April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Prostaglandin E2 (PGE2) Regulates the 15-Lipoxygenase (15-LOX) Circuit During Corneal Inflammatory Neovascularization
Author Affiliations & Notes
  • Karsten Gronert
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, California
  • Katy L. Ong
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, California
  • Sabrina Mukhtar
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, California
  • Van T. Nguyen
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, California
  • Kyle J. Seamon
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, California
  • Alexander J. Leedom
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, California
  • Elvira L. Liclican
    Vision Science, School of Optometry, University of California, Berkeley, Berkeley, California
  • Footnotes
    Commercial Relationships  Karsten Gronert, None; Katy L. Ong, None; Sabrina Mukhtar, None; Van T. Nguyen, None; Kyle J. Seamon, None; Alexander J. Leedom, None; Elvira L. Liclican, None
  • Footnotes
    Support  NIH Grant EY016136, NIH Grant P30EY003176
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 1131. doi:
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      Karsten Gronert, Katy L. Ong, Sabrina Mukhtar, Van T. Nguyen, Kyle J. Seamon, Alexander J. Leedom, Elvira L. Liclican; Prostaglandin E2 (PGE2) Regulates the 15-Lipoxygenase (15-LOX) Circuit During Corneal Inflammatory Neovascularization. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1131.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Two endogenous lipid pathways that are prominent in the cornea, namely, cyclooxygenase (COX) and 15-LOX, both play critical but opposing roles in regulating chronic inflammation-induced neovascularization. While COX-derived PGE2 exacerbates pathological heme-angiogenesis, 15-LOX-derived lipoxin A4 (LXA4) attenuates it. Importantly, if and through which receptor (EP2 or EP4) PGE2 can regulate the resident protective 15-LOX circuit during chronic nonresolving corneal inflammation is unknown, and was the aim of this study.

Methods: : Chronic nonresolving inflammation was induced in C57Bl/6J mice by the corneal suture model. Inflammatory heme- and lymph-angiogenesis were quantified by immunofluorescence using CD31 and LYVE-1 as specific markers of vascular and lymphatic endothelial cells, respectively. Lipid autacoid formation was analyzed by LC/MS/MS-based lipidomics, and expression of key markers of corneal inflammation and angiogenesis (15-LOX, 5-LOX, VEGF-D, FLT-4) was assessed by RT-PCR. Mice were treated with vehicle, a selective EP2 or EP4 agonist, or PGE2 (100 ng topically, tid) for up to 7 days.

Results: : Inflammatory heme- and lymph-angiogenesis were amplified by topical treatment with either a selective EP2 agonist (24 ± 9 and 44 ± 12% increase, respectively) or EP4 agonist (21 ± 8 and 52 ± 11% increase, respectively). PGE2 exacerbation of lymph-angiogenesis (45 ± 10% increase) was associated with an upregulation of VEGF-D and a decrease in FLT-4 expression. Interestingly, PGE2 treatment for 2 days following suture placement attenuated the increased expression of 15- and 5-LOX, key enzymes in the biosynthetic pathway for the anti-inflammatory and anti-angiogenic LXA4, which correlated with a temporally defined reduction in endogenous levels of 12- and 15-HETE.

Conclusions: : These results demonstrate that PGE2 exacerbates corneal inflammatory neovascularization via both EP2 and EP4 receptors. More importantly, they suggest that PGE2 amplification of pathological angiogenesis involves downregulation of an endogenous, protective anti-inflammatory and anti-angiogenic lipid circuit.

Keywords: inflammation • neovascularization • cornea: epithelium 
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