Rod Photoreceptor Loss in Rho<sup>−/−</sup>Mice Reduces Retinal Hypoxia and Hypoxia-Regulated Gene Expression

Gooyer, Tanyth E de; Stevenson, Kathryn A; Humphries, Pete; Simpson, David; Curtis, Tim M.; Gardiner, Tom; Stitt, Alan W.

doi:10.1167/iovs.06-0646

Cited by 34 publications

(40 citation statements)

References 35 publications

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“…This is also in agreement with the pO 2 gradient of the retina, which declines from the outer retina to the inner retina, with a relatively hypoxic inner retina with a pO 2 of only ?25 mm Hg (Wangsa-Wirawan and Linsenmeier 2003). Furthermore, these data are in agreement with those of De Gooyer et al (2006), who demonstrated hypoxia by pimonidazole in the INL and GCL of normal mouse retina that was significantly reduced in the retina of rhodopsin knockout mice lacking rod cells. Expression of stabilized HIF-1a in normal retina is probably due to the tenuous state of oxygen tension indigenous to the retina.…”

Section: Discussionsupporting

confidence: 92%

Active HIF-1 in the Normal Human Retina

Hughes

Groot

Groep

et al. 2009

J Histochem Cytochem.

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S U M M A R Y A unique feature of the retina is the presence of photoreceptors, which require an enormous amount of oxygen for the conversion of light to an electrical signal. Hypoxia-inducible factor-1 alpha (HIF-1a) is a transcription factor that is the master regulator of cellular adaptation to low oxygen tension. Only in hypoxic conditions is HIF-1a protein stabilized and translocated to the nucleus, where it induces transcription of target genes involved in oxygen delivery and energy metabolism. We hypothesized that HIF-1a is constitutively stabilized and active in the normal human retina. We investigated the cellular distribution of HIF-1a and the expression of its downstream targets, vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), and carbonic anhydrase IX (CAIX), by immunohistochemistry and immunoblotting in the retina of normal rats and human donor eyes. Both human and rat retinas displayed prominent staining of HIF-1a in nuclei of most cell types in inner and outer nuclear layers and the ganglion cell layer, a cellular distribution pattern which was confirmed in human retina by immunoblotting of nuclear extracts. A negative correlation was found between HIF-1a protein levels and postmortem times. In human retina, staining of VEGF, GLUT-1, and CAIX was found. Our observations indicate that active HIF-1 signaling occurs constitutively in the normal human and rat retina, suggesting that HIF-1 has a physiological role in the retina. (J Histochem Cytochem 58:247-254, 2010)

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Section: Discussionsupporting

confidence: 92%

Active HIF-1 in the Normal Human Retina

Hughes

Groot

Groep

et al. 2009

J Histochem Cytochem.

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“…Under normal physiologic conditions and diurnal cycles, the adult retina exists in a state of borderline hypoxia, making this tissue particularly susceptible to even subtle decreases in perfusion. 31 Nonetheless, the retina displays a remarkable natural resistance to ischemic injury, much greater than that of the brain. 1 The induction of Hsp70 production in the brain and retina is associated with cellular resistance to various types of damage.…”

Section: Discussionmentioning

confidence: 99%

Novel Mouse Model of Monocular Amaurosis Fugax

Lelong

Bièche

Perez

et al. 2007

Stroke

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Background and Purpose-Retinal ischemia is a major cause of visual impairment and is associated with a high risk of subsequent ischemic stroke. The retina and its projections are easily accessible for experimental procedures and functional evaluation. We created and characterized a mouse model of global and transient retinal ischemia and provide a comprehensive chronologic profile of some genes that display altered expression during ischemia. Methods-Ischemia and reperfusion were assessed by observing flat-mounted retinas after systemic fluorescein injection.The temporal pattern of gene expression modulation was evaluated by quantitative reverse transcription-polymerase chain reaction from the occurrence of unilateral 30-minute pterygopalatine artery occlusion until 4 weeks after reperfusion. Electroretinograms evaluated functional sequelae 4 weeks after the ischemic episode and were correlated with histologic lesions. Results-This model is the first to reproduce the features of transient monocular amaurosis fugax resulting from ophthalmic artery occlusion. The histologic structure was roughly conserved, but functional lesions affected ganglion cells, inner nuclear layer cells, and photoreceptor cells. We observed an early and strong upregulation of c-fos, c-jun, Cox-2, Hsp70, and Gadd34 gene expression and a late decrease in Hsp70 transcript levels. Conclusions-A murine model of transient retinal ischemia was successfully developed that exhibited the characteristic upregulation of immediate-early genes and persistent functional deficits. The model should prove useful for investigating mechanisms of injury in genetically altered mice and for testing novel neuroprotective drugs. (Stroke.

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“…Since the choriocapillaris is lined by fenestrated endothelial cells, the RPE instead comprises the entire outer blood-retinal barrier between the choroid and the neurosensory retina. Photoreceptors also interact with the inner retinal vasculature to some extent because mice with photoreceptor loss from retinal degeneration do not develop vascular proliferation in the inner retina in models of proliferative retinopathy (de Gooyer et al, 2006a; de Gooyer et al, 2006b). …”

Section: Evolving Architecture Of the Retinal Vasculature During Dmentioning

confidence: 99%

“…In the cat, the choroid provides 90–100% of fuel and oxygen to photoreceptors both in the dark and light and the inner retinal circulation supplies the inner retina with 100% of its supply in dark or light (Linsenmeier and Braun, 1992). Photoreceptors may derive oxygen from the inner retinal vasculature to some extent because photoreceptor loss from retinal degeneration alters the inner vasculature (de Gooyer et al, 2006a; de Gooyer et al, 2006b). This may be indirect though, since the activity of the second and third order neurons are dependent on the presence of the photoreceptors.…”

Section: Oxygen Consumption and Oxidative Phosphorylationmentioning

confidence: 99%