title: Thromboxane A synthase enhances blood flow recovery from hindlimb ischemia.
abstract: Thromboxane A synthase (TXAS) is the enzyme that converts the arachidonic acid derivative prostaglandin H2 to thromboxane A2 (TXA2). TXA2 induces platelet aggregation, vasoconstriction, and proliferation. TXAS and TXA2 receptors or thromboxane prostanoid (TP) receptors are elevated in numerous cardiovascular and inflammatory diseases. Platelets contain numerous angiogenesis stimulating factors. However, the involvement of TXAS on recovery from an ischemic condition is not well understood. We hypothesized that the TXAS-TXA2-TP receptor axis would induce blood flow recovery by platelet activation.
  
  
  
  The model of hindlimb ischemia was made by the right femoral artery ligation. The blood flow was estimated by laser Doppler images. Angiogenesis was estimated by the plasma level of the vascular endothelial growth factor and the stromal cell-derived factor-1 and by immunofluorescence analysis against CD31 and P-selectin glycoprotein ligand-1 (PSGL-1).
  
  
  
  In wild-type mice, blood flow recovery was enhanced by treatment with murine TXAS-overexpressing fibroblasts (C57-mTXAS) compared with empty vector- (EV) treated fibroblasts (C57-EV). Compared with C57-EV-treated mice, activated platelets (P-selectin(+) platelets) and plasma levels of vascular endothelial growth factor and stromal cell-derived factor-1 were increased in C57-mTXAS-treated mice. The enhanced-blood flow recovery by C57-mTXAS treatment was suppressed in the TP knockout mice (TP(-/-)). The expression of PSGL-1 in endothelial cells around the ischemic area was enhanced by C57-mTXAS treatment in wild-type but not in TP(-/-).
  
  
  
  These results indicated that local administration of C57-mTXAS-induced angiogenesis by activated platelets that bind to PSGL-1 on ischemic endothelial cells.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Amano
authors.affiliation: Department of Microbiology, Kitasato University School of Allied Health Sciences, Kanagawa, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Microbiology, Kitasato University School of Allied Health Sciences, Kanagawa, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakutani
authors.affiliation: Department of Immunology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Eshima
authors.affiliation: Department of Microbiology, Kitasato University School of Allied Health Sciences, Kanagawa, Japan.
authors.forename: Hidero
authors.initials: H
authors.lastname: Kitasato
authors.affiliation: Inovation Center for Immunoregulation Technologies and Drugs (AK project), Kyoto University Graduate School of Medicine, Kyoto City, Kyoto, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan. Electronic address: mmajima@med.kitasato-u.ac.jp.
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002317:Cardiovascular Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D005263:Femoral Artery / Q000601:surgery; D005347:Fibroblasts / Q000201:enzymology / Q000637:transplantation; D006614:Hindlimb / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000378:metabolism; D007511:Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects* / Q000502:physiology; D013928:Thromboxane A2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002317:Cardiovascular Agents; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D042461:Vascular Endothelial Growth Factor A; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase
keywords: Angiogenesis; P-selectin ligand protein-1; Platelet activation; Thromboxane A synthase; Thromboxane A2