A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade

Ting Hsing Chao, Shih Ya Tseng, Yi Heng Li, Ping Yen Liu, Chung Lung Cho, Guey Yueh Shi, Hua Lin Wu, Jyh Hong Chen

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 (mitogenactivated 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 upregulated VEGF (vascular endothelial growth factor)-A 165 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-A 165, PI3K/Akt/eNOS and cAMP/PKA pathways.

Original languageEnglish
Pages (from-to)147-159
Number of pages13
JournalClinical Science
Volume123
Issue number3
DOIs
Publication statusPublished - 2012 Aug 1

Fingerprint

Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
1-Phosphatidylinositol 4-Kinase
Vascular Endothelial Growth Factor A
Human Umbilical Vein Endothelial Cells
Hindlimb
Ischemia
cilostazol
Chemotaxis
Cyclic AMP-Dependent Protein Kinases
Ambulatory Surgical Procedures
Nitric Oxide Synthase
Action Potentials
Blood Vessels
Blood Platelets
Body Weight
Phosphorylation
Muscles

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

@article{5fb515bf79a541e9902009f8b98f214a,
title = "A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade",
abstract = "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 (mitogenactivated 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 upregulated VEGF (vascular endothelial growth factor)-A 165 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-A 165, PI3K/Akt/eNOS and cAMP/PKA pathways.",
author = "Chao, {Ting Hsing} and Tseng, {Shih Ya} and Li, {Yi Heng} and Liu, {Ping Yen} and Cho, {Chung Lung} and Shi, {Guey Yueh} and Wu, {Hua Lin} and Chen, {Jyh Hong}",
year = "2012",
month = "8",
day = "1",
doi = "10.1042/CS20110432",
language = "English",
volume = "123",
pages = "147--159",
journal = "Clinical Science",
issn = "0143-5221",
publisher = "Portland Press Ltd.",
number = "3",

}

TY - JOUR

T1 - A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade

AU - Chao, Ting Hsing

AU - Tseng, Shih Ya

AU - Li, Yi Heng

AU - Liu, Ping Yen

AU - Cho, Chung Lung

AU - Shi, Guey Yueh

AU - Wu, Hua Lin

AU - Chen, Jyh Hong

PY - 2012/8/1

Y1 - 2012/8/1

N2 - 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 (mitogenactivated 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 upregulated VEGF (vascular endothelial growth factor)-A 165 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-A 165, PI3K/Akt/eNOS and cAMP/PKA pathways.

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 (mitogenactivated 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 upregulated VEGF (vascular endothelial growth factor)-A 165 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-A 165, PI3K/Akt/eNOS and cAMP/PKA pathways.

UR - http://www.scopus.com/inward/record.url?scp=84861568324&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861568324&partnerID=8YFLogxK

U2 - 10.1042/CS20110432

DO - 10.1042/CS20110432

M3 - Article

C2 - 22339730

AN - SCOPUS:84861568324

VL - 123

SP - 147

EP - 159

JO - Clinical Science

JF - Clinical Science

SN - 0143-5221

IS - 3

ER -