Skip to main content

Advertisement

SpringerLink
Log in

Differential expression of angioregulatory factors in normal and CNV-derived human retinal pigment epithelium

  • Laboratory Investigation
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

Choroidal neovascularization (CNV) causes loss of vision in age-related macular degeneration (AMD). In CNV, choroidal capillaries penetrate Bruch’s membrane and the retinal pigment epithelium (RPE). Angiogenic factors produced by RPE cells are suspected as major contributors to CNV development. We therefore studied the differential expression of angioregulatory factors in normal and CNV-derived RPE.

Methods

Cultures of normal (ARPE-19) and CNV-derived RPE (CNV-RPE) were compared by quantitative PCR. Differential expression was verified on the protein level by immunohistochemistry in tissue samples.

Results

The angioregulatory factors VEGF-A, VEGF-B, VEGF-C, Angiopoietin-1 (Ang-1) and Angiopoietin-2, Semaphorin-3A, PEDF, HIF-1, FGF-2, and the receptors VEGF-R2, Neuropilin-1 and Neuropilin-2 were detected in both, ARPE-19 and CNV-RPE. Transcription of PEDF, FGF-2, Neuropilin-2, Ang-1 and Ang-2 was significantly upregulated in CNV-RPE. EphA7, VEGF-R1 and leptin were transcribed exclusively in CNV-RPE and Eph-A7 and VEGF-R1 proteins were present exclusively in CNV specimens.

Conclusions

A set of common factors controlling angiogenesis was detected in both, ARPE-19 cells and CNV-RPE cells. Surprisingly, PEDF and other factors inhibiting angiogenesis are strongly upregulated in CNV-RPE; thus, at least in later stages, the RPE has a potential to control angiogenesis in age-related macular degeneration.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Alberdi E, Aymerich MS, Becerra SP (1999) Binding of pigment epithelium-derived factor (PEDF) to retinoblastoma cells and cerebellar granule neurons: evidence for a PEDF receptor. J Biol Chem 274:31605–31612

    Article  CAS  PubMed  Google Scholar 

  2. Aymerich MS, Alberdi EM, Martinez A, Becerra SP (2001) Evidence for pigment epithelium-derived factor receptors in the neural retina. Invest Ophthalmol Vis Sci 42:3287–3293

    CAS  PubMed  Google Scholar 

  3. Campochiaro PA, Hackett SF, Vinores SA, Freund J, Csaky C, LaRochelle W, Henderer J, Johnson M, Rodriguez IR, Friedman Z (1994) Platelet-derived growth factor is an autocrine growth stimulator in retinal pigmented epithelial cells. J Cell Sci 107:2459–2469

    CAS  PubMed  Google Scholar 

  4. Cui JZ, Hornan D, Potter MJ, Greve MD, Hinz BJ, Samad A, Matsubara JA (2001) The role of leptin in choroidal neovascularization. Am J Ophthalmol 132:792–794

    Article  CAS  PubMed  Google Scholar 

  5. Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248

    CAS  PubMed  Google Scholar 

  6. Hageman GS, Mullins RF (1999) Molecular composition of drusen as related to substructural phenotype. Mol Vis 5:28

    CAS  PubMed  Google Scholar 

  7. Joussen AM (2001) Vascular plasticity: the role of the angiopoietins in modulating ocular angiogenesis. Graefes Arch Clin Exp Ophthalmol 239:972–975

    CAS  PubMed  Google Scholar 

  8. Kliffen M (1997) Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol 81:154–162

    Google Scholar 

  9. Leong KG, Hu X, Li L, Noseda M, Larrivee B, Hull C, Hood L, Wong F, Karsan A (2002) Activated Notch4 inhibits angiogenesis: role of Beta 1-integrin activation. Mol Cell Biol 22:2830–2841

    Article  CAS  PubMed  Google Scholar 

  10. Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M (2003) Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23:14–25

    Article  CAS  PubMed  Google Scholar 

  11. Mori K, Gehlbach P, Ando A, Dyer G, Lipinsky E, Chaudhry AG, Hackett SF, Campochiaro PA (2002) Retina-specific expression of PDGF-B versus PDGF-A: vascular versus non-vascular proliferative retinopathy. Invest Ophthalmol Vis Sci 43:2001–2006

    PubMed  Google Scholar 

  12. Ohno-Matsui K, Morita I, Tombran-Tink J, Mrazek D, Onodera M, Uetama T, Hayano M, Murota SI, Mochizuki M (2001) Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF. J Cell Physiol 189:323–333

    Article  CAS  PubMed  Google Scholar 

  13. Ohno-Matsui K, Yoshida T, Uetama T, Mochizuki M, Morita I (2003) Vascular endothelial growth factor upregulates pigment epithelium-derived factor expression via VEGFR-1 in human retinal pigment epithelial cells. Biochem Biophys Res Commun 303:962–967

    Article  CAS  PubMed  Google Scholar 

  14. Otani A, Takagi H, Oh H, Koyama S, Matsumura M, Honda Y (1999) Expressions of angiopoietins and Tie2 in human choroidal neovascular membranes. Invest Ophthalmol Vis Sci 40:1912–1920

    CAS  PubMed  Google Scholar 

  15. Reddy VM, Zamora RL, Kaplan HJ (1995) Distribution of growth factors in subfoveal neovascular membranes in age-related macular degeneration and presumed ocular histoplasmosis syndrome. Am J Ophthalmol 120:291–301

    CAS  PubMed  Google Scholar 

  16. Renno RZ, Youssri AI, Michaud N, Gragoudas ES, Miller JW (2002) Expression of pigment epithelium-derived factor in experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 43:1574–1580

    PubMed  Google Scholar 

  17. Schlunck G, Martin G, Agostini HT, Camatta G, Hansen LL (2002) Cultivation of retinal pigment epithelial cells from human choroidal neovascular membranes in age-related macular degeneration. Exp Eye Res 74:571–576

    Article  CAS  PubMed  Google Scholar 

  18. Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB, Polverini PJ, Flores-Riveros JR (1998) Biological action of leptin as an angiogenic factor. Science 281:1683–1686

    CAS  PubMed  Google Scholar 

  19. Taylor KL, Henderson AM, Hughes CC (2002) Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc Res 64:372–383

    Article  CAS  PubMed  Google Scholar 

  20. Wada M, Ogata N, Otsuji T, Uyama M (1999) Expression of vascular endothelial growth factor and its receptor (KDR/Flk-1) MRNA in experimental choroidal neovascularization. Curr Eye Res 18:203–213

    Google Scholar 

Download references

Acknowledgements

We thank Dr. Follo for help with the ABI 7700 SDS, Mrs. Buchen for the immunohistochemistry, Mrs. Mattes and Mrs. Flügel for technical assistance, and Dr. Joussen (Cologne) for providing CNV membranes. Parts of this work were presented at the DOG 2002 meeting in Berlin. This study was supported by DFG grant no. HA 2537/3–1 (SFB 1088).

Author information

Authors and Affiliations

  1. Universitaets-Augenklinik Freiburg, Killianstrasse 5, 79106, Freiburg, Germany

    Gottfried Martin, Lutz L. Hansen & Hansjürgen T. Agostini

  2. Universitaets-Augenklinik Würzburg, Würzburg, Germany

    Günther Schlunck

Authors
  1. Gottfried Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Günther Schlunck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lutz L. Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hansjürgen T. Agostini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hansjürgen T. Agostini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martin, G., Schlunck, G., Hansen, L.L. et al. Differential expression of angioregulatory factors in normal and CNV-derived human retinal pigment epithelium. Graefe's Arch Clin Exp Ophthalmol 242, 321–326 (2004). https://doi.org/10.1007/s00417-003-0838-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-003-0838-y

Keywords

Search

Navigation