Epac1 is upregulated during neointima formation and promotes vascular smooth muscle cell migration

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 295; no. 4; pp. H1547 - H1555
• Main Authors: Yokoyama, Utako, Minamisawa, Susumu, Quan, Hong, Akaike, Toru, Jin, Meihua, Otsu, Koji, Ulucan, Coskun, Wang, Xu, Baljinnyam, Erdenechimeg, Takaoka, Minoru, Sata, Masataka, Ishikawa, Yoshihiro
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.10.2008
• Subjects: Animals; Aorta - embryology; Aorta - growth & development; Aorta - metabolism; Biochemistry; Cell adhesion & migration; Cell Movement - drug effects; Cell Shape; Cells; Cells, Cultured; Cyclic AMP - analogs & derivatives; Cyclic AMP - pharmacology; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Disease Models, Animal; Female; Femoral Artery - injuries; Femoral Artery - metabolism; Femoral Artery - pathology; Gestational Age; Guanine Nucleotide Exchange Factors - antagonists & inhibitors; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Kinases; Male; Mice; Mice, Inbred ICR; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - embryology; Muscle, Smooth, Vascular - growth & development; Muscle, Smooth, Vascular - metabolism; Muscular system; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - metabolism; Pregnancy; Protein Kinase Inhibitors - pharmacology; Proteins; Rats; Rats, Wistar; Signal Transduction - drug effects; Thionucleotides - pharmacology; Time Factors; Transduction, Genetic; Tunica Intima - drug effects; Tunica Intima - embryology; Tunica Intima - growth & development; Tunica Intima - metabolism; Up-Regulation; Wound healing
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01317.2007

1 Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama; 2 Institute for Biomedical Engineering, Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, Tokyo; 3 Department of Cardiovascular Medicine, Tokyo University School of Medicine, Tokyo, Japan; and 4 Cardiovascular Research Institute, Departments of Cell Biology and Molecular Medicine and Medicine (Cardiology), New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey Submitted 9 November 2007 ; accepted in final form 4 August 2008 Vascular remodeling after mechanoinjury largely depends on the migration of smooth muscle cells, an initial key step to wound healing. However, the role of the second messenger system, in particular, the cAMP signal, in regulating such remodeling remains controversial. Exchange protein activated by cAMP (Epac) has been identified as a new target molecule of the cAMP signal, which is independent from PKA. We thus examined whether Epac plays a distinct role from PKA in vascular remodeling. To examine the role of Epac and PKA in migration, we used primary culture smooth muscle cells from both the fetal and adult rat aorta. A cAMP analog selective to PKA, 8-(4-parachlorophenylthio)-cAMP (pCPT-cAMP), decreased cell migration, whereas an Epac-selective analog, 8-pCPT-2'- O -Me-cAMP, enhanced migration. Adenovirus-mediated gene transfer of PKA decreased cell migration, whereas that of Epac1 significantly enhanced cell migration. Striking morphological differences were observed between pCPT-cAMP- and 8-pCPT-2'- O -Me-cAMP-treated aortic smooth muscle cells. Furthermore, overexpression of Epac1 enhanced the development of neointimal formation in fetal rat aortic tissues in organ culture. When the mouse femoral artery was injured mechanically in vivo, we found that the expression of Epac1 was upregulated in vascular smooth muscle cells, whereas that of PKA was downregulated with the progress of neointimal thickening. Our findings suggest that Epac1, in opposition to PKA, increases vascular smooth muscle cell migration. Epac may thus play an important role in advancing vascular remodeling and restenosis upon vascular injury. cAMP; protein kinase A; vascular remodeling; exchange protein activated by cAMP Address for reprint requests and other correspondence: Y. Ishikawa or S. Minamisawa, Cardiovascular Research Institute, Yokohama City Univ. Graduate School of Medicine, 3-9 Fukuura Kanazawa-ku, Yokohama 236-0004, Japan (e-mail: yishikaw{at}med.yokohama-cu.ac.jp )