title: Roles of prostaglandin E2-EP3/EP4 receptor signaling in the enhancement of lymphangiogenesis during fibroblast growth factor-2-induced granulation formation.
abstract: OBJECTIVE
  One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation.
  
  
  RESULTS
  Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE2 enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate-dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE2. An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts.
  
  
  CONCLUSIONS
  Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, 228-8555, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Hosono
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tamaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakagami
authors.forename: Izumi
authors.initials: I
authors.lastname: Hayashi
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D000068579:Celecoxib; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006097:Granulation Tissue / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007279:Injections, Subcutaneous; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D042583:Lymphangiogenesis / Q000187:drug effects*; D042601:Lymphatic Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles / Q000494:pharmacology; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D000098853:Podoplanin
chemical_list: D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D016222:Fibroblast Growth Factor 2; D006023:Glycoproteins; D019746:Intramolecular Oxidoreductases; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C545636:Ptger1 protein, mouse; C545645:Ptger2 protein, mouse; C545648:Ptger3 protein, mouse; C545651:Ptger4 protein, mouse; C492273:LYVE1 protein, mouse; C467483:vascular endothelial growth factor C, mouse; C077623:Ptgs2 protein, mouse