Activin A is a homodimeric protein structurally related to transforming growth factor-beta. The present study was conducted to examine the effect of activin A on the growth of rat vascular smooth muscle cells (VSMC) in culture. When serum-deprived cells were incubated with activin A, nuclear labeling of bromodeoxyuridine occurred after a 12-h lag period. The effect of activin A on nuclear labeling was dose-dependent, being maximal at 10(-9) M. Activin A also increased the number of VSMC after 30 h of incubation. Insulin-like growth factor-1 (IGF-1) had only a small effect on nuclear labeling by itself but the effects of IGF-1 and activin A were additive. When quiescent VSMC were treated with activin A for 4 h, the effect of subsequent IGF-1 was markedly enhanced. Furthermore, activin A induced an autocrine production of IGF-1 in VSMC. In contrast to these positive effects on cell growth, activin A was rather inhibitory to the action of IGF-1 in activin-primed cells. In addition, activin A inhibited platelet-derived growth factor-induced nuclear labeling. These results indicate that activin A modifies growth of VSMC by complex mechanisms involving autocrine production of IGF-1 and modification of the action of IGF-1.