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Background  Despite recent improvements in angioplasty and placement of drug‐eluting stents in treatment of atherosclerosis, restenosis and in‐stent thrombosis impede treatment efficacy and cause numerous deaths. Research efforts are needed to identify new molecular targets for blocking restenosis. We aim to establish angiogenic factor  AGGF 1 (angiogenic factor with G patch and FHA domains 1) as a novel target for blocking neointimal formation and restenosis after vascular injury.    Methods and Results   AGGF 1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury.  AGGF 1 +/−  mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells ( VSMC s) in carotid arteries after vascular injury. Importantly,  AGGF 1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of  VSMC s to the contractile phenotype in mice in vivo. In vitro,  AGGF 1 significantly inhibits  VSMC s proliferation and decreases the cell numbers at the S phase.  AGGF 1 also blocks platelet‐derived growth factor‐ BB –induced proliferation, migration of  VSMC s, increases expression of cyclin D, and decreases expression of p21 and p27.  AGGF 1 inhibits phenotypic switching of  VSMC s to the synthetic phenotype by countering the inhibitory effect of platelet‐derived growth factor‐ BB  on  SRF  expression and the formation of the myocardin/ SRF / CA rG‐box complex involved in activation of  VSMC s markers. Finally, we show that  AGGF 1 inhibits platelet‐derived growth factor‐ BB –induced phosphorylation of  MEK 1/2,  ERK 1/2, and Elk phosphorylation involved in the phenotypic switching of  VSMC s, and that overexpression of Elk abolishes the effect of  AGGF 1.    Conclusions   AGGF 1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel  AGGF 1‐ MEK 1/2‐ ERK 1/2‐Elk‐myocardin‐ SRF /p27 signaling pathway.

Targeting AGGF 1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury