title: Inhibition of cyclooxygenase-1 and -2 activity in keratinocytes inhibits PGE2formation and impairs vascular endothelial growth factor release and neovascularisation in skin wounds.
abstract: Inhibition of cyclooxygenase (Cox) enzymatic activity by non-steroidal anti-inflammatory drugs (NSAIDs) provides the molecular basis of analgesia following wounding or surgery. This study investigated the role of Cox activity in the regulation of vascular endothelial growth factor (VEGF) expression in keratinocytes and the formation of new blood vessels in acute wounds in mice. To this end, human HaCaT keratinocytes were stimulated with epidermal growth factor (EGF). EGF increased Cox-1 mRNA in the presence of the constitutively expressed Cox-1 protein in keratinocytes. EGF coinduced Cox-2 and VEGF165mRNA and protein expression and an accumulation of prostaglandin E2(PGE2) in cell culture supernatants. Inhibition of Cox isozyme activity by Cox-1 and -2 siRNA or ibuprofen reduced PGE2and VEGF165release from keratinocytes. In a mouse model of excisional wound healing, Cox-2 and VEGF165expression were colocalized in the granulation tissue of acute wounds. Oral treatment of mice with the Cox-1 and -2 inhibitor diclofenac was associated with reduced levels of VEGF165protein and an impaired blood vessel formation in acute wound tissue. In summary, our data suggest that a reduction of PGE2-triggered VEGF165protein expression in wound keratinocytes is likely to contribute to the observed impairment of wound neovascularisation upon Cox inhibition.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Itamar
authors.initials: I
authors.lastname: Goren
authors.affiliation: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Seo-Youn
authors.initials: SY
authors.lastname: Lee
authors.affiliation: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Damian
authors.initials: D
authors.lastname: Maucher
authors.affiliation: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Nüsing
authors.affiliation: Herzog-Johann-Gymnasium, Fachbereich Biologie, Simmern, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schlich
authors.affiliation: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.affiliation: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
mesh_terms: D020533:Angiogenesis Inhibitors / Q000502:physiology*; D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D012883:Skin Ulcer / Q000503:physiopathology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: Acute wound; Angiogenesis; Gene expression; Keratinocytes; Non-steroidal anti-inflammatory drugs; Wound healing