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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1547    most recent 01317.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yokoyama, U. Articles by Ishikawa, Y. Search for Related Content PubMed PubMed Citation Articles by Yokoyama, U. Articles by Ishikawa, Y.

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

¹Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama; ²Institute for Biomedical Engineering, Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, Tokyo; ³Department of Cardiovascular Medicine, Tokyo University School of Medicine, Tokyo, Japan; and ⁴Cardiovascular 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

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