title: Epoxyeicosanoids promote organ and tissue regeneration.
abstract: Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.
authors.affiliation: Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. dpanigra@bidmc.harvard.edu
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.forename: Brian T
authors.initials: BT
authors.lastname: Kalish
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
authors.forename: Diane R
authors.initials: DR
authors.lastname: Bielenberg
authors.forename: Hau D
authors.initials: HD
authors.lastname: Le
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
authors.forename: Ofra
authors.initials: O
authors.lastname: Benny
authors.forename: Dayna K
authors.initials: DK
authors.lastname: Mudge
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Butterfield
authors.forename: Akiko
authors.initials: A
authors.lastname: Mammoto
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mammoto
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.forename: Roger L
authors.initials: RL
authors.lastname: Jenkins
authors.forename: Mary A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Akino
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Tomer
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Manthati
authors.forename: Arja
authors.initials: A
authors.lastname: Kaipainen
authors.forename: Patricia A
authors.initials: PA
authors.lastname: D'Amore
authors.forename: Mark
authors.initials: M
authors.lastname: Puder
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D015777:Eicosanoids / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology*; D005123:Eye / Q000098:blood supply; D007150:Immunohistochemistry; D007668:Kidney / Q000502:physiology; D008099:Liver / Q000502:physiology; D008168:Lung / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000235:genetics; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D053719:Tandem Mass Spectrometry
chemical_list: D015777:Eicosanoids; D004852:Epoxy Compounds; D042787:Receptor, TIE-2; D004851:Epoxide Hydrolases
keywords: VEGF; angiocrine; autacoid; organ regeneration; small molecule mediator
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