Yuko Kato1, Utako Yokoyama2, Chiharu Yanai1, Rina Ishige1, Daisuke Kurotaki1, Masanari Umemura1, Takayuki Fujita1, Tetsuo Kubota1, Satoshi Okumura1, Masataka Sata1, Tomohiko Tamura1, Yoshihiro Ishikawa2. 1. From the Cardiovascular Research Institute (Y.K., U.Y., C.Y., M.U., T.F., Y.I.) and Department of Immunology (D.K., T.T.), Yokohama City University, Graduate School of Medicine, Yokohama, Japan; Department of Microbiology and Immunology, Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo, Japan (Y.K., R.I., T.K.); Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan (S.O.); and Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (M.S.). 2. From the Cardiovascular Research Institute (Y.K., U.Y., C.Y., M.U., T.F., Y.I.) and Department of Immunology (D.K., T.T.), Yokohama City University, Graduate School of Medicine, Yokohama, Japan; Department of Microbiology and Immunology, Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo, Japan (Y.K., R.I., T.K.); Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan (S.O.); and Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan (M.S.). utako@yokohama-cu.ac.jp yishikaw@med.yokohama-cu.ac.jp.
Abstract
OBJECTIVE: Vascular smooth muscle cell (SMC) migration causes neointima, which is related to vascular remodeling after mechanical injury and atherosclerosis development. We previously reported that an exchange protein activated by cAMP (Epac) 1 was upregulated in mouse arterial neointima and promoted SMC migration. In this study, we examined the molecular mechanisms of Epac1-induced SMC migration and the effect of Epac1 deficiency on vascular remodeling in vivo. APPROACH AND RESULTS: Platelet-derived growth factor-BB promoted a 2-fold increase in SMC migration in a primary culture of aortic SMCs obtained from Epac1(+/+) mice (Epac1(+/+)-ASMCs), whereas there was only a 1.2-fold increase in Epac1(-/-)-ASMCs. The degree of platelet-derived growth factor-BB-induced increase in intracellular Ca(2+) was smaller in Fura2-labeled Epac1(-/-)-ASMCs than in Epac1(+/+)-ASMCs. In Epac1(+/+)-ASMCs, an Epac-selective cAMP analog or platelet-derived growth factor-BB increased lamellipodia accompanied by cofilin dephosphorylation, which is induced by Ca(2+) signaling, whereas these effects were rarely observed in Epac1(-/-)-ASMCs. Furthermore, 4 weeks after femoral artery injury, prominent neointima were formed in Epac1(+/+) mice, whereas neointima formation was significantly attenuated in Epac1(-/-) mice in which dephosphorylation of cofilin was inhibited. The chimeric mice generated by bone marrow cell transplantation from Epac1(+/+) into Epac1(-/-) mice and vice versa demonstrated that the genetic background of vascular tissues, including SMCs rather than of bone marrow-derived cells affected Epac1-mediated neointima formation. CONCLUSIONS: These data suggest that Epac1 deficiency attenuates neointima formation through, at least in part, inhibition of SMC migration, in which a decrease in Ca(2+) influx and a suppression of cofilin-mediated lamellipodia formation occur.
OBJECTIVE: Vascular smooth muscle cell (SMC) migration causes neointima, which is related to vascular remodeling after mechanical injury and atherosclerosis development. We previously reported that an exchange protein activated by cAMP (Epac) 1 was upregulated in mouse arterial neointima and promoted SMC migration. In this study, we examined the molecular mechanisms of Epac1-induced SMC migration and the effect of Epac1deficiency on vascular remodeling in vivo. APPROACH AND RESULTS: Platelet-derived growth factor-BB promoted a 2-fold increase in SMC migration in a primary culture of aortic SMCs obtained from Epac1(+/+) mice (Epac1(+/+)-ASMCs), whereas there was only a 1.2-fold increase in Epac1(-/-)-ASMCs. The degree of platelet-derived growth factor-BB-induced increase in intracellular Ca(2+) was smaller in Fura2-labeled Epac1(-/-)-ASMCs than in Epac1(+/+)-ASMCs. In Epac1(+/+)-ASMCs, an Epac-selective cAMP analog or platelet-derived growth factor-BB increased lamellipodia accompanied by cofilin dephosphorylation, which is induced by Ca(2+) signaling, whereas these effects were rarely observed in Epac1(-/-)-ASMCs. Furthermore, 4 weeks after femoral artery injury, prominent neointima were formed in Epac1(+/+) mice, whereas neointima formation was significantly attenuated in Epac1(-/-) mice in which dephosphorylation of cofilin was inhibited. The chimeric mice generated by bone marrow cell transplantation from Epac1(+/+) into Epac1(-/-) mice and vice versa demonstrated that the genetic background of vascular tissues, including SMCs rather than of bone marrow-derived cells affected Epac1-mediated neointima formation. CONCLUSIONS: These data suggest that Epac1deficiency attenuates neointima formation through, at least in part, inhibition of SMC migration, in which a decrease in Ca(2+) influx and a suppression of cofilin-mediated lamellipodia formation occur.
Authors: Hui Wang; William G Robichaux; Ziqing Wang; Fang C Mei; Ming Cai; Guangwei Du; Ju Chen; Xiaodong Cheng Journal: Sci Rep Date: 2016-11-10 Impact factor: 4.379