Abstract
Vascular endothelial growth factor (VEGF) is not only essential for vasculogenesis and angiogenesis but also is a potent inducer of vascular permeability. Although a dissection of the molecular pathways between angiogenesis- and vascular permeability-inducing properties would be desirable for the development of angiogenic and anti-angiogenic therapies, such mechanisms have not been identified yet. Here we provide evidence for a role of the p38 MAPK as the signaling molecule that separates these two processes. Inhibition of p38 MAPK activity enhances VEGF-induced angiogenesis in vitro and in vivo, a finding that was accompanied by prolonged Erk1/2 MAPK activation, increased endothelial survival, and plasminogen activation. Conversely, the same inhibitors abrogate VEGF-induced vascular permeability in vitro and in vivo. These dualistic properties of p38 MAPK are relevant not only for therapeutic angiogenesis but also for reducing edema formation and enhancing tissue repair in ischemic diseases.
MeSH terms
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Allantoin / physiology
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Animals
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Capillary Permeability / drug effects*
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Cell Survival / drug effects
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Chick Embryo
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Chorion / blood supply
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Chorion / physiology
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Endothelial Growth Factors / pharmacology*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiopathology
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Enzyme Inhibitors / pharmacology
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Fibroblast Growth Factor 2 / pharmacology
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Humans
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Imidazoles / pharmacology
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Intercellular Signaling Peptides and Proteins / pharmacology*
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Lymphokines / pharmacology*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism*
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Neovascularization, Pathologic / enzymology*
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Neovascularization, Physiologic / drug effects
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Phosphorylation / drug effects
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Plasminogen / drug effects
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Plasminogen / metabolism
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Pyridines / pharmacology
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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p38 Mitogen-Activated Protein Kinases
Substances
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Endothelial Growth Factors
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Enzyme Inhibitors
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Imidazoles
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Pyridines
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2
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Allantoin
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Plasminogen
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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SB 203580