Epac1 deficiency inhibits basic fibroblast growth factor-mediated vascular smooth muscle cell migration
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Vascular smooth muscle cell (VSMC) migration and the subsequent intimal thickening play roles in vascular restenosis. We previously reported that an exchange protein activated by cAMP 1 (Epac1) promotes platelet-derived growth factor (PDGF)-induced VSMC migration and intimal thickening. Because basic fibroblast growth factor (bFGF) also plays a pivotal role in restenosis, we examined whether Epac1 was involved in bFGF-mediated VSMC migration. bFGF-induced lamellipodia formation and migration were significantly decreased in VSMCs obtained from Epac1−/− mice compared to those in Epac1+/+-VSMCs. The bFGF-induced phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β), which play a role in bFGF-induced cell migration, was attenuated in Epac1−/−-VSMCs. Intimal thickening induced by the insertion of a large wire was attenuated in Epac1−/− mice, and was accompanied by the decreased phosphorylation of GSK3β. These data suggest that Epac1 deficiency attenuates bFGF-induced VSMC migration, possibly via Akt/GSK3β pathways.
KeywordsExchange protein activated by cAMP 1 Intimal thickening Basic fibroblast growth factor Vascular smooth muscle cells Migration
The authors are grateful to Yuka Sawada (Yokohama City University) for histological analysis.
This study was funded by MEXT/JSPS KAKENHI (YK, JP17K08976; UY, JP17K19403, JP16H05358, JP15H05761; YI, JPH1605300), the Takeda Science Foundation (YK), the Japan Agency for Medical Research and Development (AMED) (YI, 66890007, 66891153), and the Kitsuen Research Foundation (YI, 71890005).
Supplemental movie I. Epac1+/+-VSMC migration under stimulation with 10 ng/ml of bFGF. (MPG 887 kb)
Supplemental movie II. Epac1−/−-VSMC migration under stimulation with 10 ng/ml of bFGF. (MPG 885 kb)
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