Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A2.
Angiogenin stimulates capillary and umbilical vein endothelial cell prostacyclin secretion but not that of prostaglandins of the E series. The response was quantitated by radioimmunoassay and by [3H]arachidonate labeling followed by analysis of the secreted prostaglandins. The stimulated secretion lasts for several minutes and is optimal at 2-4 min. The dose-response (peak at 1-10 ng/ml) is similar to that previously observed for activation of endothelial cell phospholipase C. Stimulated secretion was blocked by pretreatment with the inhibitors of prostacyclin synthesis, indomethacin and tranylcypromine, and also the specific inhibitor of phospholipase A2, quinacrine, as well as pertussis toxin and the diglyceryl and monoglyceryl lipase inhibitor RHC 80267. Stimulated secretion was also abolished in cells that were either pretreated for 48 hr with phorbol ester to down-regulate protein kinase C or incubated with the protein kinase inhibitor H7. Hydrolysis of phosphatidylinositol by phospholipase A2 appears to be the source of angiogenin-mobilized arachidonate; angiogenin-induced hydrolysis of phosphatidylcholine was not detected. Activation of phospholipase A2 occurs in the absence of an angiogenin-induced calcium flux. The results are discussed in terms of mechanisms of agonist-induced intracellular arachidonate mobilization and relevance to angiogenesis.
Bicknell
R
R
Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, MA 02115.
Vallee
B L
BL
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D011464:Epoprostenol / Q000378:metabolism*; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000494:pharmacology*; D037342:Pertussis Toxin; D010740:Phospholipases / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011493:Protein Kinase C / Q000378:metabolism; D011796:Quinacrine / Q000494:pharmacology; D012259:Ribonuclease, Pancreatic; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D043925:Angiogenesis Inducing Agents; D001095:Arachidonic Acids; D003512:Cyclohexanones; D006133:Growth Substances; D009363:Neoplasm Proteins; D010566:Virulence Factors, Bordetella; D003907:Dexamethasone; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D011464:Epoprostenol; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010740:Phospholipases; D010741:Phospholipases A; D008071:Lipoprotein Lipase; D054467:Phospholipases A2; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D011796:Quinacrine