39 (NOS3 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - N7Z035406B (Cilostazol)
SB  - IM
MH  - Animals
MH  - Antigens, CD34/metabolism
MH  - Apoptosis/drug effects
MH  - Blood Vessels/*drug effects/*enzymology
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cilostazol
MH  - Collagen/pharmacology
MH  - Colony-Forming Units Assay
MH  - Drug Combinations
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Hindlimb/blood supply/pathology
MH  - Human Umbilical Vein Endothelial Cells/cytology/drug effects/enzymology
MH  - Humans
MH  - Ischemia/pathology
MH  - Laminin/pharmacology
MH  - MAP Kinase Signaling System/*drug effects
MH  - Mice
MH  - Neovascularization, Physiologic/*drug effects
MH  - Nitric Oxide/biosynthesis
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Phosphorylation/drug effects
MH  - Proteoglycans/pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Stem Cells/cytology/drug effects/metabolism
MH  - Tetrazoles/*pharmacology
MH  - Up-Regulation/drug effects
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
EDAT- 2012/02/22 06:00
MHDA- 2012/05/31 06:00
CRDT- 2012/02/21 06:00
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2012/05/31 06:00 [medline]
AID - CS20110432 [pii]
AID - 10.1042/CS20110432 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2012 Aug 1;123(3):147-59. doi: 10.1042/CS20110432.