RESPONSE OF ATHEROSCLEROTIC INTIMAL SMOOTH-MUSCLE CELLS TO EPIDERMAL GROWTH-FACTOR IN-VITRO

Increased proliferation of intimal smooth muscle cells (SMCs) plays an important role in the early phase of atherogenesis. To investigate gr owth mechanisms of these cells, we used intimal SMCs from rabbits fed an atherogenic diet and examined the sequential events that may facili tate induction of intimal SMC proliferation as well as the possible ef fects of growth-promoting factors secreted by these cells. In serum-fr ee medium, epidermal growth factor (EGF) stimulated [H-3]thymidine upt ake by quiescent intimal SMCs at a rate six times higher than quiescen t medial SMCs. There was no significant difference between the two cel l types in terms of the number of specific EGF receptor per cell, the dissociation constant of EGF, and the time course of EGF binding and i nternalization. Furthermore, in both types of cells, c-fos, c-jun, and c-myc mRNAs were induced after 1, 1, and 4 hours of EGF treatment, re spectively, whereas they required 8 hours of contact with EGF to induc e proliferation. Growth response of medial SMCs to EGF was greatly enh anced when rabbit serum, deficient in lipoproteins and free of platele t-derived growth factor, was added to the medium. Moreover, EGF induce d a twofold to fourfold increase in DNA synthesis in medial SMCs cocul tured with intimal SMCs compared with medial SMCs incubated alone. Lik ewise, DNA synthesis of medial SMCs grown in medium conditioned by int imal SMCs was six times higher than that observed in medium conditione d by medial SMCs. Adding EGF to the medium conditioned by intimal SMCs increased their DNA synthesis even further. These findings suggest th at the increased growth potential of intimal SMCs may be regulated by the interaction of EGF and factor(s) secreted by SMCs themselves.