title: The cyclooxygenase-2 selective inhibitor, etodolac, but not aspirin reduces neovascularization in a murine ischemic hind limb model.
abstract: Cyclooxygenase inhibitors are often prescribed to relieve severe ischemic leg pain in critical ischemic limb patients. Prescription of high doses of aspirin and selective cyclooxygenase-2 inhibitors is reported to increase cardiovascular events through suppression of the vasodilative prostanoid prostaglandin I(2) in endothelium. Here, we evaluated the influence of aspirin and etodolac, a selective cyclooxygenase-2 inhibitor, on neovascularization using a murine ischemia hind limb model. C57BL/6J mice were treated with aspirin or etodolac for twenty-eight days after induction of ischemia. We exploited a concentration of the agents that suppressed cyclooxygenase activity efficiently, especially in prostaglandin I(2) production. Recovery of limb blood perfusion and capillary density in ischemic limbs was significantly suppressed by etodolac treatment when compared to the aspirin treated group and untreated group. Production of 6-keto prostaglandin F(1alpha) and prostaglandin E(2) was lower in the aspirin treated group when compared with the etodolac-treated group. Also, these concentrations were lower in both treatment groups compared with the untreated group. Immunohistochemical analysis suggested cyclooxygenase-2 was expressed in endothelium but not in inflammatory cells in ischemic tissue from the acute to chronic phase. Cyclooxygenase-1 was expressed strongly in inflammatory cells in the acute phase. Furthermore, bone marrow-derived mononuclear cell transplantation improved neovascularization, whereas aspirin and etodolac did not inhibit these effects. Production of arachidonic acid metabolites by transplanted cells was independent of the improvement of neovascularization. In conclusion, cyclooxygenase-2 inhibition reduces ischemia-induced neovascularization.
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, 36-1 Nishi-machi, Yonago 683-8504, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tsujimoto
authors.forename: Naonori
authors.initials: N
authors.lastname: Uozumi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kita
authors.forename: Akio
authors.initials: A
authors.lastname: Yoshida
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology; D017690:Cell Transplantation; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000096:biosynthesis / Q000097:blood; D017308:Etodolac / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D007511:Ischemia / Q000097:blood / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology*; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D015777:Eicosanoids; D017308:Etodolac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D054513:Group IV Phospholipases A2; D001241:Aspirin