Abstract
Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone-related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone-related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone-related peptide. These studies show that parathyroid hormone-related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiogenesis Inhibitors / metabolism*
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Carcinogenicity Tests
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Cell Movement
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Chick Embryo
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Endothelium, Vascular
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Enzyme Inhibitors / pharmacology
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Fibroblast Growth Factor 2 / pharmacology
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Gene Transfer Techniques
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Isoquinolines / pharmacology
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Mice
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Physiologic / drug effects
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Parathyroid Hormone-Related Protein
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Peptide Mapping
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Proteins / genetics
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Proteins / metabolism*
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Proteins / pharmacology*
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Sulfonamides*
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rac GTP-Binding Proteins / metabolism
Substances
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Angiogenesis Inhibitors
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Enzyme Inhibitors
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Isoquinolines
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Parathyroid Hormone-Related Protein
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Proteins
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Sulfonamides
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Fibroblast Growth Factor 2
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Cyclic AMP-Dependent Protein Kinases
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rac GTP-Binding Proteins
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N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide