Epoxyeicosanoids promote organ and tissue regeneration. Proc Natl Acad Sci U S A 2013 Aug 13;110(33):13528-33
Date
07/31/2013Pubmed ID
23898174Pubmed Central ID
PMC3746918DOI
10.1073/pnas.1311565110Scopus ID
2-s2.0-84882380783 (requires institutional sign-in at Scopus site) 139 CitationsAbstract
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.
Author List
Panigrahy D, Kalish BT, Huang S, Bielenberg DR, Le HD, Yang J, Edin ML, Lee CR, Benny O, Mudge DK, Butterfield CE, Mammoto A, Mammoto T, Inceoglu B, Jenkins RL, Simpson MA, Akino T, Lih FB, Tomer KB, Ingber DE, Hammock BD, Falck JR, Manthati VL, Kaipainen A, D'Amore PA, Puder M, Zeldin DC, Kieran MWAuthors
Akiko Mammoto PhD, MD Professor in the Pediatrics department at Medical College of WisconsinTadanori Mammoto PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsChromatography, Liquid
Eicosanoids
Endothelial Cells
Epoxide Hydrolases
Epoxy Compounds
Eye
Immunohistochemistry
Kidney
Liver
Lung
Mice
Mice, Transgenic
Neovascularization, Physiologic
Receptor, TIE-2
Regeneration
Tandem Mass Spectrometry
