Expression of tissue inhibitor of matrix metalloproteinases 1 by use of anadenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury

Background-Cell migration is a major contributor to injury-induced neointim al hyperplasia and depends on alteration of the proteolytic balance within the arterial wall toward matrix breakdown. This is partly mediated by the m atrix metalloproteinases (MMPs) and their natural inhibitors, the tissue in hibitors of metalloproteinases (TIMPs). Methods and Results-An increase in expression of biologically active and im munoreactive TIMP-1 was seen in vitro after infection of rat smooth muscle cells (SMCs) with Av1.TIMP1 (an adenoviral vector containing the human TLMP 1 cDNA), Infection of rat SMCs with Av1.TIMP1 reduced migration in vitro by 27% compared with control virus-infected cells (37.6 +/- 4.34 versus 51 +/ - 5.01 cells per high-power field, P < 0.05), The adenoviral vector was del ivered to the injured rat carotid artery, and 4 days later, immunoreactive protein was identified and migration of SMCs reduced by 60% (5.2 +/- 0.5 ve rsus 12.8 +/- 1.5 cells per section, P < 0.05, n = 5), Neointimal area 14 d ays after injury showed a 30% reduction in the animals receiving the Av1.TI MP1 virus compared with controls (0.09 +/- 0.01 versus 0.14 +/- 0.01 mm(2), P = 0.02, n = 14), Conclusions-The response to arterial balloon injury involves MMP-dependent SMC migration and can be attenuated in vivo by the transmural expression of TIMP-1 by adenoviral gene transfer.