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)
- 3.Stolker JM, Kennedy KF, Lindsey JB, Marso SP, Pencina MJ, Cutlip DE, Mauri L, Kleiman NS, Cohen DJ, Investigators E (2010) Predicting restenosis of drug-eluting stents placed in real-world clinical practice: derivation and validation of a risk model from the EVENT registry. Circ Cardiovasc Interv 3:327–334CrossRefPubMedGoogle Scholar
- 10.Yokoyama U, Minamisawa S, Quan H, Akaike T, Jin M, Otsu K, Ulucan C, Wang X, Baljinnyam E, Takaoka M, Sata M, Ishikawa Y (2008) Epac1 is upregulated during neointima formation and promotes vascular smooth muscle cell migration. Am J Physiol Heart Circ Physiol 295:H1547–H1555CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Yokoyama U, Minamisawa S, Quan H, Akaike T, Suzuki S, Jin M, Jiao Q, Watanabe M, Otsu K, Iwasaki S, Nishimaki S, Sato M, Ishikawa Y (2008) Prostaglandin E2-activated Epac promotes neointimal formation of the rat ductus arteriosus by a process distinct from that of cAMP-dependent protein kinase A. J Biol Chem 283:28702–28709CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Wang X, Zhu Y, Sun C, Wang T, Shen Y, Cai W, Sun J, Chi L, Wang H, Song N, Niu C, Shen J, Cong W, Zhu Z, Xuan Y, Li X, Jin L (2017) Feedback activation of basic fibroblast growth factor signaling via the Wnt/beta-catenin pathway in skin fibroblasts. Front Pharmacol 8:32PubMedPubMedCentralGoogle Scholar
- 18.Shimabukuro Y, Terashima H, Takedachi M, Maeda K, Nakamura T, Sawada K, Kobashi M, Awata T, Oohara H, Kawahara T, Iwayama T, Hashikawa T, Yanagita M, Yamada S, Murakami S (2011) Fibroblast growth factor-2 stimulates directed migration of periodontal ligament cells via PI3 K/AKT signaling and CD44/hyaluronan interaction. J Cell Physiol 226:809–821CrossRefPubMedGoogle Scholar
- 21.Namkoong S, Kim CK, Cho YL, Kim JH, Lee H, Ha KS, Choe J, Kim PH, Won MH, Kwon YG, Shim EB, Kim YM (2009) Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3 K/Akt/eNOS signaling. Cell Signal 21:906–915CrossRefPubMedGoogle Scholar
- 32.Rutherford C, Martin W, Salame M, Carrier M, Anggard E, Ferns G (1997) Substantial inhibition of neo-intimal response to balloon injury in the rat carotid artery using a combination of antibodies to platelet-derived growth factor-BB and basic fibroblast growth factor. Atherosclerosis 130:45–51CrossRefPubMedGoogle Scholar
- 34.Baljinnyam E, Umemura M, Chuang C, De Lorenzo MS, Iwatsubo M, Chen S, Goydos JS, Ishikawa Y, Whitelock JM, Iwatsubo K (2014) Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling. Pigment Cell Melanoma Res 27:611–620CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Park KW, Yang HM, Youn SW, Yang HJ, Chae IH, Oh BH, Lee MM, Park YB, Choi YS, Kim HS, Walsh K (2003) Constitutively active glycogen synthase kinase-3beta gene transfer sustains apoptosis, inhibits proliferation of vascular smooth muscle cells, and reduces neointima formation after balloon injury in rats. Arterioscler Thromb Vasc Biol 23:1364–1369CrossRefPubMedGoogle Scholar
- 56.Wang Y, Bai Y, Qin L, Zhang P, Yi T, Teesdale SA, Zhao L, Pober JS, Tellides G (2007) Interferon-gamma induces human vascular smooth muscle cell proliferation and intimal expansion by phosphatidylinositol 3-kinase dependent mammalian target of rapamycin raptor complex 1 activation. Circ Res 101:560–569CrossRefPubMedGoogle Scholar