Objective:To determine the effects of a recombinant replication-deficient adenovirus encoding human tissue inhibitor of metalloproteinase-4（Ad.TIMP-4） on vascular smooth muscle cell（VSMC） function in vitro and neointimal development in the injured rat carotid artery.Methods:Western blotting

gelatin zymography and reverse zymography were used to characterize the expression and functional activity of the TIMP-4 secreted by Ad.TIMP-4-infected VSMCs.The migration and proliferation of VSMCs in vitro were separately detected by using Millicell-PCF invasion chambers and [3H]-thymidine incorporation assay.Immunohistochemistry and morphometric analysis were used to determine the local expression of TIMP-4 and its effect on neointima development in a rat carotid artery balloon injury model.Results:VSMCs infected with Ad.TIMP-4 expressed functionally active human TIMP-4 which increased with the duration of infection.TIMP-4 expression inhibited VSMC migration

but not significantly affect VSMC proliferation.In a balloon-injured rat carotid artery model

a significant 62% reduction in neointimal area was found in Ad.TIMP-4-infected vessels at 14 days after injury.Ad.TIMP-4 infection had no effect on medial area.Conclusion:Our results indicated TIMP-4 over expression can significantly inhibit the migration of cultured VSMCs and prevent neointimal formation after vascular injury.Our findings provide additional evidence that TIMP-4 could play an important role in vascular pathophysiology

and may be an important therapeutic target for future drug development.