Intraretinal Oxygen Levels before and after Photoreceptor Loss in the RCS Rat

Intraretinal Oxygen Levels before and afterPhotoreceptor Loss in the RCS Rat

Dao-Yi Yu, Stephen J. Cringle, Er-Ning Su, and Paula K. Yu

PURPOSE. To measure the intraretinal oxygen environment at different stages in the Royal Collegeof Surgeons (RCS) rat model of retinal degeneration to determine whether changes in oxygen levelare an important aspect of the disease.

METHODS. Oxygen-sensitive microelectrodes were used to measure oxygen tension as a function ofdepth through the retina of anesthetized, mechanically ventilated RCS rats at ages ranging frompostnatal day (P)20 to P104. The oxygen profiles were correlated with histologic observations ofthe cellular changes within the dystrophic retinas and compared with those in RCS-rdy1 controlanimals and published values in normal mature rats.

RESULTS. Although the youngest rats studied exhibited some differences in intraretinal oxygendistribution compared with mature animals, the distribution in dystrophic RCS rats at P20 was notsignificantly different from that in age-matched control subjects. However, the intraretinal oxygendistribution in dystrophic RCS rats was clearly affected after approximately P30, reflecting a loss ofphotoreceptor oxygen consumption consistent with histologic observations. In contrast, oxygenuptake by the inner retina was still evident long after the loss of photoreceptors was essentiallycomplete.

CONCLUSIONS. There was no significant tissue hypoxia during photoreceptor degeneration in thedystrophic RCS rat. The changes in intraretinal oxygen distribution are consistent with the loss ofouter retinal oxygen uptake but the preservation of inner retinal oxygen metabolism. (InvestOphthalmol Vis Sci. 2000;41:3999–4006)

Retinitis pigmentosa (RP) refers to a heterogeneousgroup of inherited human diseases that cause primarydegeneration of rod and cone photoreceptors.1 The

Royal College of Surgeons (RCS) rat is commonly used as ananimal model of photoreceptor degeneration of relevance toRP.2,3 There are several lines of evidence implying a role foroxygen in the RCS rat model of retinal degeneration. LaVail andBattelle4 noted a significant sparing of photoreceptors at theextreme periphery of the retina and around the optic disc, andincreased oxygen availability in these regions due to the diffu-sion of oxygen around the edges of the photoreceptor arrayhas been put forward as an explanation for this phenomena.5

A similar explanation was proposed for the sparing of photo-receptors around the edges of photocoagulation lesions indystrophic RCS rats.6 Manipulation of environmental oxygenconditions at key stages in the dystrophic RCS rat has report-edly been able to modulate the rate of photoreceptor celldeath. Systemic hyperoxia has been shown to slow down andsystemic hypoxia to accelerate the rate of cell death in thedystrophic RCS rat model.7 Similar findings have been reported

in normal animals that undergo a more controlled process ofcell death during maturation of the retina.5,7

Despite these compelling arguments for a possible role foroxygen in the photoreceptor degeneration in the dystrophicRCS rat, there has, to date, been no direct measurement ofretinal oxygen levels at any stage of the disease. The presentstudy therefore set out to characterize for the first time theintraretinal oxygen distribution at different stages in the RCSrat model of photoreceptor degeneration.

METHODS

General

Thirty-two pink-eyed, dystrophic RCS rats3 and 14 RCS-rdy1

congenic control rats were used for this study. The animalswere bred in our own animal facilities from colonies originallysourced from Matthew LaVail. All procedures conformed to theARVO Statement for the Use of Animals in Ophthalmic andVision Research. The rats were anesthetized with an intraperi-toneal injection of 5-ethyl-5- (19-methyl-propyl)-2-thiobarbitu-rate (Inactin; Byk Gulden, Konstantz, Germany), 100 mg/kgand atropine sulfate (20 mg). Artificial ventilation was per-formed with tidal volume determined by body weight. When-ever possible, the femoral artery was cannulated for continu-ous arterial blood pressure (106.6 6 2.9 mm Hg, n 5 33) andblood gas monitoring (PO2 5 79.4 6 3.0 mm Hg, PCO2 535.9 6 1.57 mm Hg, [pH 7.40 6 0.02], n 5 32). Rectaltemperature was maintained between 36.5°C and 37.5°C usinga homeothermic blanket. The rat was positioned prone in amodified stereotaxic instrument (Stellar, Pompano Beach, FL)

From the Centre for Ophthalmology and Visual Science, TheUniversity of Western Australia, Perth.

Supported by the National Health and Medical Research Councilof Australia, and by Retina Australia.

Submitted for publication November 2, 1999; revised March 17and July 13, 2000; accepted July 19, 2000.

Commercial relationships policy: N.Corresponding author: Dao-Yi Yu, Lions Eye Institute, 2 Verdun

Street, Nedlands, Perth 6009, Western [email protected]

Investigative Ophthalmology & Visual Science, November 2000, Vol. 41, No. 12Copyright © Association for Research in Vision and Ophthalmology 3999

with the head clamped to the stereotaxic frame and the eyeimmobilized by suturing to an eye ring. The pupil was dilatedwith 1% tropicamide (Mydriacyl; Alcon, Fort Worth, TX).

Oxygen Measurements

Recessed oxygen-sensitive microelectrodes (1 mm tip) weremanufactured and calibrated in our own laboratory. The mi-croelectrode was inserted into the rat eye through a small holeposterior to the limbus. A high-quality stereoscopic view of thefundus and the electrode was achieved by an operating micro-scope and a plano concave corneal contact lens. This enabledthe observer to determine the relationship between the retinaand the electrode tip and provided a clear view of both theretinal and choroidal vasculature. The retinal locations used fordata collection were in the inferior retina, two or three discdiameters from the optic disc margin. Intraretinal PO2 profileswere measured in 10-mm steps from the retinal surface throughto the deep choroid and measurements repeated during micro-electrode withdrawal. Experience has shown that clean pene-trations of the retina are best accomplished by using a freshlymade and sharpened electrode in each experiment.8,9 No cor-rection was made for the slightly nonperpendicular angle ofthe electrode track through the retina. Measurements weretypically performed in light-adapted conditions, but both light-and dark-adapted measurements were performed in P20 dys-trophic RCS rats and RCS-rdy1 control animals to determinethe magnitude of any dark adaptation effects on outer retinaloxygen tension. All statistical testing was performed using thestatistics program SigmaStat (Jandel Scientific, San Raphael,CA). A nonparametric, Mann–Whitney rank sum test was usedto compare oxygen levels in the RCS and RCS-rdy1 groups,with a significance acceptance level of P , 0.05 (one tailed).All data are expressed as mean 6 SE, with error bars on graphsshowing the SE.

Histology

At the conclusion of each experiment, both eyes were enucleatedand used for histologic studies to characterize the retinal struc-ture, both for comparison with the oxygen measurements and forassessment of morphologic changes. The eyes were placed in2.5% glutaraldehyde in 0.1 M phosphate buffer for 24 hours.Full-thickness pieces of retina and choroid were dissected andplaced in 10% sucrose for 1 to 2 days. The specimens were thenpostfixed in osmium tetroxide, dehydrated in graded ethanols,and embedded in epoxy resin. Sections (2 mm) were cut atselected locations in the region of the microelectrode studies andstained with toluidine blue for light microscopy.

RESULTS

The dystrophic RCS rat data were collected into five groupscorresponding to increasing postnatal age, and thereforeseverity of retinal degeneration (P20, P25–P30, P30 –P35,P35–P50, and P50 –P104). There were at least six animals ineach group. Representative oxygen profiles are presentedfor each group, along with retinal histology from that ani-mal. The nature of the oxygen distribution across the retinareflects the sources of oxygen from the choroidal and retinalvascular systems and oxygen consumption within the pre-dominantly avascular retinal layers in the inner retina, suchas the inner plexiform layer, and within the completely

avascular layers of the outer retina. Regions that contain asignificant net oxygen source, or sink, have the most dra-matic changes in oxygen gradient. Figure 1A shows theintraretinal oxygen distribution in a dystrophic RCS rat atP20. The profile exhibited characteristics similar to thatreported for normal mature rats,8 –10 except that the oxygenlevel in the superficial retina and at the level of the deepcapillary layer were somewhat higher. The high value in thesuperficial retina may have been associated with the pres-ence of a patent hyaloid arterial system in the vitreous ofsuch young animals, but the prominence of the oxygen peakin the deep capillary layer indicated increased oxygen de-livery from this vascular bed. The three sources of oxygencorrespond to the superficial retinal capillary layer, the deepcapillary layer, and the choroid. The minimum oxygen levelin the inner plexiform layer between the superficial anddeep capillary layers9 and a region of high oxygen uptake inthe outer retina were consistent with normal mature rats.The retinal histology from this animal (Fig. 1B) is showntogether with labels of specific retinal layers to allow com-parison with later stages of the disease. At P20 the retinashowed a mild degree of deterioration of the outer segmentsand an accumulation of amorphous debris between theouter segments and the retinal pigment epithelium (RPE).There was evidence of deterioration of the inner segmentsof the photoreceptors, but other cell layers appeared largelyunchanged.

At P29 in the dystrophic RCS rat (Fig. 2A), the oxygenlevel in the superficial retina had reduced, but the regions ofhigh oxygen uptake in the inner and outer retina were stillevident. The histology (Fig. 2B) showed some thinning of theouter nuclear layer, and both the outer and inner segments ofthe photoreceptors were less distinct. There was an increasedamount of debris and vacuole formation.

At P32 in the dystrophic RCS rat (Fig. 3A), the level ofoxygen uptake in the outer retina was clearly reduced, but theminimum oxygen level in the inner retina persisted. Histolog-ically (Fig. 3B), the outer nuclear layer was continuouslythinned. The outer segments were indistinct because of theamorphous debris accumulation, and the remaining inner seg-ments were markedly deteriorated. Thinning of the outer andinner plexiform layer with vacuole formation was noted. Thedeep capillaries were still evident.

At P41 in the dystrophic RCS rat (Fig. 4A), the oxygenuptake in the outer retina was dramatically reduced, but theoxygen utilization by the inner retina was still evident. Oxygendelivery from the choroid and the superficial capillaries wasevident, but a contribution from the deep capillary layer couldnot be seen. Histologically (Fig. 4B), thinning of the outernuclear layer was more clearly evident, and only half theoriginal thickness remained. The outer and inner segmentswere impossible to distinguish among the amorphous debrisaccumulation. The outer plexiform layer was thinned and hardto define in some areas. The nerve fiber layer, ganglion celllayer, and inner plexiform layer were also thinned. The deepcapillaries were no longer evident.

A very similar oxygen distribution was evident at P62 inthe dystrophic RCS rat (Fig. 5A). Histologically, the degen-eration of the photoreceptors was essentially complete (Fig.5B), the outer nuclear layer was almost totally absent, andthe space between the inner nuclear layer and the RPE wasfilled with amorphous debris accumulation and a few scat-

4000 Yu et al. IOVS, November 2000, Vol. 41, No. 12

tered nuclei. The outer plexiform layer was also absent. Theinner nuclear layer was well preserved, but there was rela-tive thinning of the inner plexiform layer and nerve fiberlayer.

The changes in intraretinal oxygen distribution at differentstages of the RCS model of retinal degeneration can best beillustrated by superimposition of the mean data for each group(Fig. 6). A total of 103 oxygen profiles were included, with at

FIGURE 1. (A) Intraretinal oxygen distribution in a dystrophic RCS rat at P20, along with a retinal section (B) from the same animal. The oxygentension is shown as a function of electrode track distance from the surface of the retina. The retinal layers are labeled in the adjacent bar. NF/GC,nerve fiber and ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; IS,inner segments of the photoreceptors; OS, outer segments; RPE/BM, retinal pigment epithelium and Bruch’s membrane (abbreviations apply toFigs. 1 through 7). Long arrows: Signs of the early stages of debris accumulation; short arrows: location of the deep capillaries. Magnification,3344.

FIGURE 2. Intraretinal oxygen distribution (A) in a dystrophic RCS rat at postnatal day 29, along with a retinal section (B) from the same animal.Long arrows: Debris accumulation; short arrows: location of the deep capillaries. Magnification, 3344.

IOVS, November 2000, Vol. 41, No. 12 Intraretinal Oxygen Tension in the RCS Rat 4001

least 15 from each age group (2 or 3 profiles for each animal).To accommodate the marked degree of retinal thinning as thedegeneration progressed, the data were aligned with respect tothe most consistent feature across all ages, the inner retinalminimum oxygen tension. Figure 6 demonstrates the intrareti-nal oxygen distribution before, during, and after the loss of

oxygen uptake by the photoreceptors. Thus, at all ages theintraretinal oxygen distribution in the dystrophic RCS ratsexhibited a minimum oxygen tension between the superficialand deep capillary layers of the retinal circulation, reflecting asignificant oxygen uptake by the inner plexiform layer.9 In theouter retina, before approximately P30 there was a high level

FIGURE 3. Intraretinal oxygen distribution (A) in a dystrophic RCS rat at postnatal day 32, along with a retinal section (B) from the same animal.The deep capillaries were still visible (short arrows). Magnification, 3344.

FIGURE 4. Intraretinal oxygen distribution (A) in a dystrophic RCS rat at P41, along with a retinal section (B) from the same animal. The outerplexiform layer was missing in localized areas (thin arrows), and the deep capillaries were no longer apparent. Magnification, 3344.


of oxygen uptake in the region of the inner segments of thephotoreceptors, which was more pronounced at P20 than thatseen in normal mature rats.9 However, at later stages in thedystrophic RCS model, the oxygen distribution in the outerretina changed markedly, and the oxygen uptake by the pho-toreceptors was massively reduced.

The mean values for oxygen tension in the choroid in thedystrophic RCS rats at all ages was not significantly different

from that previously reported for normal mature rats underequivalent ventilation conditions.9 The lowest oxygen tensionsseen within the inner retina in the dystrophic RCS rats was alsonot different from that in normal mature animals.9 In thesuperficial retina in the P20 dystrophic RCS group, the oxygenlevel (28.2 6 0.6 mm Hg) was significantly higher than innormal mature rats. This, we believe, was a reflection of theoxygen contribution of the hyaloid artery system, which is stillpatent in such young animals. Measurements of oxygen tensionin the vicinity of the hyaloid vessels in the youngest RCS ratsconfirmed that they were indeed a source of vitreal oxygen-ation.

In comparison to mature rats, the influence of the deepcapillary layer and the trough in the outer retina was moreevident in the younger (P20) dystrophic RCS rats.8,9 How-ever, the minimum oxygen level in the outer retina was notsignificantly lower than in mature rats. This suggests thatmuch of the additional oxygen contribution from the deepcapillary layer was consumed within the outer retina. Toexamine this further, we performed a series of measure-ments in age-matched RCS-rdy1 control rats. A typical pro-file is shown in Figure 7 for a P20 RCS-rdy1 control animal,together with a retinal section from that animal. The averagedata from all P20 RCS-rdy1 control animals tested (n 5 6)are shown in Figure 8, along with the mean data for the P20dystrophic RCS rats (n 5 6). The notable oxygen contribu-tion from the deep capillary layer and the outer retinaltrough were also evident in the RCS-rdy1 control group atP20. There was no significant difference in oxygen level atany retinal location between the dystrophic RCS and RCS-rdy1 groups. The intraretinal oxygen distribution in moremature RCS-rdy1 control rats is shown in Figure 9 for theP40 to P50 age group (n 5 8). The intraretinal oxygendistribution was indistinguishable from that seen in matureSprague–Dawley rats.8,9

FIGURE 5. Intraretinal oxygen distribution (A) in a dystrophic RCS rat at P62, along with a retinal section (B) from the same animal. Magnification,3344.

FIGURE 6. Average intraretinal oxygen distribution in dystrophic RCSrats at different age groups. To accommodate the changes in retinalthickness, the oxygen profiles were aligned in relation to the innerretinal minimum, which was preserved at all stages of the disease. Theloss of oxygen uptake in the outer retina in the older animals and anoverall thinning of the retina were evident.


The effect of dark adaptation was investigated in a sub-group of P20 dystrophic RCS rats (n 5 5) and their age-matched control animals (n 5 5). Figure 10A shows a pair ofintraretinal oxygen measurements under light-adapted anddark-adapted conditions in a dystrophic RCS rat. The equiva-lent data for an RCS-rdy1 control rat at P20 are shown in Figure10B. Dark adaptation caused a reduction in the oxygen tensionin the region of the outer retinal minimum in both groups. The

magnitude of the effect was not significantly different betweenthe dystrophic RCS and RCS-rdy1 control groups: 6.1 6 0.5 (n5 5) mm Hg, and 5.1 6 0.4 (n 5 5) mm Hg, respectively. Theminimum oxygen level in the outer retina under dark-adaptedconditions did not reach zero in either group, reducing tomean values of 5.3 6 0.6 mm Hg and 7.7 6 1.3 mm Hg indystrophic RCS and RCS-rdy1 control groups at P20, and theseminimum values were not significantly different.

FIGURE 7. Intraretinal oxygen distribution (A) in an RCS-rdy control rat at postnatal day 20, along with a retinal section (B) from the same animal.Magnification, 3344.

FIGURE 8. Average intraretinal oxygen distribution in dystrophic RCSrats and RCS-rdy1 control rats at P20. There was no significant differ-ence in oxygen level at any retinal location between the two groups.

FIGURE 9. Average intraretinal oxygen distribution in RCS-rdy controlrats at P40 through P50. The intraretinal oxygen distribution wasindistinguishable from that previously reported in mature rats.9


DISCUSSION

This study provides the first quantitative data for oxygen dis-tribution within the retina of the dystrophic RCS rat. Thechanges in oxygen distribution correlated well with the loss ofphotoreceptors that is characteristic of this model of retinaldegeneration. The loss of oxygen uptake by the photorecep-tors coincided with the loss of distinction of the photoreceptorinner segments in histologic sections. In contrast, the oxygendistribution across the inner retina was much less disturbed,even at the late stages of the disease, long after the photore-ceptor loss was essentially complete. This finding is consistent

with the in vitro work of Graymore11 who found a significantlevel of oxygen uptake in isolated retinas from RCS rats withretinal dystrophy. The maintenance of inner retinal oxygenmetabolism in the dystrophic RCS rat is in stark contrast to thefindings from an alternative model of retinal degeneration. Inthe urethane-induced retinopathy model in rats, the oxygendistribution across the inner retina was markedly affected,becoming uniform, which indicates a loss of oxygen uptake inthe inner retina.12 Histologic examination of the inner retina inthese two models does not reveal any overt changes to retinalstructure that could account for the very different outcomes inoxygen metabolism.12 Presumably, the different behavior ofthe inner retina is related to the different mechanisms respon-sible for the retinal degeneration in each case. The substantialmaintenance of inner retinal oxygen uptake, even after thecomplete loss of signal input from the photoreceptors, is in-triguing and provides further evidence that the inner retinamay remain viable for considerable periods after the degener-ation of the outer retina.

In the present study, we found no evidence for decreasedoxygen levels in either the retinal or choroidal vascular beds indystrophic RCS rats. Neither was there a significant decrease inoxygen levels within the retina in the dystrophic RCS ratswhen compared with age matched controls or published val-ues for mature rats. It had been hypothesized that the build-upof cell debris in the outer retina could constitute a diffusionbarrier for oxygen diffusing from the choroid7 and result inintraretinal hypoxia. Although our measurements cannot quan-tify the oxygen diffusion properties of the outer retinal layers,the absence of overt intraretinal hypoxia suggests that oxygensupply is not compromised at P20. Previous observations thatsupplemental oxygen exposure during a critical period (P16–P22) was able to slow down the rate of photoreceptor celldegeneration5 cannot apparently be explained in terms of asimple relief from intraretinal hypoxia at the level of the pho-toreceptors.7 However, we cannot rule out the possibility thathypoxic events before P20 somehow triggered the later pho-toreceptor cell loss.

The suggestion that outer retinal oxygen uptake may beincreased at P20 in both dystrophic RCS and RCS-rdy1 controlrats requires further investigation. A quantitative study of oxy-gen consumption in specific retinal layers at even earlier stagesmay indicate which regions are most at risk from oxygen stressduring the maturation of the juvenile rat retina. Isolated retinastudies have confirmed that there is a dramatic increase in totalretinal oxygen consumption between P10 and P20 in controland dystrophic RCS rats.11 It is possible that an inability of thedystrophic RCS rat retina to cope with such fluctuations inenergy demand may play a vital role in the subsequent disease.Such an analysis must await technological improvements toallow the measurement of the intraretinal oxygen environmentin even younger animals to be accomplished.

A similar study in normal rats would also be of interest inconfirming the role that changes in oxygen supply and con-sumption is thought to have in the normal development pro-cesses within the retina.13 Aside from the surgical difficulty inconducting work of this sort on such young animals, there arealso differences in the intraocular environment when com-pared with more mature animals.8 The hyaloid system andassociated membranes are more evident in younger animals,making intraocular manipulation of microelectrodes consider-ably more difficult.

FIGURE 10. Sequential oxygen profiles in the light- and dark-adaptedstate in P20 dystrophic RCS rats (A) and RCS-rdy1 control rats (B). Anoxicregions within the retina were not present in either group during darkadaptation, and the magnitude of the dark-induced reduction in theouter retinal oxygen minimum was not significantly different.


Many other factors, apart from oxygen metabolism, havealso been proposed as important to the disease in the dystro-phic RCS.1,2,14 A recent study has reported that a short periodof light stress at P23 has a sustained protective effect on thephotoreceptors in the dystrophic RCS rat model.15 This pro-tective effect was attributed to a sustained increase in basicfibroblast growth factor expression and not to any alterationsin oxygen supply.15 Winkler et al.16 have previously demon-strated that the rat retina is remarkably resistant to hypoxicinsult and have demonstrated the ability of the rat outer retinato switch to glycolytic pathways under hypoxic conditions.The interaction between these metabolic pathways providesother avenues by which manipulation of oxygen supply couldhave effects on retinal metabolism far more complex than thesimple relief of tissue hypoxia.

Dark adaptation in the rat did not result in the develop-ment of anoxic regions in the outer retina, a finding that isconsistent with a much smaller light–dark effect in the rat16

when compared with that reported for the cat.17

We have demonstrated that a consequence of the photo-receptor depletion in the dystrophic RCS rats is that oxygenlevels are increased in some regions of the remaining outerretina. Other groups have proposed that oxygen toxicity mayplay an important role in photoreceptor degeneration.18,19 Ourstudies were not able to assess the cause and effect of the oxy-gen changes that we observed in the dystrophic RCS animals.

An intriguing aspect of the intraretinal oxygen distributionin the later stages of dystrophic RCS disease is the absence ofany apparent oxygen contribution from the deep capillarylayer. Our histologic observations suggest a reduction in thenumber of capillaries in the deep capillary layer, a point thathas been confirmed quantitatively elsewhere.13 It is not clearwhether such changes are a consequence of photoreceptorloss or a factor contributing to the disease.

In summary, our measurements do not support the casethat a simple hypoxic insult is responsible for the pathologicchanges seen in the dystrophic RCS rat. The changes in in-traretinal oxygen level that are seen during the time course ofphotoreceptor cell depletion are consistent with a reduction inouter retinal oxygen uptake and a relative maintenance ofinner retinal oxygen metabolism.

Acknowledgments

The authors thank Dean Darcey for expert technical assistance.

References

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Intraretinal Oxygen Levels before and after Photoreceptor Loss in the RCS Rat

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