In our present study we focused on soluble VCAM-1 (sVCAM-1)/α 4 integrin-induced angiogenesis and found that this type of angiogenesis was mediated through p38 mitogen-activated protein kinase and focal adhesion kinase (FAK). HUVEC expressed both α 4 and β 1 integrins, and it was reported that expression of α 4 integrin and its counterreceptor, sVCAM-1/VCAM-1, was enhanced in response to an inflammatory cytokine, TNF-α. In endothelial cells phosphorylation of p38 and FAK, but not that of extracellular signal-regulated kinase 1/2 was induced by sVCAM-1. Migration of endothelial cells was stimulated in response to sVCAM-1 at similar levels as those induced by vascular endothelial growth factor, and sVCAM-1-induced migration was almost completely blocked by neutralizing Ab against α 4 integrin, by either an inhibitor of p38 (SB203580), or by adenovirus containing FAK-related nonkinase. sVCAM-1 also induced the formation of blood vessels in Matrigel plug assay in vivo, and this neovascularization was blocked by SB203580 or neutralizing Ab against α 4 integrin. Moreover, we also confirmed that both TNF-α and sVCAM-1 could synergistically induce angiogenesis in the corneas of mice when each factor at used dose could not induce. This angiogenesis by TNF-α and sVCAM-1 was almost completely blocked by coadministration of SB203580 and also by neutralizing Ab against α 4 integrin. These results suggest that sVCAM-1/α 4 integrin induces angiogenesis through p38 and FAK signaling pathways.