OVEREXPRESSION OF TISSUE INHIBITOR OF MATRIX METALLOPROTEINASE-1 INHIBITS VASCULAR SMOOTH-MUSCLE CELL FUNCTIONS IN-VITRO AND IN-VIVO

Arterial smooth muscle cells (SMCs) are in a quiescent growth state un der normal physiological conditions, but they can be stimulated to pro liferate and migrate from one tissue compartment to another if the ves sel is injured. This response might require a selective and focal incr ease in tissue degradation, which might be mediated through the increa sed production of matrix metalloproteinases (MMPs). Blockade of MMP ac tivity might therefore inhibit the SMC response to injury. To test thi s hypothesis, we developed clones of rat SMCs that overexpress baboon tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), using retrovi rally mediated gene transfer, and characterized the functional capacit y of these cells in vitro and in vivo. SMCs transduced with the TIMP-1 vector (LTSN) grew more slowly and also migrated through a gel matrix in a Boyden chamber assay more slowly than the vector alone (LXSN) ce lls. The conditioned medium from LTSN cells completely inhibited the p latelet-derived growth factor-BB-induced migration of normal SMCs acro ss a matrix-coated filler, while the LXSN cell conditioned medium had no effect. The inhibitory activity in the LTSN conditioned medium coul d be neutralized with an antibody to TIMP-1. In vivo, local overexpres sion of TIMP-1 using LTSN cells implanted onto balloon-injured rat car otid artery inhibited intimal hyperplasia. Neutralizing antibodies aga inst TIMP-1 suppressed the effect of LTSN cell seeding on intimal thic kening. These data support the conclusion that the process of SMC acti vation lending to a thickened intima is dependent on MMP activity and that TIMP-1 could be utilized to inhibit this process.