title: Signaling of Prostaglandin E Receptors, EP3 and EP4 Facilitates Wound Healing and Lymphangiogenesis with Enhanced Recruitment of M2 Macrophages in Mice.
abstract: Lymphangiogenesis plays an important role in homeostasis, metabolism, and immunity, and also occurs during wound-healing. Here, we examined the roles of prostaglandin E2 (PGE2) receptor (EP) signaling in enhancement of lymphangiogenesis in wound healing processes. The hole-punch was made in the ears of male C57BL/6 mice using a metal ear punch. Healing process and lymphangiogenesis together with macrophage recruitment were analyzed in EP knockout mice. Lymphangiogenesis was up-regulated in the granulation tissues at the margins of punched-hole wounds in mouse ears, and this increase was accompanied by increased expression levels of COX-2 and microsomal prostaglandin E synthase-1. Administration of celecoxib, a COX-2 inhibitor, suppressed lymphangiogenesis in the granulation tissues and reduced the induction of the pro-lymphangiogenic factors, vascular endothelial growth factor (VEGF) -C and VEGF-D. Topical applications of selective EP receptor agonists enhanced the expressions of lymphatic vessel endothelial hyaluronan receptor-1 and VEGF receptor-3. The wound-healing processes and recruitment of CD11b-positive macrophages, which produced VEGF-C and VEGF-D, were suppressed under COX-2 inhibition. Mice lacking either EP3 or EP4 exhibited reduced wound-healing, lymphangiogenesis and recruitment of M2 macrophages, compared with wild type mice. Proliferation of cultured human lymphatic endothelial cells was not detected under PGE2 stimulation. Lymphangiogenesis and recruitment of M2 macrophages that produced VEGF-C/D were suppressed in mice treated with a COX-2 inhibitor or lacking either EP3 or EP4 during wound healing. COX-2 and EP3/EP4 signaling may be novel targets to control lymphangiogenesis in vivo.
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.|Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.|Department of Physiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Hosono
authors.affiliation: Department of Physiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Isonaka
authors.affiliation: Department of Physiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kawakami
authors.affiliation: Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.|Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004423:Ear / Q000502:physiology; D055786:Gene Knockout Techniques; D042583:Lymphangiogenesis / Q000187:drug effects; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071876:Prostaglandin-E Synthases / 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; D015854:Up-Regulation / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis; D014945:Wound Healing / Q000187:drug effects
chemical_list: D039481:CD11b Antigen; D052246:Cyclooxygenase 2 Inhibitors; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D051546:Cyclooxygenase 2; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse