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

研究成果: Article同行評審

23 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)147-159
頁數13
期刊Clinical Science
123
發行號3
DOIs
出版狀態Published - 2012 8月

All Science Journal Classification (ASJC) codes

  • 一般醫學

指紋

深入研究「A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade」主題。共同形成了獨特的指紋。

引用此