Abstract
gamma-Secretase cleaves the transmembrane domains of several integral membrane proteins involved in vasculogenesis. Here, we investigated the role of gamma-secretase in the regulation of postnatal angiogenesis using gamma-secretase inhibitors (GSI). In endothelial cell (EC), gamma-secretase activity was up-regulated under hypoxia or the treatment of vascular endothelial growth factor (VEGF). The treatment of GSI significantly attenuated growth factor-induced EC proliferation and migration as well as c-fos promoter activity in a dose-dependent manner. In vascular smooth muscle cell (VSMC), treatment of GSI significantly attenuated growth factor-induced VEGF and fibroblast growth factor-2 (FGF-2) expression. Indeed, GSI attenuated VEGF-induced tube formation and inhibited FGF-2-induced angiogenesis on matrigel in mice as quantified by FITC-lectin staining of EC. Overall, we demonstrated that gamma-secretase may be key molecule in postnatal angiogenesis which may be downstream molecule of growth factor-induced growth and migration in EC, and regulate the expression of angiogenic growth factors in VSMC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Animals
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Blood Vessels / drug effects
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Blood Vessels / enzymology
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Blood Vessels / physiology
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Blotting, Western
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Carbamates / pharmacology
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Cattle
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Dipeptides / pharmacology
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism*
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Epidermal Growth Factor / pharmacology
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Fibroblast Growth Factor 2 / pharmacology
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Gene Expression / drug effects
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Humans
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Immunohistochemistry
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism*
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Platelet Endothelial Cell Adhesion Molecule-1 / analysis
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-fos / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Substrate Specificity
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Vascular Endothelial Growth Factor A / pharmacology
Substances
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Carbamates
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Dipeptides
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L 685458
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N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
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Platelet Endothelial Cell Adhesion Molecule-1
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Proto-Oncogene Proteins c-fos
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Vascular Endothelial Growth Factor A
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Fibroblast Growth Factor 2
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Epidermal Growth Factor
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Amyloid Precursor Protein Secretases