Skip to main content

Advertisement

Log in

Hypoxia-inducible factor and vascular endothelial growth factor in the neuroretina and retinal blood vessels after retinal ischemia

  • Published:
Journal of Ocular Biology, Diseases, and Informatics

Abstract

Retinal ischemia arises from circulatory failure. As the retinal blood vessels are key organs in circulatory failure, our aim was to study the retinal vasculature separately from the neuroretina to elucidate the role of hypoxia-inducible factor (HIF) 1α and 1β and vascular endothelial growth factor (VEGF) in retinal ischemia. Retinal ischemia was induced in porcine eyes by applying an intraocular pressure, followed by 12 h of reperfusion. HIF-1α mRNA expression was not affected by ischemia, while immunofluorescence staining was higher after ischemia in the neuroretina. HIF-1β immunoreactivity and mRNA expression were unaffected. VEGF protein levels in the vitreous humor and VEGF staining in the neuroretina were more pronounced in eyes subjected to ischemia than in the sham eyes. VEGF may be activated downstream of HIF-1 and is known to stimulate retinal neovascularization, which causes sight-threatening complications. These results emphasize the need for pharmacological treatment to block the HIF and VEGF signaling pathways in retinal ischemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Osborne NN, Casson RJ, Wood JP, Chidlow G, Graham M, Melena J. Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res. 2004;23(1):91–147.

    Article  CAS  PubMed  Google Scholar 

  2. Curtis TM, Scholfield CN. The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy. Diabetes Metab Res Rev. 2004;20(1):28–43.

    Article  CAS  PubMed  Google Scholar 

  3. Dorrell M, Uusitalo-Jarvinen H, Aguilar E, Friedlander M. Ocular neovascularization: basic mechanisms and therapeutic advances. Surv Ophthalmol. 2007;52 Suppl 1:S3–19.

    Article  PubMed  Google Scholar 

  4. Comer GM, Ciulla TA. Pharmacotherapy for diabetic retinopathy. Curr Opin Ophthalmol. 2004;15(6):508–18.

    Article  PubMed  Google Scholar 

  5. Hessellund A, Jeppesen P, Aalkjaer C, Bek T. Characterization of vasomotion in porcine retinal arterioles. Acta Ophthalmol Scand. 2003;81(3):278–82.

    Article  PubMed  Google Scholar 

  6. Holmgaard K, Aalkjaer C, Lambert JD, Bek T. N-methyl-d-aspartic acid causes relaxation of porcine retinal arterioles through an adenosine receptor dependent mechanism. Invest Ophthalmol Vis Sci. 2008;49(10):4590–4.

    Article  PubMed  Google Scholar 

  7. Nagaoka T, Hein TW, Yoshida A, Kuo L. Resveratrol, a component of red wine, elicits dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels. Invest Ophthalmol Vis Sci. 2007;48(9):4232–9.

    Article  PubMed  Google Scholar 

  8. Chavez A, Miranda LF, Pichiule P, Chavez JC. Mitochondria and hypoxia-induced gene expression mediated by hypoxia-inducible factors. Ann N Y Acad Sci. 2008;1147:312–20.

    Article  CAS  PubMed  Google Scholar 

  9. Ozaki H, Yu AY, Della N, Ozaki K, Luna JD, Yamada H, et al. Hypoxia inducible factor-1alpha is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci. 1999;40(1):182–9.

    CAS  PubMed  Google Scholar 

  10. Zhu Y, Zhang Y, Ojwang BA, Brantley Jr MA, Gidday JM. Long-term tolerance to retinal ischemia by repetitive hypoxic preconditioning: role of HIF-1alpha and heme oxygenase-1. Invest Ophthalmol Vis Sci. 2007;48(4):1735–43.

    Article  PubMed  Google Scholar 

  11. Weinberg RA. Biology of cancer. London: Taylor & Francis; 2006.

    Google Scholar 

  12. Arjamaa O, Nikinmaa M. Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. Exp Eye Res. 2006;83(3):473–83.

    Article  CAS  PubMed  Google Scholar 

  13. Thiersch M, Raffelsberger W, Frigg R, Samardzija M, Wenzel A, Poch O, et al. Analysis of the retinal gene expression profile after hypoxic preconditioning identifies candidate genes for neuroprotection. BMC Genomics. 2008;9:73.

    Article  PubMed  Google Scholar 

  14. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480–7.

    Article  CAS  PubMed  Google Scholar 

  15. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci U S A. 1995;92(3):905–9.

    Article  CAS  PubMed  Google Scholar 

  16. Buckley CH, Hadoke PW, O'Brien CJ. Use of isolated ocular arteries in vitro to define the pathology of vascular changes in glaucoma. Br J Ophthalmol. 1997;81(7):599–607.

    Article  CAS  PubMed  Google Scholar 

  17. Rootman J. Vascular system of the optic nerve head and retina in the pig. Br J Ophthalmol. 1971;55(12):808–19.

    Article  CAS  PubMed  Google Scholar 

  18. Rozen S, Skaletsky HJ. Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S, editor. Bioinformatics methods and protocols: methods in molecular biology. Totowa: Humana; 2000. p. 365–86.

    Google Scholar 

  19. Bustin SA. Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. J Mol Endocrinol. 2000;25(2):169–93.

    Article  CAS  PubMed  Google Scholar 

  20. Abràmoff MD, Magelhaes PJ, Ram SJ. Image Processing with ImageJ. Biophotonics Int. 2004;11(7):36–42.

    Google Scholar 

  21. Bignami A, Dahl D. The radial glia of Muller in the rat retina and their response to injury. An immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein. Exp Eye Res. 1979;28(1):63–9.

    Article  CAS  PubMed  Google Scholar 

  22. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, et al. Muller cells in the healthy and diseased retina. Prog Retin Eye Res. 2006;25(4):397–424.

    Article  CAS  PubMed  Google Scholar 

  23. Iandiev I, Uckermann O, Pannicke T, Wurm A, Tenckhoff S, Pietsch UC, et al. Glial cell reactivity in a porcine model of retinal detachment. Invest Ophthalmol Vis Sci. 2006;47(5):2161–71.

    Article  PubMed  Google Scholar 

  24. Kim HA, Mahato RI, Lee M. Hypoxia-specific gene expression for ischemic disease gene therapy. Adv Drug Deliv Rev. 2009;61:614–22.

    Article  CAS  PubMed  Google Scholar 

  25. Yi JH, Park SW, Kapadia R, Vemuganti R. Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage. Neurochem Int. 2007;50(7–8):1014–27.

    Article  CAS  PubMed  Google Scholar 

  26. Ziello JE, Jovin IS, Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007;80(2):51–60.

    CAS  PubMed  Google Scholar 

  27. Forooghian F, Razavi R, Timms L. Hypoxia-inducible factor expression in human RPE cells. Br J Ophthalmol. 2007;91(10):1406–10.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the Swedish Medical Research Council, Lund University Faculty of Medicine, the Swedish Government Grant for Clinical Research, the Lund University Hospital Research Grants, the Swedish Medical Association, the Royal Physiographic Society in Lund, the Åke Wiberg Foundation, the Anders Otto Swärd Foundation/Ulrika Eklund Foundation, the Magn Bergvall Foundation, the Crafoord Foundation, the Anna-Lisa and Sven-Erik Nilsson Foundation, Jeansson’s Foundation, Kronprinsessan Margaretas Arbetsnämnd för synskadade, Synskadade i Malmöhus län, Anna and Edvin Berger’s Foundation, the Märta Lundqvist Foundation, and the Lars Hierta Memorial Foundation.

Competing interests statement

The authors declare that they have no competing financial interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Malin Malmsjö.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Håkansson, G., Gesslein, B., Gustafsson, L. et al. Hypoxia-inducible factor and vascular endothelial growth factor in the neuroretina and retinal blood vessels after retinal ischemia. j ocul biol dis inform 3, 20–29 (2010). https://doi.org/10.1007/s12177-010-9050-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12177-010-9050-6

Keywords

Navigation