Role of nitric oxide in autocrine control of growth and apoptosis of endothelial cells.

Nitric oxide (NO) is a growth inhibitor for diverse cellular types. In the present study, we have found that the inhibition of NO production in bovine endothelial cells by an L-arginine competitive antagonist induces DNA replication and promotes the transition from prereplicative to replicative phases of the endothelial cell cycle and an increase in c-myc and c-fos oncogene-encoded protein expression. The inhibition of NO generation had, however, a markedly different outcome depending on the state of confluence of the cells, i.e., proliferation was found in subconfluent cells, whereas apoptosis occurred in confluent cells. Moreover, Western blot analysis revealed differences in the constitutive NO synthase expression in proliferating compared with growth-arrested cells. In conclusion, these results disclose an alternative mechanism of endothelial cell apoptosis at the confluent state, which is related to NO inhibition. Moreover, the fact that the apoptotic phenomenon occurred in the presence of growth factors indicates the existence of apoptotic mechanisms that do not require growth factor deprivation.