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Constitutive and oxidative-stress-induced expression of VEGF in the RPE are differently regulated by different Mitogen-activated protein kinases

  • Basic Science
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Abstract

Purpose

Vascular endothelial growth factor (VEGF) is a fundamental factor for angiogenesis. It plays important roles in pathological conditions (e.g. the development of wet AMD), but also in the healthy organism) e.g. in maintaining the vasculature and supporting the retina). Recent therapies to treat the wet AMD focus on neutralizing VEGF indiscriminately. VEGF is constitutively expressed in the retina, but its expression is upregulated by various (noxious) stimuli, e.g. oxidative stress or hypoxia. Discrimination between constitutive expression of VEGF and its pathological upregulation might provide the possibility of focusing on inhibiting the pathological expression only. Here, we focused on the influence of different mitogen-activated protein kinase (MAPK) (p38, Erk, JNK) on the secretion and expression of VEGF, with or without being challenged by oxidative stress.

Methods

VEGF secretion was measured using a perfusion organ culture model; expression was examined in primary RPE culture and Western blotting.

Results

Constitutive VEGF expression and secretion can be diminished by inhibiting p38, while inhibiting Erk or JNK does not show a significant effect. When challenged with oxidative stress (250 µM t-butylhydroperoxide), VEGF expression and secretion increases and the influence of the MAPK changes: While p38 still accounts for about 30% of the secretion, Erk shows a similar influence. Inhibiting JNK presents conflicting results. In organ culture, inhibiting JNK significantly increases VEGF secretion after stimulation with 250 µM tBH, while with regard to VEGF expression in RPE cell culture, this effect could not be seen.

Conclusion

Constitutive and oxidative stress induced VEGF secretion, and expression is differently regulated, which might offer an opportunity to selectively inhibit pathological VEGF expression only.

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Acknowledgements

We would like to thank K. Lange for her excellent technical assistance. This work was financially supported by the CAU Medical Faculty Intramural Research Grant.

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Authors and Affiliations

  1. Department of Ophthalmology, UKS-H, Campus Kiel, Hegewischstr. 2, 24105, Kiel, Germany

    Alexa Klettner & Johann Roider

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  1. Alexa Klettner
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  2. Johann Roider
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Correspondence to Alexa Klettner.

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No financial relationships. This work was financially supported by the CAU Medical Faculty Intramural Research Grant.

The authors have full control of all primary data, and agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review their data upon request.

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Klettner, A., Roider, J. Constitutive and oxidative-stress-induced expression of VEGF in the RPE are differently regulated by different Mitogen-activated protein kinases. Graefes Arch Clin Exp Ophthalmol 247, 1487–1492 (2009). https://doi.org/10.1007/s00417-009-1139-x

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