Abstract
Intracellular signaling mechanisms by the angiogenesis inhibitors endostatin and angiostatin remain poorly understood. We have found that endostatin (2 microg/ml) and angiostatin (5 microg/ml) elicited transient, approximately threefold increases in intracellular Ca(2+) concentration ([Ca(2+)](i)). Acute exposure to angiostatin or endostatin nearly abolished subsequent endothelial [Ca(2+)](i) responses to carbachol or to thapsigargin; conversely, thapsigargin attenuated the Ca(2+) signal elicited by endostatin. The phospholipase C inhibitor U-73122 and the inositol trisphosphate (IP(3)) receptor inhibitor xestospongin C both inhibited endostatin-induced elevation in [Ca(2+)](i), and endostatin rapidly elevated endothelial cell IP(3) levels. Pertussis toxin and SB-220025 modestly inhibited the endostatin-induced Ca(2+) signal. Removal of extracellular Ca(2+) inhibited the endostatin-induced rise in [Ca(2+)](i), as did a subset of Ca(2+)-entry inhibitors. Peak Ca(2+) responses to endostatin and angiostatin in endothelial cells exceeded those in epithelial cells and were minimal in NIH/3T3 cells. Overnight pretreatment of endothelial cells with endostatin reduced the subsequent acute elevation in [Ca(2+)](i) in response to vascular endothelial growth factor or to fibroblast growth factor by approximately 70%. Intracellular Ca(2+) signaling may initiate or mediate some of the cellular actions of endostatin and angiostatin.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Angiostatins
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Animals
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Aorta, Thoracic
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COS Cells
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Calcium / metabolism
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Calcium Channels
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Cattle
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Cell Line
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Cells, Cultured
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Chlorocebus aethiops
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Collagen / pharmacology*
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Endostatins
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiology*
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Enzyme Inhibitors / pharmacology
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Estrenes / pharmacology
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Humans
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Imidazoles / pharmacology
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Inositol 1,4,5-Trisphosphate Receptors
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Macrocyclic Compounds
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Mice
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Oxazoles / pharmacology
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Peptide Fragments / pharmacology*
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Pertussis Toxin
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Plasminogen / pharmacology*
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Pulmonary Artery
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Pyrimidines / pharmacology
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Pyrrolidinones / pharmacology
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Recombinant Proteins / pharmacology
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Thapsigargin / pharmacology
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Transfection
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Type C Phospholipases / metabolism
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Virulence Factors, Bordetella / pharmacology
Substances
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Angiogenesis Inhibitors
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Calcium Channels
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Endostatins
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Enzyme Inhibitors
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Estrenes
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ITPR1 protein, human
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Imidazoles
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Inositol 1,4,5-Trisphosphate Receptors
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Macrocyclic Compounds
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Oxazoles
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Peptide Fragments
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Pyrimidines
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Pyrrolidinones
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Receptors, Cytoplasmic and Nuclear
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Recombinant Proteins
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SB 220025
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Virulence Factors, Bordetella
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xestospongin A
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1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
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Thapsigargin
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Angiostatins
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Plasminogen
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Collagen
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Pertussis Toxin
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Type C Phospholipases
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Calcium