Inhibition of neointima formation by anti-vascular endothelial growth factor and receptor-1 peptides in a balloon-injured rat carotid artery

Background and Objectives: Vascular endothelial growth factor (VEGF) is a potent endothelial cell-specific mitogen. This study was undertaken to test the hypothesis that the neointima hyperplasia induced by a balloon injury is inhibited by blocking VEGF and VEGF receptor-1 (VEGFR-1) with anti-VEGF peptides. Materials and Methods: Anti-VEGF RRKRRR peptide (dRK6) and anti-VEGFR-1 peptide (anti-flt-1) were synthesized at Pohang University of Science and Technology, Korea. Male Sprague-Dawley rats, weighing 300-350 g, were subcutaneously injected 0.5 mg/kg of dRK6 or 0.5 mg/kg of anti-flt-1, dissolved in phosphate buffer solution, 2 days before induction of a carotid balloon-injury, and then daily in the same manner post carotid balloon injury for 2 weeks. Results: Neointima formation was suppressed in both the dRK6 and anti-flt-1 groups compared to that in the untreated controls at 2 weeks post carotid balloon-injury (neointimal area; control group 0.44±0.09 mm ², dRK6 group 0.25±0.05 mm², anti-flt-1 group 0.19±0.05 mm², p<0.01). Anti-flt-1 peptide and dRK6 reduced the numbers of proliferative bromodeoxyuridine-labeled cells in the neointima (control group 16.4±10.6%, dRK6 group 3.7±2.1%, anti-flt-1 group 5.9±3.4%, p<0.05). In addition, an inflammatory response, as determined by monocyte chemoattractant protein-1 and interleukin-6 upregulation, which was evident in the controls, was inhibited by both dRK6 and anti-flt-1. Conclusion: This study suggests anti-vascular endothelial growth factor peptides can reduce the inflammation and neointima formation in balloon injured rat carotid arteries.