title: Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release.
abstract: Bleeding and delayed healing of ulcers are well recognized clinical problems associated with the use of aspirin and other nonsteroidal antiinflammatory drugs, which have been attributed to their antiaggregatory effects on platelets. We hypothesized that antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors, such as vascular endothelial growth factor (VEGF), from platelets. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily oral treatment with vehicle, aspirin, or ticlopidine (an ADP receptor antagonist) was started 3 days later and continued for 1 week. Ulcer induction resulted in a significant increase in serum levels of VEGF and a significant decrease in serum levels of endostatin (an antiangiogenic factor). Although both aspirin and ticlopidine markedly suppressed platelet aggregation, only ticlopidine impaired gastric ulcer healing and angiogenesis as well as reversing the ulcer-associated changes in serum levels of VEGF and endostatin. The effects of ticlopidine on ulcer healing and angiogenesis were mimicked by immunodepletion of circulating platelets, and ticlopidine did not influence ulcer healing when given to thrombocytopenic rats. Incubation of human umbilical vein endothelial cells with serum from ticlopidine-treated rats significantly reduced proliferation and increased apoptosis, effects reversed by an antibody directed against endostatin. Ticlopidine treatment resulted in increased platelet endostatin content and release. These results demonstrate a previously unrecognized contribution of platelets to the regulation of gastric ulcer healing. Such effects likely are mediated through the release from platelets of endostatin and possibly VEGF. As shown with ticlopidine, drugs that influence gastric ulcer healing may do so in part through altering the ability of platelets to release growth factors.
authors.affiliation: Mucosal Inflammation Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.forename: S N
authors.initials: SN
authors.lastname: Elliott
authors.forename: G
authors.initials: G
authors.lastname: Cirino
authors.forename: A
authors.initials: A
authors.lastname: Buret
authors.forename: L J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: J L
authors.initials: JL
authors.lastname: Wallace
mesh_terms: D020533:Angiogenesis Inhibitors / Q000097:blood / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D017209:Apoptosis; D001241:Aspirin / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000097:blood / Q000502:physiology*; D004195:Disease Models, Animal; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000097:blood / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D008222:Lymphokines / Q000097:blood / Q000502:physiology*; D008297:Male; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000097:blood / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D013988:Ticlopidine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D043169:Endostatins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003094:Collagen; D013988:Ticlopidine; D001241:Aspirin