title: Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kato
authors.affiliation: 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.
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.affiliation: 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.).
authors.forename: Chiharu
authors.initials: C
authors.lastname: Yanai
authors.affiliation: 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.).
authors.forename: Rina
authors.initials: R
authors.lastname: Ishige
authors.affiliation: 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.).
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kurotaki
authors.affiliation: 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.).
authors.forename: Masanari
authors.initials: M
authors.lastname: Umemura
authors.affiliation: 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.).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.affiliation: 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.).
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kubota
authors.affiliation: 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.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.affiliation: 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.).
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.affiliation: 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.).
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tamura
authors.affiliation: 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.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D016026:Bone Marrow Transplantation; D020013:Calcium Signaling; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D010766:Phosphorylation; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D020827:rap1 GTP-Binding Proteins
keywords: arterial injury; intima-media thickness; migration; signal transduction; vascular smooth muscle