Matrix metalloproteinase and alpha v beta 3 integrin-dependent vascular smooth muscle cell invasion through a type I collagen lattice

Smooth muscle cell (SMC) migration from the tunica media to the intima is a key event in the development of atherosclerotic lesions and in restenosis after angioplasty. SMCs require not only migratory but also degradative abi lities that enable them to migrate through extracellular matrix proteins, w hich surround and embed these cells. We used a collagen type I lattice as a coating on top of a porous filter as a matrix barrier in a chamber to test the invasive behavior of SMCs in response to a chemoattractant (invasion a ssay) and compared that behavior with simple SMC migration through collagen type I-coated filters (migration assay). Inhibitors of matrix metalloprote inase, KB-R8301, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), T IMP-2, and peptide 74, attenuated platelet-derived growth factor-BB (PDGF-B B)-directed SMC invasion across the collagen lattice, whereas no effect was seen with these inhibitors on simple SMC migration through collagen-coated filters. RGD peptide inhibited SMC invasion but did not affect SMC migrati on. Anti-alpha v beta 3 integrin antibody attenuated PDGF-BB-directed SMC i nvasion, whereas other antibodies against RGD-recognizing integrins, namely alpha v beta 5 and alpha 5: had no effect. None of these antibodies had an y effect on simple SMC migration. RGD peptide and anti-alpha v beta 3 antib ody inhibited the attachment and spreading of SMCs an denatured collagen bu t not on native collagen. These findings indicate that there is a differenc e in the mechanisms between simple SMC migration across a collagen-coated f ilter and SMC invasion through a fibrillar collagen barrier. A proteolytic process is required for SMC invasion, and the degradation of matrix protein s alters the relationship between matrix protein molecules and SMC surface integrins.