title: Cytochrome P450-derived epoxyeicosatrienoic acids accelerate wound epithelialization and neovascularization in the hairless mouse ear wound model.
abstract: OBJECTIVE
  Epoxyeicosatrienoic acids (EETs) are known to modulate proliferation and angiogenesis in vitro. Tissue levels of EETs are regulated by the cytochrome P450 (CYP) epoxygenases that generate them as well as by the soluble epoxide hydrolase metabolizes them to their less active diols. The aim of this study was to determine the effect of locally administered EETs (11,12- and 14,15-EETs) and the selective sEH inhibitor (sEHI) trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB) on wound healing in vivo.
  
  
  METHODS
  Standardized full thickness dermal wounds were created on the dorsum of hairless mouse ears. Wound epithelialization was directly viewed and measured using intravitalmicroscopy and computerized planimetry every second day until healing was complete. Wound sections were analyzed by immunostaining for endothelial lineage marker CD31, vascular endothelial growth factor (VEGF), and angiogenic cytokine stromal cell-derived factor (SDF) 1α on days 2, 4, and 13.
  
  
  RESULTS
  Treatment with EETs and t-AUCB, respectively, significantly accelerated wound epithelialization and neovascularization by synergistic upregulation of SDF1α and VEGF in vivo.
  
  
  CONCLUSIONS
  These findings demonstrated that exogenous CYP-derived EETs and globally decreased EET hydrolysis by sEH inhibition significantly accelerated wound epithelialization and neovascularization in unimpaired healing wounds. Given that hypoxia induces CYP expression and subsequently EET-dependent angiogenesis, EETs and sEHIs provide a promising new class of therapeutics for ischemic non-healing wounds.
authors: Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany. AnnaLena.Sander@kgu.de
authors: Anna Lena
authors: AL
authors: Sander
authors: Heike
authors: H
authors: Jakob
authors: Katharina
authors: K
authors: Sommer
authors: Christian
authors: C
authors: Sadler
authors: Ingrid
authors: I
authors: Fleming
authors: Ingo
authors: I
authors: Marzi
authors: Johannes
authors: J
authors: Frank
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D004195:Disease Models, Animal; D004431:Ear, External / Q000293:injuries* / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology; D014947:Wounds and Injuries / Q000188:drug therapy* / Q000473:pathology
chemical_list: D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2