title: Intracellular Ca(2+) signaling in endothelial cells by the angiogenesis inhibitors endostatin and angiostatin.
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.
authors: Molecular Medicine and Renal Units and The Cancer Center, Beth Israel Deaconess Medical Center and Departments of Medicine and Cell Biology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: L
authors: L
authors: Jiang
authors: V
authors: V
authors: Jha
authors: M
authors: M
authors: Dhanabal
authors: V P
authors: VP
authors: Sukhatme
authors: S L
authors: SL
authors: Alper
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins; D000818:Animals; D001013:Aorta, Thoracic; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003094:Collagen / Q000494:pharmacology*; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D037342:Pertussis Toxin; D010958:Plasminogen / Q000494:pharmacology*; D011651:Pulmonary Artery; D011743:Pyrimidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D015220:Calcium Channels; D043169:Endostatins; D004791:Enzyme Inhibitors; D004963:Estrenes; C506926:ITPR1 protein, human; D007093:Imidazoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D010446:Peptide Fragments; D011743:Pyrimidines; D011760:Pyrrolidinones; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; C110631:SB 220025; D010566:Virulence Factors, Bordetella; C108644:xestospongin A; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D019284:Thapsigargin; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D002118:Calcium