We examined whether angiotensin II (Ang II) and tumor necrosis factor- (TNF-) cooperatively induce vascular inflammation using the expression of monocyte chemoattractant protein-1 (MCP-1) as a marker of vascular inflammation. Ang II and TNF- stimulated MCP-1 expression in a synergistic manner in vascular smooth muscle cells. Ang II-induced MCP-1 expression was potently inhibited to a nonstimulated basal level by blockade of the p38-dependent pathway but only partially inhibited by blockade of the nuclear factor kappa B (NFB)-dependent pathway. In contrast, TNF--induced MCP-1 expression was potently suppressed by blockade of NFB activation but only modestly suppressed by blockade of p38 activation. Ang II- and TNF--induced activation of the NFB- and p38-dependent pathways was partially inhibited by pharmacological inhibitors of reactive oxygen species (ROS) production. Furthermore, Ang II- and TNF--stimulated MCP-1 expression was partially suppressed by ROS inhibitors. We also examined whether endogenous Ang II and TNF- cooperatively promote vascular inflammation in vivo using a wire injury model of the rat femoral artery. Blockade of both Ang II and TNF- further suppressed neointimal formation, macrophage infiltration and MCP-1 expression in an additive manner compared with blockade of Ang II or TNF- alone.These results suggested that Ang II and TNF- synergistically stimulate MCP-1 expression via utilization of distinct intracellular signaling pathways-the p38- and NFB-dependent pathways-and that these pathways are activated in ROS-dependent and -independent manners. These results also suggest that Ang II and TNF- cooperatively stimulate vascular inflammation in vivo as well as in vitro.