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

Abstract

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.

Laminin regulates mouse embryonic stem cell migration: involvement of Epac1/Rap1 and Rac1/cdc42

“…These results are indicative of laminin-induced cell migration mainly through cAMP/Epac1/Rap1 rather than PKA. Likewise, our results and those of Yokoyama et al (62) found Epac1, in opposition to PKA, increases vascular smooth muscle cell migration. However, Lorenowicz et al (41) reported a contradictory result, in which both PKA and Epac1 operate through two parallel and independent signaling pathways that positively regulate endothelial integrity and endothelial cell migration.…”

“…cAMP is a pivotal second messenger that regulates a wide range of cellular processes. Signaling through cAMP and PKA has been implicated in cytoskeletal regulation and cell migration depends on cell types (9,30,36,41,62). cAMP also activates the guanine nucleotide exchange factor Epac (exchange protein directly activated by cAMP) that can subsequently activate the small GTPase Rap (9).…”

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

“…71 Although this study was performed mainly in vitro and requires further investigation in animal models of vascular remodeling, one could speculate that cAMP-producing agonists such as beraprost might help slow restenosis after angioplasty by inhibiting VSMC migration through EPAC activation. In contrast to the finding of a vasculoprotective effect of EPAC, Yokoyama et al 20 has reported that a synthetic EPAC activator used at high concentrations enhanced rat aortic smooth muscle cell migration. The same group recently extended their observation in vivo showing that vascular injury-induced intimal thickening was significantly inhibited in EPAC1-deleted mice.…”

“…17 Also only EPAC1 is upregulated in the area of intimal thickening after injury of mouse femoral artery. 20 Therefore, the dysregulation of EPAC expression, and perhaps an imbalance in the expression of EPAC isoforms observed during cardiovascular remodeling suggest a potential implication of these cAMP-GEFs in cardiovascular disease progression (see below).…”

Epac inhibits migration and proliferation of human prostate carcinoma cells

“…We and others have recently shown that Epac proteins have an important role in several cellular processes, including proliferation and apoptosis, possibly by their signalling capacity to ERK and phosphoinositide-3 kinase-dependent Akt (Fang and Olah, 2007;Grandoch et al, 2009). It is important that very recent studies could show an involvement of Epac in cell migration (Mei and Cheng, 2005;Yokoyama et al, 2008;Bastian et al, 2009), although the effects (inhibitory or stimulatory) were not consistent.…”