Epoxyeicosanoids promote organ and tissue regeneration

Dipak Panigrahy, Brian T. Kalish, Sui Huang, Diane R. Bielenberg, Hau D. Le, Jun Yang, Matthew L. Edin, Craig R. Lee, Ofra Benny, Dayna K. Mudge, Catherine E. Butterfield, Akiko Mammoto, Tadanori Mammoto, Bora Inceoglu, Roger L. Jenkins, Mary A. Simpson, Tomoshige Akino, Fred B. Lih, Kenneth B. Tomer, Donald E. Ingber & 8 others Bruce D. Hammock, J R Falck, Vijaya L. Manthati, Arja Kaipainen, Patricia A. D'Amore, Mark Puder, Darryl C. Zeldin, Mark W. Kieran

Research output: Contribution to journalArticle

79 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13528-13533
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number33
DOIs
StatePublished - Aug 13 2013

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Regeneration
Growth
Liver Regeneration
Endothelium
Corneal Neovascularization
Pharmacology
Epoxide Hydrolases
Lung
Angiogenesis Inducing Agents
Wound Healing
Cytochrome P-450 Enzyme System
Blood Vessels
Intercellular Signaling Peptides and Proteins
Homeostasis
Endothelial Cells
Inflammation
Kidney
Lipids
Acids

Keywords

  • Angiocrine
  • Autacoid
  • Organ regeneration
  • Small molecule mediator
  • VEGF

ASJC Scopus subject areas

  • General

Cite this

Panigrahy, D., Kalish, B. T., Huang, S., Bielenberg, D. R., Le, H. D., Yang, J., ... Kieran, M. W. (2013). Epoxyeicosanoids promote organ and tissue regeneration. Proceedings of the National Academy of Sciences of the United States of America, 110(33), 13528-13533. https://doi.org/10.1073/pnas.1311565110

Epoxyeicosanoids promote organ and tissue regeneration. / Panigrahy, Dipak; Kalish, Brian T.; Huang, Sui; Bielenberg, Diane R.; Le, Hau D.; Yang, Jun; Edin, Matthew L.; Lee, Craig R.; Benny, Ofra; Mudge, Dayna K.; Butterfield, Catherine E.; Mammoto, Akiko; Mammoto, Tadanori; Inceoglu, Bora; Jenkins, Roger L.; Simpson, Mary A.; Akino, Tomoshige; Lih, Fred B.; Tomer, Kenneth B.; Ingber, Donald E.; Hammock, Bruce D.; Falck, J R; Manthati, Vijaya L.; Kaipainen, Arja; D'Amore, Patricia A.; Puder, Mark; Zeldin, Darryl C.; Kieran, Mark W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 33, 13.08.2013, p. 13528-13533.

Research output: Contribution to journalArticle

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, MW 2013, 'Epoxyeicosanoids promote organ and tissue regeneration', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 33, pp. 13528-13533. https://doi.org/10.1073/pnas.1311565110
Panigrahy, Dipak ; Kalish, Brian T. ; Huang, Sui ; Bielenberg, Diane R. ; Le, Hau D. ; Yang, Jun ; Edin, Matthew L. ; Lee, Craig R. ; Benny, Ofra ; Mudge, Dayna K. ; Butterfield, Catherine E. ; Mammoto, Akiko ; Mammoto, Tadanori ; Inceoglu, Bora ; Jenkins, Roger L. ; Simpson, Mary A. ; Akino, Tomoshige ; Lih, Fred B. ; Tomer, Kenneth B. ; Ingber, Donald E. ; Hammock, Bruce D. ; Falck, J R ; Manthati, Vijaya L. ; Kaipainen, Arja ; D'Amore, Patricia A. ; Puder, Mark ; Zeldin, Darryl C. ; Kieran, Mark W. / Epoxyeicosanoids promote organ and tissue regeneration. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 33. pp. 13528-13533.
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T1 - Epoxyeicosanoids promote organ and tissue regeneration

AU - Panigrahy, Dipak

AU - Kalish, Brian T.

AU - Huang, Sui

AU - Bielenberg, Diane R.

AU - Le, Hau D.

AU - Yang, Jun

AU - Edin, Matthew L.

AU - Lee, Craig R.

AU - Benny, Ofra

AU - Mudge, Dayna K.

AU - Butterfield, Catherine E.

AU - Mammoto, Akiko

AU - Mammoto, Tadanori

AU - Inceoglu, Bora

AU - Jenkins, Roger L.

AU - Simpson, Mary A.

AU - Akino, Tomoshige

AU - Lih, Fred B.

AU - Tomer, Kenneth B.

AU - Ingber, Donald E.

AU - Hammock, Bruce D.

AU - Falck, J R

AU - Manthati, Vijaya L.

AU - Kaipainen, Arja

AU - D'Amore, Patricia A.

AU - Puder, Mark

AU - Zeldin, Darryl C.

AU - Kieran, Mark W.

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N2 - 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.

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KW - Autacoid

KW - Organ regeneration

KW - Small molecule mediator

KW - VEGF

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