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Animal Models |
From the Departments of Ophthalmology and Neuroscience,*
The Johns Hopkins University School of Medicine, Baltimore, Maryland,
and the Department of Microbiology and Kaplan Cancer
Center,
New York University School of
Medicine, New York, New York
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several models of CNV have been described, and each has provided useful information. The laser-induced model in primates has provided important knowledge concerning the natural history of CNV, the role of the retinal pigmented epithelium (RPE) in re-establishing the blood-retinal barrier (BRB), and the participation of the RPE in the scarring process;3 it has also been used to investigate drug treatment,4 although it is limited by its tremendous expense. Models in rats are less expensive and more feasible to use for investigating new therapies.5,6 In addition, they have provided important information concerning altered expression of growth factors during the development of CNV.7 Models in minipigs8 and rabbits9 have demonstrated that sustained elevation of basic fibroblast growth factor (FGF2) in the subretinal or suprachoroidal space is capable of stimulating CNV.
Although each of these models is useful, a model of CNV in mice would have an important additional benefit; manipulation of gene expression is more feasible in mice than in other animals, making it possible to investigate the effect of altered expression of individual genes in the retina and RPE on the development of CNV. In this study, we produced and characterized a model of CNV in mice and then applied it to mice with targeted disruption of the FGF2 gene to investigate its role in the development of CNV. A portion of this study has been published in abstract form.10
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice used in this study were handled according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Thirteen adult male C57BL/6J mice were anesthetized by intraperitoneal injection of 0.3 ml of ketamine hydrochloride diluted 1:10 with sterile water. The pupils were dilated with 1% tropicamide, and three burns of krypton laser photocoagulation (50-µm spot size; 0.05 seconds duration; 350 to 400 mW) were delivered to each retina using a slit lamp delivery system and a cover glass as a contact lens. Burns were performed in the 9, 12, and 3 o'clock positions of the posterior pole of the retina so that each burn could be identified postmortem and compared with respect to fluorescein angiographic and histopathological characteristics.
Fluorescein angiograms were done in some mice by taking serial fundus photographs with a TRC-50FT camera (Topcon, Paramus, NJ) after intraperitoneal injection of 0.3 ml of 1% fluorescein sodium (Alcon, Fort Worth, TX). At various times after laser treatment, mice were sacrificed and their eyes were enucleated and fixed in 2% paraformaldehyde/2% glutaraldehyde in 0.1 mol/L cacodylate buffer (pH 7.4) for 24 hours at 4°C or in the same buffer containing only 4% paraformaldehyde. The eyes fixed in paraformaldehyde were embedded in paraffin for another study. The eyes embedded in paraformaldehyde and glutaraldehyde were dissected, each burn was identified and isolated under a dissecting microscope, and the tissue strips were post-fixed with 2% osmium tetroxide/cacodylate buffer (pH 7.4). The tissues were dehydrated through a series of graded alcohols and embedded in Poly/Bed 812 resin (Polysciences, Warrington, PA), and 1-µm serial sections were cut with an ultramicrotome, stained with toluidine blue, and examined by light microscopy. To get an estimate of the incidence of CNV at various time points after laser treatment, burns were randomly selected: 16 at 1 week, 11 at 2 weeks, and 11 at 4 weeks. For each, 1-µm serial sections were cut through the entire lesion, stained, and examined by light microscopy. For some lesions, ultrathin sections were prepared, counterstained with uranyl acetate and lead citrate, and examined with a transmission electron microscope (JEOL 100CX).
Comparison of Laser-Induced CNV in FGF2-Deficient and Control Mice
Mice with targeted disruption of the FGF2 gene were produced by homologous recombination, and their characterization has been published elsewhere.11 FGF2-deficient and control mice with the same genetic background were treated with krypton laser in each eye as described above. After 2 weeks, fluorescein angiography was done, the mice were sacrificed, and their eyes were removed and fixed in 4% glutaraldehyde in 0.1 mol/L cacodylate buffer (pH 7.4). Each burn was identified and isolated under a dissecting microscope, and the tissue was processed as described above. One-micron serial sections were cut through each burn in entirety, stained, and examined to determine the presence or absence of CNV.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A bubble, suggesting rupture of Bruch's membrane, was
observed in association with 67 of 75 burns (87%) in 25 eyes (13 mice)
treated with laser photocoagulation. This resulted in chalk-white
retinal burns without subretinal hemorrhage (Figure 1)
. Fluorescein angiography was done 1
week after laser treatment in 10 mice that had a total of 60 laser
burns. Of the 60 burns, 34 (57%) showed evidence of dye leakage,
judged by the presence of a hyperfluorescent spot that increased in
size and developed blurred margins over time (Figure 2)
. The range of leaking hyperfluorescent
spots was one to three per eye, with most mice showing fluorescein
leakage in two of three lesions. In 56 burns in which a bubble had been
produced, 34 (61%) leaked fluorescein. Ten burns (18%) showed a
hyperfluorescent spot that increased to become a large bright
fluorescent spot, suggesting extensive leakage of dye. Fluorescein
angiography 4 weeks after laser treatment in three mice showed leakage
in 7 of 18 burns (39%); 2 burns (11%) showed extensive leakage.
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. All
layers of the choroid were destroyed within the laser burn, and the
surrounding choriocapillaris was collapsed. There was no subretinal
hemorrhage. Three days after laser treatment, there was cellular tissue
extending from the choroid through the rupture in Bruch's membrane
(Figure 3b)
. In association with this tissue, there were many
pigment-containing macrophage-like cells, and at the borders of the
burn there were many retinal pigmented epithelial (RPE) cells. One week
after laser treatment, newly formed vessels with wide lumens extended
from the choroid into the subretinal space where they became partially
enveloped by RPE cells (Figure 3c)
. The mass of blood vessels was often
accompanied by an overlying serous retinal detachment. Two weeks after
laser treatment, large collections of vascular channels were seen in
the subretinal space. In burns that had shown leakage of dye by
fluorescein angiography, there was serous detachment overlying the
vascular channels, and the channels were not completely covered by RPE
cells (Figure 3d)
. Burns that had shown little or no fluorescein
leakage, usually still contained choroidal neovascularization, but the
vessels were small with narrow lumens and there was prominent RPE
proliferation along the margins of the vessels and no or minimal serous
detachment (Figure 3e)
. Four weeks after laser treatment, there were
still many blood vessels with large lumens in the subretinal space;
however, all lesions examined appeared to be completely engulfed by RPE
cells (Figure 3f)
. Electron microscopy showed fenestrated vessels with
large lumens in areas of choroidal neovascularization (Figure 4)
. As noted on light micrographs, RPE
cells surrounded the neovascular tissue and appeared to engulf it.
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Comparison of Laser-Induced CNV in FGF-2-Deficient and Control Mice
Krypton laser photocoagulation was done in FGF2-deficient and
wild-type control mice in the same manner as that described for
C57BL/6J mice. Because in C57BL/6J mice it appeared that production of
a bubble at the time of laser was an important factor in obtaining CNV,
only mice in which a bubble was produced for all three burns were used
(six FGF2-deficient and five controls). Two weeks after treatment,
fluorescein angiography showed leakage in 63% of burns in control mice
compared with 39% in FGF2-deficient mice, a difference that was
statistically significant (Table 1)
.
Examination of serial sections showed that 87% of lesions in control
mice contained CNV compared with 75% in FGF2-deficient mice, which was
not a statistically significant difference. There was no identifiable
difference in the light microscopic (not shown) or ultrastructural
appearance (Figure 5)
of lesions in
FGF2-deficient mice versus controls.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The murine model of CNV compares favorably with previously published rat models with respect to the features listed above. CNV occurred in 6 of 14 rat eyes 1 to 3 months after multiple moderate krypton laser burns5 and in 60 to 78% of lesions 1 month after intense laser burns meant to rupture Bruch's membrane.6 Thirty-eight percent of rats immunized with interphotoreceptor retinol-binding protein synthetic peptides developed CNV after 45 days.12 However, the major benefit of the mouse model is that, unlike other animals in which CNV has been produced, genetic manipulations are feasible in mice; therefore, the model can be used to investigate the impact of overexpression or underexpression of individual genes on the development of CNV.
We selected FGF2 for investigation because several lines of evidence have suggested that it may be an important stimulus for CNV. Cultured RPE cells produce FGF2, and it stimulates proliferation, migration, and tube formation by choroidal endothelial cells.13 Surgically removed CNV membranes show immunohistochemical staining for FGF2, including staining within RPE cells.14-17 In a rat model of laser-induced CNV, an increase in FGF2 mRNA was seen in RPE-like cells, choroidal vascular endothelial cells, and fibroblast-like cells in the lesions.18 Sustained release of FGF2 in the subretinal space of minipigs8 or rabbits9 results in CNV.
Our data demonstrate that the incidence of CNV after laser-induced rupture of Bruch's membrane is not statistically different in FGF2-deficient and control mice. This means that despite the fact that exogenous administration of FGF2 is capable of stimulating CNV, endogenous FGF2 is not required for CNV to occur. However, this does not mean that FGF2 does not contribute to the development of CNV. There was significantly less fluorescein leakage associated with laser-induced lesions in FGF2-deficient mice compared with wild type mice, and we have noted that small areas of CNV are less likely to leak fluorescein than large lesions. Therefore, it is possible that the areas of CNV were smaller in FGF2-deficient mice, but we were unable to obtain a direct quantitative assessment of the size of the lesions and we cannot be sure there was a difference.
Although our data do not permit a determination as to whether or not FGF2 contributes to CNV, they clearly demonstrate that it is not necessary for its occurrence, indicating that, in the absence of FGF2, other growth factors may be involved. One possibility is that another member of the FGF family could compensate for the absence of FGF2. A reasonable candidate is FGF1, which has similar activity and characteristics and is present in retina and RPE; generation of mice deficient in FGF1 will help to address this issue. Growth factors outside the FGF family may also participate. Vascular endothelial growth factor (VEGF) is an angiogenic factor that has been localized to CNV membranes and could play a role.16,17,19 We have recently demonstrated that transgenic mice that overexpress VEGF in photoreceptors develop neovascularization originating from retinal blood vessels but not from choroidal vessels.20 This could mean that choroidal vessels do not respond to VEGF, but it more likely means that disruption of Bruch's membrane, a component of our model, is necessary for CNV to develop. Tumor necrosis factor is an angiogenic factor produced by macrophages,21 and macrophage-like cells are seen in our model and in some patients with CNV due to age-related macular degeneration.22
To our knowledge, this is the first study to use targeted gene disruption to investigate the involvement of a particular gene in a model of CNV. We have recently used this approach to demonstrate that FGF2 does not play a major role in stimulating retinal neovascularization.23 This is a potentially useful strategy to identify genes that either stimulate or inhibit the development of ocular neovascularization and may help guide attempts to develop new treatments.
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Acknowledgements |
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Footnotes |
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Supported by PHS grants EY05951, EY10017, EY09769, and core grant P30EY1765 from the National Eye Institute, a Juvenile Diabetes Foundation fellowship grant (to NO), a Lew R. Wasserman Merit Award (to PAC), an unrestricted grant from Research to Prevent Blindness, Inc., the Rebecca P. Moon, Charles M. Moon, Jr., and Dr. P. Thomas Manchester Research Fund, a CA42568 grant from the National Cancer Institute, a grant from Mrs. Harry J. Duffey, and a grant from Dr. and Mrs. William Lake. PAC is the George S. and Dolores Doré Professor of Ophthalmology.
Accepted for publication August 5, 1998.
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References |
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A. Ando, A. Yang, H. Nambu, and P. A. Campochiaro Blockade of Nitric-Oxide Synthase Reduces Choroidal Neovascularization Mol. Pharmacol., September 1, 2002; 62(3): 539 - 544. [Abstract] [Full Text] [PDF]
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K. Mori, P. Gehlbach, A. Ando, D. McVey, L. Wei, and P. A. Campochiaro Regression of Ocular Neovascularization in Response to Increased Expression of Pigment Epithelium-Derived Factor Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2428 - 2434. [Abstract] [Full Text] [PDF]
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K. Mori, P. Gehlbach, S. Yamamoto, E. Duh, D. J. Zack, Q. Li, K. I. Berns, B. J. Raisler, W. W. Hauswirth, and P. A. Campochiaro AAV-Mediated Gene Transfer of Pigment Epithelium-Derived Factor Inhibits Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., June 1, 2002; 43(6): 1994 - 2000. [Abstract] [Full Text] [PDF]
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C.-C. Lai, W.-C. Wu, S.-L. Chen, X. Xiao, T.-C. Tsai, S.-J. Huan, T.-L. Chen, R. J.-F. Tsai, and Y.-P. Tsao Suppression of Choroidal Neovascularization by Adeno-associated Virus Vector Expressing Angiostatin Invest. Ophthalmol. Vis. Sci., September 1, 2001; 42(10): 2401 - 2407. [Abstract] [Full Text] [PDF]
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K. Mori, A. Ando, P. Gehlbach, D. Nesbitt, K. Takahashi, D. Goldsteen, M. Penn, C. T. Chen, K. Mori, M. Melia, et al. Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin Am. J. Pathol., July 1, 2001; 159(1): 313 - 320. [Abstract] [Full Text] [PDF]
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V. LAMBERT, C. MUNAUT, A. NOEL, F. FRANKENNE, K. BAJOU, R. GERARD, P. CARMELIET, M. P. DEFRESNE, J.-M. FOIDART, and J.-M. RAKIC Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization FASEB J, April 1, 2001; 15(6): 1021 - 1027. [Abstract] [Full Text] [PDF]
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N. Kwak, N. Okamoto, J. M. Wood, and P. A. Campochiaro VEGF Is Major Stimulator in Model of Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., September 1, 2000; 41(10): 3158 - 3164. [Abstract] [Full Text]
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K. Spilsbury, K. L. Garrett, W.-Y. Shen, I. J. Constable, and P. E. Rakoczy Overexpression of Vascular Endothelial Growth Factor (VEGF) in the Retinal Pigment Epithelium Leads to the Development of Choroidal Neovascularization Am. J. Pathol., July 1, 2000; 157(1): 135 - 144. [Abstract] [Full Text] [PDF]
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 P. Parsons-Wingerter, K. E. Elliott, J. I. Clark, and A. G. Farr Fibroblast Growth Factor-2 Selectively Stimulates Angiogenesis of Small Vessels in Arterial Tree Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1250 - 1256. [Abstract] [Full Text] [PDF]
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M. S. Seo, N. Kwak, H. Ozaki, H. Yamada, N. Okamoto, E. Yamada, D. Fabbro, F. Hofmann, J. M. Wood, and P. A. Campochiaro Dramatic Inhibition of Retinal and Choroidal Neovascularization by Oral Administration of a Kinase Inhibitor Am. J. Pathol., June 1, 1999; 154(6): 1743 - 1753. [Abstract] [Full Text] [PDF]
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