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C. Ergorul, A. Ray, B. T. Lapp, D. Y. Wang, W. Huang, C. L. Grosskreutz; Endogenous Elevation of HIF1- Levels Does Not Lead to Neovascularization in the Glaucomatous Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5497.
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Hypoxia Inducible Factor 1-α (HIF1-α) activation is an early cellular response to hypoxia and leads to neovascularization (NV) in ischemic retinopathies. Although ischemia has been implicated in the development of glaucoma, there is no NV in glaucoma. Interestingly, a previous immunohistochemical study reported that HIF1-α is increased in postmortem human glaucomatous donor retinas (Tezel and Wax, 2004). Here we further investigated HIF1-α in the retina in experimental glaucoma. We hypothesized that HIF1-α would be increased in the glaucomatous retina at a level that does not lead to NV.
Intraocular pressure (IOP) was unilaterally elevated in male Brown Norway rats by injecting 1.9M hypertonic saline solution in the episcleral veins as described by Morrison. The contralateral eye served as the control. Subsequently, IOP was measured every other day with a Tonopen. Following 10 days of elevated IOP, HIF1-α protein levels were analyzed in whole retinal lysates from normal (n= 6) and glaucomatous (n= 6) eyes. In a different group of rats, retinal ganglion cells were retrogradely labeled by injecting Fluorogold in the superior colliculus a week before the hypertonic saline injection. Following 10 days of elevated IOP, posterior eye cups were cross-sectioned using a cryostat. Next, HIF1-α levels and localization were examined in retinal sections by immunohistochemistry.
Immunoblot analysis indicated a significant increase in HIF1-α levels in the glaucomatous retinas compared to controls (mean ± SE) (1.34 ± 0.13 fold; n= 6; p= 0.02). Immunohistochemistry analysis also confirmed that HIF1-α levels were increased in the glaucomatous retina. HIF1-α staining was primarily localized to Müller glia as suggested by double-labeling with Vimentin. In addition, HIF1-α staining was seen in some blood vessels in the inner retina in glaucoma.
Here we demonstrated that HIF1-α levels are increased in the retina in experimental glaucoma. These data suggest that if ischemia contributes to the pathogenesis of glaucoma, the level of HIF1-α elevation may not be sufficient to induce NV. Our findings extend the immunohistochemical observations previously made in postmortem human glaucomatous retinas. In addition, HIF1-α appears to be localized primarily in Müller glia which span the entire thickness of the retina and connect with all types of retinal neurons. The combination of increased HIF1-α levels in Müller glia and the lack of NV suggests an alternative role for HIF1-α (e.g. neuroprotective) in the glaucomatous retina.
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