title: Novel mechanisms and signaling pathways of esophageal ulcer healing: the role of prostaglandin EP2 receptors, cAMP, and pCREB.
abstract: Clinical studies indicate that prostaglandins of E class (PGEs) may promote healing of tissue injury e.g., gastroduodenal and dermal ulcers. However, the precise roles of PGEs, their E-prostanoid (EP) receptors, signaling pathways including cAMP and cAMP response element-binding protein (CREB), and their relation to VEGF and angiogenesis in the tissue injury healing process remain unknown, forming the rationale for this study. Using an esophageal ulcer model in rats, we demonstrated that esophageal mucosa expresses predominantly EP2 receptors and that esophageal ulceration triggers an increase in expression of the EP2 receptor, activation of CREB (the downstream target of the cAMP signaling), and enhanced VEGF gene expression. Treatment of rats with misoprostol, a PGE1 analog capable of activating EP receptors, enhanced phosphorylation of CREB, stimulated VEGF expression and angiogenesis, and accelerated esophageal ulcer healing. In cultured human esophageal epithelial (HET-1A) cells, misoprostol increased intracellular cAMP levels (by 163-fold), induced phosphorylation of CREB, and stimulated VEGF expression. A cAMP analog (Sp-cAMP) mimicked, whereas an inhibitor of cAMP-dependent protein kinase A (Rp-cAMP) blocked, these effects of misoprostol. These results indicate that the EP2/cAMP/protein kinase A pathway mediates the stimulatory effect of PGEs on angiogenesis essential for tissue injury healing via the induction of CREB activity and VEGF expression.
authors: Medical and Research Services, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California, and the Department of Medicine/Gastroenterology, University of California, Irvine, California.
authors: Amrita
authors: A
authors: Ahluwalia
authors: Medical and Research Services, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California, and the Department of Medicine/Gastroenterology, University of California, Irvine, California.
authors: Dolgor
authors: D
authors: Baatar
authors: Medical and Research Services, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California, and the Department of Medicine/Gastroenterology, University of California, Irvine, California.
authors: Michael K
authors: MK
authors: Jones
authors: Medical and Research Services, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California, and the Department of Medicine/Gastroenterology, University of California, Irvine, California andrzej.tarnawski@va.gov.
authors: Andrzej S
authors: AS
authors: Tarnawski
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004935:Esophageal Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004947:Esophagus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D016595:Misoprostol / Q000494:pharmacology; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000187:drug effects / Q000378:metabolism*; D015290:Second Messenger Systems; D013997:Time Factors; D014456:Ulcer / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C545644:PTGER2 protein, human; D047428:Protein Kinase Inhibitors; C545646:Ptger2 protein, rat; D012333:RNA, Messenger; D058307:Receptors, Prostaglandin E, EP2 Subtype; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D016595:Misoprostol; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: angiogenesis; cyclic AMP; esophageal ulcers; misoprostol; prostaglandin E; wound healing