Epac1 promotes neointimal thickening via calcium/calcineurin-dependent smooth muscle cell polarization and migration after vascular injury.

机械性损伤后的血管重构主要依赖于主动脉平滑肌细胞（ASMC）的迁移。我们已经报道了由cAMP 1激活的交换蛋白（Epac 1）的激活促进ASMC迁移。Epac 1在体内血管损伤后促进血管重构的作用及其细胞内机制尚不清楚，PDGF-BB诱导的Epac 1 KO ASMCs定向迁移明显减少。PDGF-BB介导的Epac 1 KO ASMCs细胞内Ca 2+升高显著降低。为了评估在用PDGF-BB刺激下细胞极化的建立，Epac 1 KO ASMC中的cofilin的活化被显著地降低。WT ASMCs中cofilin的激活被钙调磷酸酶抑制剂环孢素A抑制。Epac 1 KO的内膜增厚与平滑肌层的比率显著低于WT。这些结果表明Epac 1通过钙/钙调神经磷酸酶介导的cofilin激活促进ASMC的定向迁移。

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, and the intracellular mechanisms remain unknown.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,activation of cofilin in Epac1KO ASMCs was significantly degreased. Activation 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.These results suggest that Epac1 promotes directional migration of ASMC via calcium/calcineurin-mediated activation of cofilin.