| 研究概要 |
Vascular remodeling after mechanoinjury largely depends on migration of aortic smooth muscle cell (ASMC). We have reported that activation of exchange protein activated by cAMP 1 (Epac1) promotes ASMC migration. However, the role of Epac1 in advancing vascular remodeling upon vascular injury, in vivo remains unknown. We assessed the role of Epac1 in advancing vascular remodeling upon vascular injury, in vivo and the intracellular mechanisms of Epac1-mediated migration in ASMC.
PDGF-BB-induced directional migration of Epac1KO ASMCs was significantly decreased. PDGF-BB-mediated intracellular Ca2+ elevation of Epac1KO ASMCs was significantly reduced . To assess the establishment of cell polarization under stimulation with PDGF-BB, expression of phosphorylated cofilin in ASMCs was evaluated by immunocytochemistry. Dephosphorylation of cofilin in Epac1KO ASMCs was significantly degreased. Dephosphorylation of cofilin in WT ASMCs was suppressed by cyclosporine A, a calcineurin inhibitor. Ratio intimal thickening to smooth muscle layer of Epac1KO was significantly lower than that of WT. Area of internal lumen of Epac1KO mice were significantly increased compared to that of Epac1+/+.
These results suggest that Epac1 promotes directional migration of ASMC via calcium/calcineurin-mediated dephosphorylation of cofilin. Futhermore, Epac1 deficiency may inhibit neointimal thickening and restenosis after vascular injury.
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