Role of matrix metalloproteinases and their tissue inhibitors in the regulation of coronary cell migration

The migration of vascular cells is regulated by matrix metalloproteinases ( MMPs) and their tissue inhibitors (TIMPs). Because the activation of advent itial fibroblasts has been implicated in coronary repair, we have examined regional differences in cell outgrowth and the synthesis of MMPs/TIMPs in d ifferent layers of porcine coronary arteries. Coronary medial explants demo nstrated significantly Slower cell outgrowth than coronary adventitia in cu lture (P<0.001). These observations were paralleled by the predominant expr ession of TIMP-1 and -2 in the media (14-fold and 37-fold higher than in ad ventitia, respectively, P<0.001), whereas higher gelatinolytic activities ( MMP-2 and -9) were released from adventitial explants. Smooth muscle cell o utgrowth from the media was regulated by endogenous TIMPs, since TIMP inhib ition (recombinant MMP-2 or neutralizing anti-TIMP antibodies) facilitated cell outgrowth (P<0.001). In contrast, the addition of recombinant TIMP-1 o r -2 decreased adventitial cell outgrowth. In the coculture experiments, th e presence of coronary media retarded adventitial cell outgrowth,: whereas medial damage abrogated these effects, allowing for fibroblast migration (P <0.001), In conclusion, this study demonstrated differential migratory prop erties and distinct MMP/TIMP synthesis by coronary fibroblasts and smooth m uscle cells, Endogenous TIMPs in the media may play an important role in ma intaining coronary arterial wall homeostasis, whereas high levels of matrix -degrading. activities confer the "invasive" characteristics of adventitial fibroblasts.