Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury.

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 AGGF1 (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: AGGF1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury. AGGF1+/- mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells (VSMCs) in carotid arteries after vascular injury. Importantly, AGGF1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of VSMCs to the contractile phenotype in mice in vivo. In vitro, AGGF1 significantly inhibits VSMCs proliferation and decreases the cell numbers at the S phase. AGGF1 also blocks platelet-derived growth factor-BB-induced proliferation, migration of VSMCs, increases expression of cyclin D, and decreases expression of p21 and p27. AGGF1 inhibits phenotypic switching of VSMCs 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/CArG-box complex involved in activation of VSMCs markers. Finally, we show that AGGF1 inhibits platelet-derived growth factor-BB-induced phosphorylation of MEK1/2, ERK1/2, and Elk phosphorylation involved in the phenotypic switching of VSMCs, and that overexpression of Elk abolishes the effect of AGGF1.

CONCLUSIONS: AGGF1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel AGGF1-MEK1/2-ERK1/2-Elk-myocardin-SRF/p27 signaling pathway.