title: Synergistic effect of TNF-alpha in soluble VCAM-1-induced angiogenesis through alpha 4 integrins.
abstract: In our present study we focused on soluble VCAM-1 (sVCAM-1)/alpha(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 alpha(4) and beta(1) integrins, and it was reported that expression of alpha(4) integrin and its counterreceptor, sVCAM-1/VCAM-1, was enhanced in response to an inflammatory cytokine, TNF-alpha. 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 alpha(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 alpha(4) integrin. Moreover, we also confirmed that both TNF-alpha 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-alpha and sVCAM-1 was almost completely blocked by coadministration of SB203580 and also by neutralizing Ab against alpha(4) integrin. These results suggest that sVCAM-1/alpha(4) integrin induces angiogenesis through p38 and FAK signaling pathways.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwano
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000235:genetics / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen; D003315:Cornea / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D004338:Drug Combinations; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005822:Genetic Vectors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007106:Immune Sera / Q000494:pharmacology; D039441:Integrin alpha4 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D007797:Laminin; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans; D011725:Pyridines / Q000494:pharmacology; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007106:Immune Sera; D007797:Laminin; D011509:Proteoglycans; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C059485:matrigel; D039441:Integrin alpha4; D003094:Collagen; C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580