NITRIC-OXIDE MEDIATES CYTOTOXICITY AND BASIC FIBROBLAST GROWTH-FACTORRELEASE IN CULTURED VASCULAR SMOOTH-MUSCLE CELLS - A POSSIBLE MECHANISM OF NEOVASCULARIZATION IN ATHEROSCLEROTIC PLAQUES

To define the pathophysiological role of nitric oxide (NO) released fr om vascular smooth muscle cells (VSMC), we examined whether NO release d from VSMC induces cytotoxicity in VSMC themselves and adjacent endot helial cells (EC) using a coculture system. Prolonged incubation with interleukin-1 (IL-1) induced large amounts of NO release and cytotoxic ity in VSMC. N-G-Monomethyl-L-arginine, an inhibitor of NO synthesis, inhibited both NO release and cytotoxicity induced by IL-1. In contras t, DNA synthesis in cocultured EC was not inhibited but rather stimula ted by prolonged incubation with IL-1 or sodium nitroprusside (SNP), a NO donor. However, IL-1 and SNP did not stimulate but inhibited DNA s ynthesis in EC alone. On the other hand, conditioned medium from VSMC incubated for a long period with IL-1 or SNP stimulated DNA synthesis in EC alone. Furthermore, the concentration of basic fibroblast growth factor in the conditioned medium was increased and correlated with th e degree of cytotoxicity in VSMC. These results indicate that NO relea sed from VSMC induces VSMC death, which results in release of basic fi broblast growth factor, which then stimulates adjacent EC proliferatio n. Thus, NO released from VSMC may participate in the mechanism of neo vascularization in atherosclerotic plaques.