Abstract
Inhibition of angiogenesis could be a treatment strategy for diseases such as cancer, rheumatoid arthritis, and diabetic retinopathy. PP2 is a pharmacological inhibitor of Src family kinases and was found to inhibit FGF-2 induced angiogenesis in vivo. Experiments in vitro showed that PP2 inhibited invasive growth and sprouting of both endothelial and vascular smooth muscle cells into a fibrin matrix. PP2 inhibited the formation of lamellopodia and expression of kinase inactive c-Src reduced phosphorylation of cortactin and paxillin, suggesting a model in which Src kinases are involved in organization of the actin cytoskeleton. Consequently, endothelial cells expressing kinase inactive c-Src failed to spread and form cord-like structures on a collagen matrix. These data suggest that pharmacological inactivation of Src family kinases inhibits FGF-2 stimulated angiogenesis by interference with organization of the actin cytoskeleton in both endothelial and vascular smooth muscle cells, which affects cell migration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actin Cytoskeleton / drug effects
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Actin Cytoskeleton / metabolism*
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Animals
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Cell Line, Transformed
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Cell Movement / drug effects
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Cell Movement / physiology
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Chick Embryo
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Cortactin
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Cytoskeletal Proteins / metabolism
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Cytoskeleton / drug effects
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Cytoskeleton / metabolism*
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DNA / biosynthesis
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DNA / drug effects
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology*
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Enzyme Inhibitors / pharmacology
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Fibroblast Growth Factor 2 / antagonists & inhibitors
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Fibroblast Growth Factor 2 / metabolism
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Microfilament Proteins / metabolism
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / enzymology
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / enzymology
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Neovascularization, Pathologic / physiopathology
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Paxillin
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Phosphoproteins / metabolism
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Pseudopodia / drug effects
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Pseudopodia / enzymology
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Pyrimidines / pharmacology
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / deficiency*
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src-Family Kinases / genetics
Substances
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AG 1879
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Cortactin
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Cytoskeletal Proteins
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Enzyme Inhibitors
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Microfilament Proteins
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Paxillin
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Phosphoproteins
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Pyrimidines
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Fibroblast Growth Factor 2
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DNA
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src-Family Kinases
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Mitogen-Activated Protein Kinase 1