Synergistic Effect of TNF-α in Soluble VCAM-1-Induced Angiogenesis Through α4 Integrins

Publisher Website
Google Scholar
Abstract
In our present study we focused on soluble VCAM-1 (sVCAM-1)/α4 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 α4 and β1 integrins, and it was reported that expression of α4 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 α4 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 α4 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 α4 integrin. These results suggest that sVCAM-1/α4 integrin induces angiogenesis through p38 and FAK signaling pathways.