December 2017
Volume 58, Issue 14
Open Access
Review  |   December 2017
Animal Models of Retinal Vein Occlusion
Author Affiliations & Notes
  • Meiaad Khayat
    Wellcome-Wolfson Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, United Kingdom
    Department of Anatomy, College of Medicine–Rabigh Branch, King Abdulaziz University, Jeddah, Saudi Arabia
  • Noemi Lois
    Wellcome-Wolfson Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, United Kingdom
  • Michael Williams
    Centre for Medical Education, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, United Kingdom
  • Alan W. Stitt
    Wellcome-Wolfson Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, United Kingdom
  • Correspondence: Noemi Lois, Wellcome-Wolfson Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, BT9 7AE, Belfast, United Kingdom; n.lois@qub.ac.uk
Investigative Ophthalmology & Visual Science December 2017, Vol.58, 6175-6192. doi:10.1167/iovs.17-22788
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      Meiaad Khayat, Noemi Lois, Michael Williams, Alan W. Stitt; Animal Models of Retinal Vein Occlusion. Invest. Ophthalmol. Vis. Sci. 2017;58(14):6175-6192. doi: 10.1167/iovs.17-22788.

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Abstract

Purpose: To provide a comprehensive and current review on the available experimental animal models of retinal vein occlusion (RVO) and to identify their strengths and limitations with the purpose of helping researchers to plan preclinical studies on RVO.

Methods: A systematic review of the literature on experimental animal models of RVO was undertaken. Medline, SCOPUS, and Web of Science databases were searched. Studies published between January 1, 1965, and March 31, 2017, and that met the inclusion criteria were reviewed. The data extracted included animal species used, methods of inducing RVO, and the clinical and histopathologic features of the models, especially in relation to strengths, limitations, and faithfulness to clinical sequelae.

Results: A total of 128 articles fulfilling the inclusion criteria were included. Several species were used to model human branch and central RVO (BRVO; CRVO) with nonhuman primates being the most common, followed by rodents and pigs. BRVO and CRVO were most commonly induced by laser photocoagulation and all models showed early features of clinical disease, including retinal hemorrhages and retinal edema. These features made many of the models adequate for studying the acute phase of BRVO and CRVO, although macular edema, retinal ischemia, and neovascular complications were observed in only a few experimental animal models (laser-induced model in rodents, pigs, and nonhuman primates, diathermy-induced model in pigs, and following intravitreal injection of PD0325901 in rabbits for BRVO; and in the laser-induced model in rodents, rabbits, and nonhuman primates, diathermy-induced model in nonhuman primates, following permanent ligation of the central retinal vein in nonhuman primates, and with intravitreal injection of thrombin in rabbits for CRVO).

Conclusions: Experimental animal models of RVO are available to study the pathogenesis of this disease and to evaluate diagnostic/prognostic biomarkers and to develop new therapeutics. Data available suggest laser-induced RVO in pigs and rodents to be overall the best models of BRVO and the laser-induced RVO rodents the best model for CRVO.

Retinal vein occlusion (RVO) is the second most common vascular cause of visual loss, surpassed only by diabetic retinopathy.15 Obstruction of the retinal venous system is commonly caused by thrombus formation, which may result in devastating consequences, including macular edema and neovascular complications, leading to visual impairment and blindness.1,614 RVO has been typically classified into central (CRVO), branch (BRVO), hemicentral and hemispheric types based on the site of the occlusion.1,2,4,5,1517 Each of these RVO types has been further subclassified into ischemic and nonischemic forms based on the severity of the disease and the likelihood of developing neovascular complications. Ischemic RVO (iRVO) is the most severe form, associated with higher risk of complications and having a poorer prognosis than non-iRVO.1,2,4,15,17,18 
Current treatments of RVO, including laser photocoagulation, intravitreal anti-VEGF therapies, intravitreal steroids, and pars plana vitrectomy, target the complications of RVO, namely macular edema and neovascularization and its consequences,1,5,7,16,17,1924 and may not fully reverse the functional and structural damage result of the disease.10,2559 Furthermore, each of these treatments carries a risk to patients, such as destruction of the retina following laser photocoagulation, endophthalmitis following intravitreal injections, and cataract and glaucoma as a result of steroid administration. Treatments for macular edema that are a result of RVO have been predominantly investigated for the nonischemic form, with most randomized clinical trials excluding or including only few with the iRVO.35,39,40,45,47,5255,60 In trials in which they have been included, only approximately 50% or less of patients with iRVO show a meaningful improvement in visual acuity following these therapies,34,37,38,45,4851,57 with often poor final visual acuity (≤ 20/100) despite treatment.10,34,3638,41,43,51,57 
Further research is still needed to improve current understanding of the pathogenesis of RVO as well as to identify more clinically effective and cost-effective therapeutic options. This is especially true for patients with iRVO. 
Experimental animal models often can be useful to study disease mechanisms and to test the efficacy and potential toxicity of new treatments. Such animal approaches have been successful in ophthalmic research, allowing advancement in our understanding of pathogenesis and development of improved novel therapies.6166 Experimental animal models of RVO also are available, which variably develop functional and structural features resembling those present in people with this disorder. Herein, we aim at providing a comprehensive up-to-date review on experimental animal models of RVO including species, methods of vessel occlusion, their clinico-histopathologic features, and the limits of their translational value. Taken together, this focused and in-depth review ought to help researchers design future studies and appreciate the strengths and weaknesses of the animal models they use. 
Methods
A systematic review of the literature was conducted, and data sources were Medline, SCOPUS, and Web of Science databases. Keywords including “retinal vein occlusion,” “retinal vein thrombosis,” and “retinal vein obstruction” were combined with “experimental models” or “animal models.” The search covered published articles from January 1, 1965, to March 31, 2017, and was filtered to include articles in English only. The included articles of studies describing methods of creating animal models of RVO and their findings were analyzed, and data contained in these articles were used to inform species-specific model systems, the range of methods for inducing vein occlusion, pathologic and clinical features developed in these models, and strengths and limitations of available models. The information extracted was used to populate Tables 1 through 8 of this review. In addition, their clinical value and potential translational implications for the management of patients with this disorder was considered. Changes on levels of cytokines/chemokines/growth factors and other biochemical and molecular events occurring as a result of the induction or RVO in these models, as well as effects of treatments tested in these animal models are beyond the scope of this review and, thus, are not summarized herein. 
Table 1
 
Animal Species and Techniques Used to Induce BRVO
Table 1
 
Animal Species and Techniques Used to Induce BRVO
Results
Studies Included
After removal of duplicates, a total of 320 titles were identified and their abstracts obtained and evaluated for potential inclusion in the review. Of the 320 abstracts, 193 were found to relate to studies outside the scope of this review and, thus, were excluded. Full articles of the remaining 128 studies were obtained, found to be directly related to the topic of this review, and used to extract pertinent data. 
Species
Several animal species have been used to study RVO, including rodents,67100 rabbits,101114 cats,115124 dogs,125127 pigs,128156 and nonhuman primates82,111,129,157196 (Tables 1, 2). Each of these species has its own size and anatomic advantages, but also ethical challenges and cost implications; these have been summarized in Table 3. Although the retina and retinal vessels of these animals share many anatomic features with humans, differences still exist and are more pronounced in some species (Table 4). None of the animal models, with the exception of the nonhuman primate, have an anatomic macula or fovea centralis.197 Pigs,198202 cats,201,203 and dogs198,204 have a central retinal area with high density of ganglion cells and cone photoreceptors known as area centralis, which would correspond to the fovea centralis in humans but is less specialized and cannot be identified by gross fundus examination.198,204 Unlike primates, the posterior segment of eyes of cats205208 and dogs207209contains a reflective tapetum layer, which serves to intensify vision in dim light, and may affect the functional results when compared with humans.205208 With the exception of the rabbit, all above-mentioned animals, like humans, have a holangiotic retinal vasculature (i.e., vessels emerge from the optic disc and ramify, distributing over the entire retina).210213 Rabbits, in contrast, have a merangiotic retinal vascular pattern (i.e., vessels are not distributed all over the retina), by which the main temporal and nasal retinal vessels extend horizontally from the optic disc to the sides, giving smaller branches to form two wing-shaped vascularized areas and leave the rest of the retina avascular.211,214,215 Some animals, namely pigs,212,213 dogs,210 and cats,211 do not have a single central retinal artery; instead, they have multiple retinal arteries entering the retina at the margin of the optic disc. Furthermore, cats do not have a single central retinal vein but multiple veins instead.211 Unlike humans and other species that normally have relatively straight retinal vessels (i.e., nontortuous), retinal vessels of dogs normally have various degrees of tortuosity.210 Pigs are similar to humans in that they have an intraretinal arrangement of retinal capillaries,212 as well as comparable scleral thickness, which makes them ideal for transscleral surgical or drug-delivery approaches.200 
Table 2
 
Animal Species and Techniques Used to Induce CRVO
Table 2
 
Animal Species and Techniques Used to Induce CRVO
Table 3
 
Advantages and Inconveniences of Species Used as Animal Models of RVO
Table 3
 
Advantages and Inconveniences of Species Used as Animal Models of RVO
Table 4
 
Similarities and Differences of Retina and Retinal Vasculature of the Different Animal Species Used in RVO Studies
Table 4
 
Similarities and Differences of Retina and Retinal Vasculature of the Different Animal Species Used in RVO Studies
Generally, of all species used, nonhuman primates were found to have the closest ocular anatomy to the human eye,210 followed by pigs. Unsurprisingly, this makes them superior choices to most other species, especially when considering only their retina and retinal vessel anatomy. 
Methods of Inducing RVO
Several techniques have been used to induce an RVO in experimental animals. These have been summarized, including their advantages and disadvantages, in Table 5. In most cases, experimental RVO has been induced by traumatizing one or more retinal veins using laser photocoagulation.6775,8092,96,97,101,104111,115118,125127,129147,156167,174,176194,216 
Table 5
 
Advantages and Disadvantages of the Different Methods Used to Induce RVO
Table 5
 
Advantages and Disadvantages of the Different Methods Used to Induce RVO
Branch Retinal Vein Occlusion
Experimentally, BRVO has been produced by using laser photocoagulation,70,80,89,96,97,100,105,127,132,142,146,156,176,178,181,216 photodynamic coagulation,9395,112,119,148,149 diathermic cauterization,75,120124,150152 or intravitreal injection of PD032590.114 
Laser Photocoagulation
In this method, laser irradiation is performed on selected retinal veins to produce BRVO.70,80,89,96,97,100,105,127,132,142,146,156,176,178,181,216 Classically, burns are placed approximately 0.5 to 2.0 disc areas from the optic disc, avoiding damage to the retinal arteries.69,70,74,80,81,92,97,99,117,186,217 Laser photocoagulation is typically done on the slit-lamp using a contact lens.6872,74,8183,86,8892,97,99,100,104,108,117,126,132,134,135,137,139,141,186,187,192194,196 Some studies have combined laser photocoagulation with vitrectomy.147,176178 Different types of laser and wavelengths have been used, commonly 514-nm Argon, and their parameters varied depending on the type of laser used, type of animal, and use or not of adjuvants (Table 6). Photosensitizers, such as Rose Bengal,6770,73,81,89,96,99101,104,106,107,109,110,126,127,132,134,135,137,139,141,143,146,147,217 erythrosin B,74 sodium fluorescein,71,83,85,86,88,97,142,175,187,190194,218 chloroaluminium sulfonated phthalocyanine,105 PAD-S31,186 and mono-L-aspartyl chlorin e6 (NPe6)82 have been commonly used with the laser photocoagulation to minimize the amount of the laser energy required to produce the RVO. Rose Bengal has been the most commonly used photosensitizer,6770,73,81,89,96,99101,104,106,107,109,110,126,127,132,134,135,137,139,141,143,146,147,217 whereby the dye is infused systemically (10–50 mg/kg) and the retinal vessels are exposed to highly focused laser irradiation.6770,73,81,89,96,99,101,104,106,107,109,110,126,127,132,134,135,137,139,141,143,146,147,217 Combination of intravitreal injection of thrombin (50 units) and laser photocoagulation has also been reported. Endophotocoagulation has also been used to achieve a vein occlusion; for this technique, an endolaser probe is inserted into the eye through a sclerostomy (without removing the vitreous) and retinal veins are then photocoagulated until evidence of occlusion is seen.146,147 
Table 6
 
Parameters of Laser Photocoagulation Used in the Different Animal Models
Table 6
 
Parameters of Laser Photocoagulation Used in the Different Animal Models
Photodynamic Therapy
Photodynamic coagulation is another method that has been used to induce BRVO.9395,112,119,148,149 This method involves light illumination using a slit-lamp and a contact lens, or an endo illuminator in combination with vitrectomy aiming at selected retinal vein or veins, with care not to damage retinal arteries, for a duration ranging between 6 and 20 minutes until evidence of venous occlusion is observed.9395,112,119,148,149 Photosensitizers, such as Rose Bengal,9395,112,119,148,149 sodium fluorescein,119 and NPe6,82 have been used in different doses depending on the species used to facilitate thrombus formation. 
Diathermic Cauterization
An alternative way to produce experimental BRVO is by using diathermy, which has been undertaken via a pars plana sclerotomy.75,120124,150152 In cats, BRVO has been induced with indirect ophthalmoscopy and 20-gauge bipolar diathermy that is applied to the targeted vein/veins for 5 seconds.120124 In pigs, a technique has been described that produces a BRVO following a temporal canthotomy, conjunctival incision, and performance of three sclerotomies at 10, 2, and 5 o'clock, 2 mm posterior to the corneal limbus.150153 In this method, a light source and a blunt bipolar diathermy probe are inserted into the vitreous and one or two major retinal veins are coagulated approximately 1 disc diameter away from the optic disc for 5 to 7 seconds after 5 seconds of compression and under direct view through an operating microscope and with the aid of a fundus contact lens.150153 This procedure does not involve vitrectomy.150153 
Intravitreal Injection of Substances
PD0325901 (N-[2,3-dihyroxy-propoxy]-3,4-difluoro-2-[fluoro-4-iodo-phenylamino]-benzamide) is a mitogen-activated protein kinase inhibitor that has been used in clinical trials for the treatment of solid tumors and has been found to be associated with development of BRVO. Based on this, one study established a rabbit model of BRVO by a single intravitreal injection of PD0325901 (0.5 or 1.0 mg per eye) using a 27-gauge needle inserted approximately 3 mm posterior to the limbus at the superior temporal quadrant and advanced until into the midvitreous cavity.114 
Central Retinal Vein Occlusion
CRVO has been produced by laser photocoagulation,6775,101,111,157167 diathermic cauterization,168170,172,195 permanent ligation of the central retinal vein,174 transient clamping/ligation of the optic nerve,7679 or intravitreal injection of thrombin,102,219 NPe6,103 or endothelin-1 (ET-1).113 
Laser Photocoagulation
In this method, all major branches are irradiated with laser to produce CRVO,6775,101,111,142,157167 classically 0.5 to 2.0 disc areas from the optic disc, avoiding damaging the retinal arteries.69,70,74,80,81,92,97,99,117,186,217 Similar to BRVO, laser photocoagulation is typically done on the slit-lamp using a contact lens.6872,74,8183,86,8892,97,99,104,108,117,126,132,134,135,137,139,141,186,187,192194,196 with or without vitrectomy.147,176178 Different types of laser, wavelengths, and photosensitizers have been used.6771,73,74,81,83,85,86,88,89,96,97,99,101,104107,109,110,126,127,132,134,135,137,139,141143,146,147,166,175,186,187,190194,217,218,220 In one study, a through-and-through suture was placed in the cornea, in addition to the laser photocoagulation in nonhuman primate models, to create an aqueous leak and subsequent hypotony to produce iris neovascularization.166 
Diathermic Cauterization
Diathermic cauterization of the central retinal vein has been achieved through a lateral orbitotomy approach in nonhuman primates to produce CRVO.168170,172,195 In this method, diathermy is applied at the central retinal vein on the inferiomedial aspect of the optic nerve as it exits the optic nerve sheath, avoiding injury to the ciliary vessels.168170,172,195 
Mechanical Ligation
  •  
    Permanent ligation of central retinal vein: Mechanical ligation of the central retinal vein was used in nonhuman primates to produce CRVO in one study.174 Through a lateral orbital approach and using the operating microscope to aid visualization and achieve adequate magnification, the central retinal vein was identified and ligated using an 8–0 silk suture. Two approaches were then used to achieve a CRVO: (1) a small incision was made proximal to the suture and neoprene was introduced through a cannula into the central retinal vein where it solidified, or (2) the central retinal vein was cut after ligation.174
  •  
    Transient ligation or clamping of the optic nerve: Transient ligation/clamping (60–120 minutes) of the optic nerve using a lateral orbital approach has been used also to produce CRVO in rats and in pigs.7679 This method, however, included the ciliary vessels and the central retinal artery and, thus, not reproducing an isolated CRVO.
Intravitreal Injection of Substances
  •  
    Thrombin: A different CRVO model, the Hirosaki model, was developed in rabbits as described in one study.102 Based on the premise that the extrinsic coagulation mechanism can be triggered by thromboplastin in the perivascular connective tissues, CRVO was successfully created through the intravitreal injection of thrombin over the wall of the rabbit's retinal veins (thrombin solution 0.01 mL [5 units]) under direct vision using a 27-gauge needle. A Goldmann contact lens and operational microscope were used to view the fundus.102
  •  
    NPe6: Another animal model of CRVO, also in rabbits, described in one study, involved an intravitreal injection of a hydrophilic photosensitizer, mono-L-aspartyl chlorin e6 (NPe6) (50 and 100 μg). In this model, there was no direct exposure to a light source, instead the animals were naturally exposed to the daily light-dark cycle. The injection was performed approximately 2 to 3 mm posterior to the limbus using a 30-gauge needle and a 1-mL syringe.103 In this particular model, CRVO, central retinal artery occlusion, and various degrees of vitreous hemorrhage developed after 1 week following injection.103
  •  
    ET-1: ET-1 is a peptide with vasoconstrictive properties normally produced by vascular endothelial cells.113 Intravitreal injection of 1000 pmol of ET-1 solution over the disc, as observed by ophthalmoscope, using a 29-gauge needle and a 1-mL syringe was used to induce CRVO in rabbits in one study.113 In this model, the occlusion lasted only 50 to 70 minutes.113
Clinical and Histopathologic Features of RVO Models
Clinical and/or histopathologic features observed in animal models of BRVO and CRVO were described in 89 and 38 articles, respectively, identified in our search. Macular edema has been addressed in only 4 of 21 studies on nonhuman primate models of BRVO, all laser-induced180,186,190,193and in only 2 of 21 studies in nonhuman primate models of CRVO, both diathermy-induced.170,195 Ischemia, defined by development of neovascular complications, extensive areas of capillary nonperfusion (capillary dropout), or both, or capillary nonperfusion associated with atrophy/cell loss of the inner retinal layers, has been reported in 28 of 89 studies in laser-induced BRVO models of rodents (n = 8),80,83,85,89,90,92,96,97 pigs (n = 6),130134,154 and nonhuman primates (n = 13)175,176,178181,184,187190,192,193; PD0325901-induced BRVO models of rabbits (n = 1) 114; and in 16 of 38 studies in laser-induced CRVO models in rodents (n = 4),6769,74 rabbits (n = 1),101 and nonhuman primates (n = 9),157160,162166 in permanent ligation of central retinal vein CRVO models in nonhuman primates (n = 1),174 and in thrombin-induced CRVO models in rabbits (n = 1).102 The features described in this section, unless otherwise specified, do not refer to the changes observed at the site of the occlusion and caused by the procedure used to create the RVO itself, but rather those result of the vein occlusion. 
All models showed early features classically observed in human BRVO and CRVO, including cessation of blood flow and venous dilation, engorgement, and tortuosity distal to the occlusion site. Moreover, all models, except the ET-1–induced CRVO, showed retinal hemorrhages and various degrees of retinal edema, which were commonly observed within the first 48 hours of RVO induction,67,70,74,75,80,8385,89,90,93,9699,102,104,108,115,120122,124129,132,133,137,139,145,148152,155157,167,169,170,178,180,187,189,191,192,195,216,221 peaked at day 4,70,74,84,98 and resolved 7 to 28 days following occlusion.70,74,75,89,96,97,102,108,129,156,169,170,172,192,195,221 Various degrees of exudative retinal detachment developed in many eyes of laser-induced and diathermy-induced BRVO 67,74,80,85,89,96,97,105,115,121,124,126,132,186 and laser-induced CRVO eyes.67,70,174 Bullous retinal detachment also was observed in many models that resolved spontaneously during follow-up.67,70,74,83,85 Changes in the thickness of the overall retina and individual retinal layers as a result of the edema (thickening) or ischemia (thinning) were evaluated mainly by histopathology70,74,76,8992,94,95,114,121,129,131133,151,154,169,174,179,187,189,190,192; in five studies, optical coherence tomography (OCT) was used also for this purpose.75,80,90,91,100 Both CRVO and BRVO models showed significant increase in the thickness of the inner retinal layers 1 to 4 days postinduction, followed by gradual reduction over time, with follow-up periods ranging between 7 and 28 days. In many models, retinal thickness was reduced during the follow-up to values below those detected at baseline (atrophic thinning); this was observed at 7 to 14 days from RVO induction.75,80,90,91,100 
Branch Retinal Vein Occlusion
Macular Edema
Macular edema in the nonhuman primate models was observed as early as 1 to 6 hours following venous occlusion190,193 and became prominent at 7 to 9 days postocclusion.180,193 It was found in up to 100% of treated eyes in one of the four studies on nonhuman primate models that described macular edema in induced BRVO (see above).180 Both intracellular neural and extracellular edema were reported.190,193 The edema was mainly observed in the nerve fiber layer and outer plexiform layer.190,193 Capillaries adjacent to the extracellular edema often appeared shrunken or compressed.190 In addition, macular edema was often associated with photoreceptor cell loss, which persisted after resolution of macular edema.180,186,193 Spontaneous resolution of macular edema occurred in all occluded eyes between 14 days and 2 year after laser photocoagulation clinically.180,186,190,193 In one study, histopathologic examination of six eyes at 48 months showed cystic spaces in the outer plexiform layer in four of six eyes.180 
Retinal Capillary Nonperfusion and Reperfusion
Various degrees of capillary nonperfusion in laser-induced, diathermy-induced, and PD0325901-induced models of BRVO were reported.70,74,80,85,89,92,97,100,132,133,150,175,179,180,189,191193,221,222 Areas of capillary nonperfusion were observed as early as 3 days following venous occlusion85,89 and found to progress with time.179,192 Extensive or severe areas of capillary nonperfusion were prominent 1 to 4 weeks following vein occlusion132,187,192,222 and were observed in up to 75% of eyes.96,133,221 The areas of capillary nonperfusion persisted during the follow-up, which ranged between 1 and 20 weeks, despite reperfusion.70,80,85,89,92,96,97,132,133,150,175,179,189,191193,221,222 Reperfusion in these models was either by recanalization/reopening of the occluded vessels in some or all eyes,70,80,85,89,90,92,93,9597,104,105,110,112,115,120,126,129,132,133,137,186,187,222 or development of collateral vessels.85,89,92,96,104,105,120,121,124,129,133,139,175,179,180,183,187,189,192,221,222 Recanalization was observed in 0% to 100% of eyes of BRVO models 1 to 14 days following induction.70,80,85,89,92,93,9597,104,105,110,112,126,129,132,137,186,221 Collateral vessels were prominent 5 to 14 days following establishment of the RVO92,129,179,180,192 (Tables 7, 8). 
Table 7
 
Clinical and Histopathologic Features of BRVO Animal Models
Table 7
 
Clinical and Histopathologic Features of BRVO Animal Models
Table 8
 
Clinical and Histopathologic Features of CRVO Animal Models
Table 8
 
Clinical and Histopathologic Features of CRVO Animal Models
Neovascular Complications
Posterior segment neovascularization occurred in some laser-induced BRVO models in rodents,83,89,96 pigs,132134,154,221,222 and nonhuman primates,175,188,189,192 but not in the other BRVO models. Retinal and/or disc neovascularization was observed in 8.3% of eyes as early as 7 days postocclusion,89 and in 60% to 70% of eyes 14 days following laser induction in rodent models.83,89 In laser-induced pig models, retinal and/or disc neovascularization were described in approximately 50% to 93% of eyes 3 to 4 weeks following RVO induction132,133,221,222 and up to 100% of eyes at 6 weeks.134,154 In laser-induced nonhuman primate models, 9% of eyes developed retinal neovascularization at 4 weeks.192 Anterior segment neovascularization was observed in laser-induced nonhuman primate models when three major branches were targeted.176,178,181,184 In this model, up to 100% of eyes developed iris neovascularization within the first 6 days of occlusion176,178,181,184 and 17% to 20% developed neovascular glaucoma within 25 days of follow-up.176,178 There was no spontaneous regression during follow-up of 28 to 84 days.136, 90 
Vascular Endothelial and Pericyte Cell Loss
Damage and loss of the vascular endothelial cells and pericytes was detected by histopathologic examination in experimental animal models of BRVO,90,107,120,187,190,193 which resulted in ghost acellular vessels with glial invasion179,187,193 observed as early as 1 to 48 hours postocclusion.120,190,193 Endothelial cell apoptosis was detected as early as 1 day postocclusion.90 Pericyte loss was observed 3 days following occlusion and significantly worsened at 7 days with 40% pericyte cell loss detected.90 
Retinal Atrophy
Atrophy (thinning/loss) of the inner retinal layers70,74,80,89,91,92,94,95,121,127,132,133,151,154,179,187,189,190,192,193,222 and replacement with glia151,187 has been reported. The loss of the inner retinal layers was first observed 3 days postocclusion80 and was marked at 7 to 28 days of follow-up.70,74,80,89,91,92,95,132,133,151,190,192 Damage of the outer retinal layers and loss of the photoreceptors was observed distal to the site of the occlusion in some eyes with laser-induced BRVO and ischemia at 3 to 6 weeks postocclusion.132,133,222 Photoreceptor cell loss was observed in 67% of eyes at 3 months following the occlusion180 Damage to the photoreceptors was reported in photodynamic-induced thrombosis in rats within 2 days of the occlusion, which was most likely related to the photodynamic therapy itself rather than the result of ischemia.112 Unspecified RPE changes were reported 4 weeks to 3 months following occlusion in laser-induced BRVO nonhuman primate models.152,180,192 
Functional Changes
When conducted, ERG studies showed reduction of the “a” and “b” wave amplitudes of both scotopic and photopic ERG at 1, 2, 3, 4, 6, and 7 days following laser-induced BRVO in rat models.80,100 In multifocal ERG, a significant decrease in the P1 and N1 amplitudes and prolonged implicit times in the affected retina were observed 4 weeks following thrombus formation in diathermy-induced BRVO in pig models.151,152 
Other Features
Other features also were observed in some eyes with experimental animal BRVO, such as cotton wool spots, detected at 3 days to 6 weeks in laser-induced nonhuman primate models,180,192 venous sheathing between 7 days and 3 months,125,127,129,152,192 microaneurysms 1 to 8 months,120,125 and reduction of preretinal oxygen saturation measured at different time points between 60 minutes and 3 weeks following occlusion.110,121,123,133,150,222 
Central Retinal Vein Occlusion
Macular Edema
Macular edema was observed as early as 48 hours following venous thrombosis in 14% to 66% of CRVO nonhuman primate models induced by diathermy.170,195 This had resolved spontaneously in all eyes 14 days following induction170,195 (Tables 7, 8). 
Capillary Nonperfusion and Reperfusion
Various degrees of capillary nonperfusion were reported in laser-induced, permanent ligation of the central retinal vein, and thrombin-induced CRVO models.69,108,157,158,162,174 In one of these studies, it was found to become extensive 2 to 4 weeks following the induction of CRVO and progressed to involve up to 75% of the retinal area 7 weeks postinduction of RVO by laser photocoagulation in 67% of eyes.157 In thrombin-induced CRVO in rabbits, extensive areas of retinal capillary nonperfusion were observed at 3 months following the occlusion.102 Recanalization or reopening of the occluded vessels was reported in many studies of laser-induced CRVO.70,74,108,111,157159 This was observed 1 to 21 days postocclusion70,74,108,111,159 in 6% to 80% of eyes.108,111,157,158 Collateral vessels also were reported in some eyes at 2 weeks to 2 months of follow-up following laser-induced and thrombin-induced CRVO.102,108,157 
Neovascular Complications
Neovascular complications were observed in laser-induced and thrombin-induced CRVO.68,69,74,102,157160,162166 Preretinal neovascularization was observed 1 to 3 weeks following laser photocoagulation in 17% to 90% of rats, with no spontaneous regression described.6769,74 In nonhuman primate models, however, posterior segment neovascularization was described in only one study, in which disc neovascularization was detected in 17% of eyes at 15 to 26 days postocclusion that resolved spontaneously at day 87,157 but not in other studies with follow-up periods ranging between 1 and 24 weeks.111,158,160,162167 Thrombin-induced CRVO in rabbits showed retinal neovascularization in 60% of eyes at 3 months following injection.102 Spontaneous regression of neovascularization in this model was not reported. Iris neovascularization was observed only in laser-induced nonhuman primate models.157160,162166 This was detected 4 to 22 days postocclusion159,160,162166 in up to 100% of eyes,157,163,166 with some having spontaneous regression 13 to 60 days following laser photocoagulation.157 Iris fluorescein leakage from iris new vessels was observed at 5 days of follow-up in 50% of eyes.157 Neovascular glaucoma developed in 18% to 33% of eyes in the laser-induced nonhuman primate model 12 to 21 days following occlusion.158,160 
Vascular Endothelial and Pericyte Cell Loss
Vascular endothelial and pericyte cell loss has not been described in experimental models of CRVO. 
Retinal Atrophy
Atrophic thinning of the inner retinal layers and cell loss was reported 7 to 21 days in rodents and rabbit models following laser photocoagulation70,74,75,101; 3 to 10 days in diathermy-induced nonhuman primate models, which was in this model associated with gliosis169; 3 to 7 days in nonhuman primate models of permanent ligation of the central retinal vein174; and 4 days in temporary (60 minutes) ligation of the optic nerve.76 These changes were not reversible in any of the models during the follow-up, which ranged from 1 to 6 weeks.70,7476,169,174 The ganglion cell loss in overall retina (central, midperipheral, and peripheral retinal regions) was reported to be approximately 11% at 7 days,74 30% to 31% at 14 days,70,74 and 40% at 21 days following laser-induced RVO in rodents.74 Atrophy of the outer nuclear layers distal to the site of laser photocoagulation was reported as early as 4 days following vein occlusion using laser photocoagulation in rodent models.70,74 RPE changes were observed in many of the CRVO models76,101,103,157,170 (Tables 7, 8). 
Functional Changes
Loss of retinal function in these models was confirmed with ERG studies that showed significant reduction of amplitudes in both scotopic and photopic ERG in laser-induced CRVO in rodents70 and temporary ligation of optic nerve in rodents.79 
Other Features
Disc hyperemia was observed within 48 hours in up to 100% of diathermy-induced CRVO in nonhuman primate models, which was secondary to the procedure rather than to the CRVO.168,195 
Strengths and Limitations of Available Animal Models
Although none of the animal RVO models described above develop all features occurring in human RVO, almost all models demonstrate the early characteristics of this disease, including retinal hemorrhages and edema, which may make them adequate models to study the acute phase of both BRVO and CRVO. Only a few models, however, developed macular edema (i.e., laser photocoagulation in BRVO nonhuman primate models and diathermy in CRVO nonhuman primate models) (Tables 7, 8),170,180,186,190,193,195 which makes the study of this particular feature difficult. 
Most animal models of RVO demonstrated spontaneous reperfusion and/or vascular remodeling, which seemed to occur more rapidly and effectively than in humans with RVO. As a result, persistent ischemic features failed to develop in most models, and iris neovascularization was not observed, except in laser-induced nonhuman primate models,157160,162166,176,178,181,184 making the study of the ischemic form of RVO more challenging. This might be attributed, even if partly, to the fact that the animals used for these studies were young and healthy, whereas patients with BRVO and CRVO are often older and many have underlying systemic risk factors, such as hypertension, dyslipidemia, dysfunctional thrombotic responses, or impaired glucose tolerance/diabetes, among others. The ischemic form of RVO, however, is the one that requires further research more urgently, given its very limited treatment options and often poorer outcomes. 
The laser-induced models of BRVO in rodents, pigs, and nonhuman primates and of CRVO in rodents and nonhuman primates were found to be the most successful at achieving nonperfusion and posterior segment neovascularization (see Tables 7, 8). The lack of ischemic features (i.e., extensive areas of retinal nonperfusion and/or neovascularization) being observed in other models may be attributed to the inadequate follow-up time in some of the studies or may be due to other factors such as the nature of the occlusion induced by the various techniques, including duration of the occlusion, and the timing and characteristics of the reperfusion that followed. There are still limitations of the models available that reproduce best retinal ischemia and neovascularization. For example, the laser-induced rodent model of BRVO and CRVO may pose difficulties due to the small size of the eye (Fig.), the large crystalline lens, and the thin and delicate sclera, which may make the undertaking of functional and imaging studies as well as therapeutic interventions challenging. The lack of a macula in many nonprimate models makes it impossible to study macular edema and, although as stated above the occlusion can be produced with high success (92%–100%, see Table 8), neovascularization occurs variably (60%–70% and 17%–90% in models of BRVO and CRVO, respectively). The laser-induced pig model of BRVO appears to be ideal due to anatomic similarities (see Table 4), including the presence of an area centralis, and the high success at achieving vein occlusion (93%–100%) and development of neovascularization (100%) in a relatively short period (6 weeks). Furthermore, the larger size of the eye in this model facilitates functional, structural, and interventional studies. Pigs are larger animals, posing other difficulties (see Tables 3, 5). Nonhuman primate models of laser-induced ischemic CRVO and BRVO best mimic the clinical and histopathologic features observed in humans; however, the use of this species carries major ethical considerations and other inconveniences, such as high cost (see Tables 3, 5) and are not available to most researchers. 
Figure
 
Fundus fluorescein angiogram obtained in a mouse eye immediately following induction of RVO with laser photocoagulation. Note an area of thinning in a retinal vein at the site of the attempted occlusion, but still presence of flow through the vein (arrow). An area of retinal edema blocking the view of the vein itself, which remains perfused, is also seen (arrowhead). Achieving a full occlusion of the vein is challenging in mice given that appropriate focusing of the laser beam, even the smallest available, on the very small retinal vein is difficult.
Figure
 
Fundus fluorescein angiogram obtained in a mouse eye immediately following induction of RVO with laser photocoagulation. Note an area of thinning in a retinal vein at the site of the attempted occlusion, but still presence of flow through the vein (arrow). An area of retinal edema blocking the view of the vein itself, which remains perfused, is also seen (arrowhead). Achieving a full occlusion of the vein is challenging in mice given that appropriate focusing of the laser beam, even the smallest available, on the very small retinal vein is difficult.
Although thrombin-induced CRVO rabbit models showed ischemic features, namely areas of capillary nonperfusion and development of retinal neovascularization in 60% of eyes,102 this feature was observed at or after 3 months, which makes the study of the neovascularization in this model time-consuming. In addition, the success rate of developing RVO in this model is as low as 43%,102 and there are not enough studies in the literature that would allow validating the findings in this model. Similarly, laser-induced iCRVO101 and PD0325901-induced iBRVO114 in rabbits do not have adequate supporting literature. 
Clinical Value of RVO Models
Although therapeutic strategies are available for people suffering from RVO, these are limited, and a relatively large proportion of patients still lose sight as a result, especially those with iRVO. Treatment is, at present, delivered only once complications (macular edema and neovascularization) have occurred. Thus, it is clear that advances in the management of people with RVO are much needed. Animal models of RVO have helped to better understand the pathogenic events taking place as a result of the disease as well as to trial new treatments. It is likely that several pathways may be implicated in the development and progression of the disease and that different compensatory responses may take place, which would explain the heterogeneity of the natural course and treatment responses observed in humans; experimental animal models of RVO have advanced the knowledge on this area. As retinal ischemia, macular edema, and anterior/posterior segment neovascularization are the major causes of visual loss due to RVO, experimental animal models that more reproducibly develop these complications would be expected to have the major translational potential. Understanding why reperfusion occurs more readily in experimental animal models of RVO when compared with humans with this disorder may provide important clues for the development of new therapeutic interventions. 
Conclusions
Several experimental animal models of RVO are available to study the pathogenesis and to test new diagnostic/prognostic/therapeutic interventions for this disease. Selecting the most appropriate ones, based on the information provided in this review, will allow researchers to better adhere to two of the three “Rs” of “reduction” and “refinement,” as “replacement” is not an option when understanding the complex events that take place in RVO. It will also help researchers in the development of new treatment modalities by allowing them to select those that mimic more closely the human disease, that develop its features more consistently and in shorter periods of time. This will subsequently reduce testing times and costs and will improve the planning and design of future, more successful studies as well as the potential for translation to clinical practice. 
Acknowledgments
The authors thank Paul Canning for kindly providing the illustration for this manuscript. 
Supported by the King Abdulaziz University and the Saudi Arabian Cultural Bureau in London (Grant Number R8384CEM), Elizabeth Sloan, and the Sir Jules Thorn Trust. 
Disclosure: M. Khayat, None; N. Lois, None; M. Williams, None; A.W. Stitt, None 
References
Buehl W, Sacu S, Schmidt-Erfurth U. Retinal vein occlusions. Dev Ophthalmol. 2010; 46: 54–72.
Hayreh SS. Retinal vein occlusion. Indian J Ophthalmol. 1994; 42: 109–132.
Jaulim A, Ahmed B, Khanam T, Chatziralli IP. Branch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature. Retina. 2013; 33: 901–910.
MacDonald D. The ABCs of RVO: a review of retinal venous occlusion. Clin Exp Optom. 2014; 97: 311–323.
Yau JWY, Lee P, Wong TY, Best J, Jenkins A. Retinal vein occlusion: an approach to diagnosis, systemic risk factors and management. Intern Med J. 2008; 38: 904–910.
Lim H, Kim M, Jo Y, Kim J. Prediction of retinal ischemia in branch retinal vein occlusion: spectral-domain optical coherence tomography study. Invest Ophthalmol Vis Sci. 2015; 56: 6622–6629.
Kiire CA, Chong NV. Managing retinal vein occlusion. BMJ. 2012; 344: e499.
Hayreh SS, Podhajsky PA, Zimmerman MB. Natural history of visual outcome in central retinal vein occlusion. Ophthalmology. 2011; 118: 119–133.e2.
McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2010; 117: 1113–1123.e15.
Leizaola-Fernández C, Suárez-Tatá L, Quiroz-Mercado H, et al. Vitrectomy with complete posterior hyaloid removal for ischemic central retinal vein occlusion: series of cases. BMC Ophthalmol. 2005; 5: 10.
Prisco D, Marcucci R. Retinal vein thrombosis: risk factors, pathogenesis and therapeutic approach. Pathophysiol Haemost Thromb. 2002; 32: 308–311.
Ikuno Y, Ikeda T, Sato Y, Tano Y. Tractional retinal detachment after branch retinal vein occlusion. Influence of disc neovascularization on the outcome of vitreous surgery. Ophthalmology. 1998; 105: 417–423.
Apostolopoulos M, Koutsandrea C, Chatjoulis D, Ladas J, Theodossiadis G. Late complications in branch retinal vein occlusion. Int Ophthalmol. 1996; 19: 281–285.
Hayreh SS, Rojas P, Podhajsky P. Ocular neovascularization with retinal vascular occlusion. III. Incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology. 1983; 90: 488–506.
Arunakirinathan M, Ting MAJ, Crawley L. Recognizing and managing retinal vein occlusion. Br J Hosp Med. 2014; 75: 8–12.
Ehlers JP, Fekrat S. Retinal vein occlusion: beyond the acute event. Surv Ophthalmol. 2011; 56: 281–299.
Rehak M, Wiedemann P. Retinal vein thrombosis: pathogenesis and management. J Thromb Haemost. 2010; 8: 1886–1894.
Wykoff CC, Brown DM, Croft DE, Major JCJ, Wong TP. Progressive retinal nonperfusion in ischemic central retinal vein occlusion. Retina. 2015; 35: 43–47.
Sivaprasad S, Amoaku WM, Hykin P. The Royal College of Ophthalmologists Guidelines on retinal vein occlusions: executive summary. Eye (Lond). 2015; 29: 1633–1638.
Yeh S, Kim SJ, Ho AC, et al. Therapies for macular edema associated with central retinal vein occlusion: a report by the American Academy of Ophthalmology. Ophthalmology. 2015; 122: 769–778.
Ford JA, Shyangdan D, Uthman OA, Lois N, Waugh N. Drug treatment of macular oedema secondary to central retinal vein occlusion: a network meta-analysis. BMJ Open. 2014; 4: e005292.
Edwards SJ, Barton S, Trevor N, Lois N, Nherera L, Hamilton V. Comparisons of the clinical effectiveness of treatments for macular oedema (MO) caused by retinal vein occlusion (RVO). Value Health. 2012; 15: A568.
Channa R, Smith M, Campochiaro PA. Treatment of macular edema due to retinal vein occlusions. Clin Ophthalmol. 2011; 5: 705–713.
Gewaily D, Muthuswamy K, Greenberg PB. Intravitreal steroids versus observation for macular edema secondary to central retinal vein occlusion. Cochrane Database Syst Rev. 2015; 9: CD007324.
Kjeka O, Jansson RW, Bredrup C, Krohn J. Early panretinal photocoagulation for ERG-verified ischaemic central retinal vein occlusion. Acta Ophthalmol. 2013; 91: 37–41.
Recupero SM, Perdicchi A, Scuderi GL, Amodeo S, Medori EM, Leonardi A. Visual acuity in central and branch vein retinal occlusion in the presence of macular edema: 1 year of follow-up. Ann Ophthalmol. 2006; 38: 107–110.
The Central Vein Occlusion Study Group N report. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. Ophthalmology. 1997; 102: 1434–1444.
Murdoch IE, Rosen PH, Shilling JS. Neovascular response in ischaemic central retinal vein occlusion after panretinal photocoagulation. Br J Ophthalmol. 1991; 75: 459–461.
Gomolin JE. Efficacy of panretinal photocoagulation in central retinal vein occlusion. Ophthalmologica. 1989; 199: 24–27.
Magargal LE, Brown GC, Augsburger JJ, Donoso LA. Efficacy of panretinal photocoagulation in preventing neovascular glaucoma following ischemic central retinal vein obstruction. Ophthalmology. 1982; 89: 780–784.
Laatikainen L, Kohner EM, Khoury D, Blach RK. Panretinal photocoagulation in central retinal vein occlusion: a randomised controlled clinical study. Br J Ophthalmol. 1977; 61: 741–753.
Hayreh S, Klugman M, Podhajsky P, Servais G, Perkins E. Argon laser panretinal photocoagulation in ischemic central retinal vein occlusion. A 10-year prospective study. Graefe's Arch Clin Exp Ophthalmol. 1990; 228: 281–296.
Noma H, Shimada K, Mimura T. Influence of retinal ischemia on macular function after pars plan vitrectomy for macular edema with branch retinal vein occlusion. Int Ophthalmol. 2013; 33: 677–686.
Parodi MB, Lacono P, Petruzzi G, Parravano M, Varano M, Bandello F . Dexamethasone implant for macular edema secondary to ischemic retinal vein occlusions. Retina. 2015; 35: 1387–1392.
Haller JA, Bandello F, Belfort RJ, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010; 117: 1134–1146.e3.
Noma H, Mimura T, Shimada K. Changes of macular sensitivity and morphology after pars plana vitrectomy for macular edema with central retinal vein occlusion: a case series. BMC Ophthalmol. 2013; 13: 1–7.
Chen SDM, Sundaram V, Lochhead J, Patel CK. Intravitreal triamcinolone for the treatment of ischemic macular edema associated with branch retinal vein occlusion. Am J Ophthalmol. 2006; 141: 876–883.
Ozdek SC, Aydin B, Gurelik G, Bahceci U, Hasanreisoglu B. Effects of intravitreal triamcinolone injection on macular edema and visual prognosis in central retinal vein occlusion. Int Ophthalmol. 2005; 26: 27–34.
Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009; 127: 1101–1114.
Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009; 127: 1115–1128.
Priglinger SG, Wolf AH, Kreutzer TC, et al. Intravitreal bevacizumab injections for treatment of central retinal vein occlusion: six-month results of a prospective trial. Retina. 2007; 27: 1004–1012.
Ramezani A, Esfandiari H, Entezari M, et al. Three intravitreal bevacizumab versus two intravitreal triamcinolone injections in recent-onset branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2012; 250: 1149–1160.
Ramezani A, Esfandiari H, Entezari M, et al. Three intravitreal bevacizumab versus two intravitreal triamcinolone injections in recent onset central retinal vein occlusion. Acta Ophthalmol. 2014; 92: e530–e539.
Clark WL, Boyer DS, Heier JS, et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion 52-week results of the VIBRANT study. Ophthalmology. 2016; 123: 330–336.
Campochiaro PA, Clark WL, Boyer DS, et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the VIBRANT study. Ophthalmology. 2015; 122: 538–544.
Ogura Y, Roider J, Korobelnik J, et al. Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18-month results of the phase 3 GALILEO study. Am J Ophthalmol. 2014; 158: 1032–1038.
Holz FG, Roider J, Ogura Y, et al. VEGF trap-eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013; 97: 278–284.
Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013; 155: 429–437.e7.
Tadayoni R, Waldstein SM, Boscia F, et al. Individualized stabilization criteria-driven ranibizumab versus laser in branch retinal vein occlusion. Ophthalmology. 2016; 123: 1332–1344.
Larsen M, Waldstein SM, Boscia F, et al. Individualized ranibizumab regimen driven by stabilization criteria for central retinal vein occlusion: twelve-month results of the CRYSTAL study. Ophthalmology. 2016; 123: 1101–1111.
Brown DM, Wykoff CC, Wong TP, et al. Ranibizumab in preproliferative (ischemic) central retinal vein occlusion: the rubeosis anti-VEGF (RAVE) trial. Retina. 2014; 34: 1728–1735.
Pielen A, Mirshahi A, Feltgen N, et al. Ranibizumab for branch retinal vein occlusion associated macular edema study (RABAMES): six-month results of a prospective randomized clinical trial. Acta Ophthalmol. 2015; 93: e29–e37.
Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010; 117: 1102–1112.e1.
Kinge B, Stordahl PB, Forsaa V, et al. Efficacy of ranibizumab in patients with macular edema secondary to central retinal vein occlusion: results from the sham-controlled ROCC study. Am J Ophthalmol. 2010; 150: 310–314.
Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010; 117: 1124–1133.e1.
Tomomatsu Y, Tomomatsu T, Takamura Y, et al. Comparative study of combined bevacizumab/targeted photocoagulation vs bevacizumab alone for macular oedema in ischaemic branch retinal vein occlusions. Acta Ophthalmol. 2016; 94: e225–e230.
Parodi M, Stefano G, Ravalico G. Grid laser treatment for exudative retinal detachment secondary to ischemic branch retinal vein occlusion. Retina. 2008; 28: 97–102.
The Central Vein Occlusion Study Group M report. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. Ophthalmology. 1995; 102: 1425–1433.
The Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol. 1984; 98: 271–282.
Beutel J, Ziemssen F, Luke M, et al. Intravitreal bevacizumab treatment of macular edema in central retinal vein occlusion: one-year results. Int Ophthalmol. 2010; 30: 15–22.
Minhas G, Anand A. Animal models of retinal ischaemia. In: Agarwal A, ed. Brain Injury - Pathogenesis, Monitoring, Recovery and Management. 1st ed. Rijeka: InTech; 2012: 153.
Pang I, Clark AF. Animal Models for Retinal Diseases. 1st ed. New York: Humana Press; 2010.
Fletcher EL, Jobling AI, Vessey KA, Luu C, Guymer RH, Baird PN. Animal models of retinal disease. Prog Mol Biol Transl Sci. 2011; 100: 211–286.
Iwata T. Animal models for eye diseases. In: Hau J, Schapiro S, eds. Handbook of Laboratory Animal Science. 3rd ed. New York: CRC Press; 2013: 195.
Chan CC. Animal Models of Ophthalmic Diseases. 1st ed. London: Springer International Publishing; 2016.
Niwa M, Aoki H, Hirata A, Tomita H, Green PG, Hara A. Retinal cell degeneration in animal models. Int J Mol Sci. 2016; 17: e110.
Ham DI, Chang K, Chung H. Preretinal neovascularization induced by experimental retinal vein occlusion in albino rats. Korean J Ophthalmol. 1997; 11: 60–64.
Lai CC, Wu WC, Chuang LH, Yeung L, Wei W, Yang KJ. Quantitative grading of preretinal neovascularization in adults rats. Acta Ophthalmol Scand. 2005; 83: 590–594.
Lai CC, Wu WC, Chen SL, et al. Recombinant adeno-associated virus vector expressing angiostatin inhibits preretinal neovascularization in adult rats. Ophthalmic Res. 2005; 37: 50–56.
Zhang Y, Fortune B, Atchaneeyasakul LO, et al. Natural history and histology in a rat model of laser-induced photothrombotic retinal vein occlusion. Curr Eye Res. 2008; 33: 365–376.
Drechsler F, Koferl P, Hollborn M, et al. Effect of intravitreal anti-vascular endothelial growth factor treatment on the retinal gene expression in acute experimental central retinal vein occlusion. Ophthalmic Res. 2012; 47: 157–162.
Rehak M, Drechsler F, Koferl P, et al. Effects of intravitreal triamcinolone acetonide on retinal gene expression in a rat model of central retinal vein occlusion. Graefe's Arch Clin Exp Ophthalmol. 2011; 249: 1175–1183.
Du ZJ, Yamamoto T, Ueda T, Suzuki M, Tano Y, Kamei M. Activated protein c rescues the retina from ischemia-induced cell death. Invest Ophthalmol Vis Sci. 2011; 52: 987–993.
Chen W, Wu Y, Zheng M, Gu Q, Zheng Z, Xia X. Establishing an experimental rat model of photodynamically-induced retinal vein occlusion using erythrosin B. Int J Ophthalmol. 2014; 7: 232–238.
Shan L, Zheng M, Zhang Y, et al. Correlation of vascular endothelial growth factor production with photochemical reaction-induced retinal edema. Chin Med J (Engl). 2016; 129: 2944–2950.
Stefansson E, Wilson C, Schoen T, Kuwabara T. Experimental ischemia induces cell mitosis in the adult rat retina. Invest Ophthalmol Vis Sci. 1988; 29: 1050–1055.
Ohira A, de Juan EJr, Tano Y, Wilson CA. Immunohistochemical distribution of basic fibroblast growth factor in experimental retinal ischaemia and reperfusion in the rat. Histochem J. 1996; 28: 607–611.
Lu N, Shimura M, Kinukawa Y, Yoshida M, Tamai M. Quantitative analysis of leukocyte dynamics in retinal microcirculation of rats with short-term ischemia-reperfusion injury. Curr Eye Res. 1999; 19: 403–410.
Miyaki K, Matsubara A, Nishiwaki A, et al. Pitavastatin attenuates leukocyte-endothelial interactions induced by ischemia-reperfusion injury in the rat retina. Curr Eye Res. 2009; 34: 10–17.
Sun C, Li XX, He XJ, Zhang Q, Tao Y. Neuroprotective effect of minocycline in a rat model of branch retinal vein occlusion. Exp Eye Res. 2013; 113: 105–116.
Kang SG, Chung H, Hyon JY. Experimental preretinal neovascularization by laser-induced thrombosis in albino rats. Korean J Ophthalmol. 1999; 13: 65–70.
Peyman GA, Kazi AA, Moshfeghi D, et al. Threshold and retreatment parameters of NPe6 photodynamic therapy in retinal and choroidal vessels. Ophthalmic Surg Lasers. 2000; 31: 323–327.
Saito Y, Park L, Skolik SA, et al. Experimental preretinal neovascularization by laser-induced venous thrombosis in rats. Curr Eye Res. 1997; 16: 26–33.
Ieki Y, Nishiwaki H, Miura S, et al. Quantitative evaluation for blood-retinal barrier breakdown in experimental retinal vein occlusion produced by photodynamic thrombosis using a new photosensitizer. Curr Eye Res. 2002; 25: 317–323.
Genevois O, Paques M, Simonutti M, et al. Microvascular remodeling after occlusion-recanalization of a branch retinal vein in rats. Invest Ophthalmol Vis Sci. 2004; 45: 594–600.
Rehak M, Hollborn M, Iandiev I, et al. Retinal gene expression and Muller cell responses after branch retinal vein occlusion in the rat. Invest Ophthalmol Vis Sci. 2009; 50: 2359–2367.
Chuang L, Yeung L, Wang N, Chen HS, Ku W, Lai C. Secondary ocular hypertension after intravitreal injection with 2 mg or 4 mg of triamcinolone in retinal vein occlusion. J Ocul Pharmacol Ther. 2010; 26: 325–328.
Koferl P, Hollborn M, Rehak J, et al. Effects of arteriolar constriction on retinal gene expression and Muller cell responses in a rat model of branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2014; 252: 257–265.
Zhang H, Sonoda K, Qiao H, Oshima T, Hisatomi T, Ishibashi T. Development of a new mouse model of branch retinal vein occlusion and retinal neovascularization. Jpn J Ophthalmol. 2007; 51: 251–257.
Dominguez E, Raoul W, Calippe B, et al. Experimental branch retinal vein occlusion induces upstream pericyte loss and vascular destabilization. PLoS One. 2015; 10: e0132644.
Ebneter A, Agca C, Dysli C, Zinkernagel MS. Investigation of retinal morphology alterations using spectral domain optical coherence tomography in a mouse model of retinal branch and central retinal vein occlusion. PLoS One. 2015; 10: e0119046.
Ebneter A, Kokona D, Schneider N, Zinkernagel MS. Microglia activation and recruitment of circulating macrophages during ischemic experimental branch retinal vein occlusion. PLoS One. 2017; 58: 944–953.
Wilson CA, Hatchell DL. Photodynamic retinal vascular thrombosis: rate and duration of vascular occlusion. Invest Ophthalmol Vis Sci. 1991; 32: 2357–2365.
Matini P, Moroni F, Lombardi G, Faussone-Pellegrini MS, Moroni F. Ultrastructural and biochemical studies on the neuroprotective effects of excitatory amino acid antagonists in the ischemic rat retina. Exp Neurol. 1997; 146: 419–434.
Yamamoto M, Ohira A, Honda O, et al. Analysis of localization of adult T-cell leukemia-derived factor in the transient ischemic rat retina after treatment with OP-1206 α-CD, a prostaglandin E1 analogue. J Histochem Cytochem. 1997; 45: 63–70.
Shen W, He S, Han S, Ma Z. Preretinal neovascularisation induced by photodynamic venous thrombosis in pigmented rat. Aust N Z J Ophthalmol. 1996; 24: 50–52.
Hayashi A, Kim HC, de Juan EJr. Alterations in protein tyrosine kinase pathways following retinal vein occlusion in the rat. Curr Eye Res. 1999; 18: 231–239.
Chuang L, Wu W, Yeung L, et al. Serum concentration of bevacizumab after intravitreal injection in experimental branch retinal vein occlusion. Ophthalmic Res. 2011; 45: 31–35.
Yuan YZ, Yuan F, Xu QY, Yu J, Li L, Zhang JL. Effect of fufang xueshuantong capsule on a rat model of retinal vein occlusion. Chin J Integr Med. 2011; 17: 296–301.
Fuma S, Nishinaka A, Inoue Y, et al. A pharmacological approach in newly established retinal vein occlusion model. Sci Rep. 2017; 7: 43509.
Ameri H, Ratanapakorn T, Rao NA, Chader GJ, Humayun MS. Natural course of experimental retinal vein occlusion in rabbit; arterial occlusion following venous photothrombosis. Graefes Arch Clin Exp Ophthalmol. 2008; 246: 1429–1439.
Tamura M. Neovascularization in experimental retinal venous obstruction in rabbits. Jpn J Ophthalmol. 2001; 45: 144–150.
El-Dessouky ES, Moshfeghi AA, Peyman GA, et al. Toxicity of the photosensitizer NPe6 following intravitreal injection. Ophthalmic Surg Lasers. 2001; 32: 316–321.
Oncel M, Peyman GA, Khoobehi B. Tissue plasminogen activator in the treatment of experimental retinal vein occlusion. Retina. 1989; 9: 1–7.
Iliaki OE, Naoumidi II, Tsilimbaris MK, Pallikaris IG . Photothrombosis of retinal and choroidal vessels in rabbit eyes using chloroaluminum sulfonated phthalocyanine and a diode laser. Lasers Surg Med. 1996; 19: 311–323.
Larsson J, Carlson J, Olsson SB. Ultrasound enhanced thrombolysis in experimental retinal vein occlusion in the rabbit. Br J Ophthalmol. 1998; 82: 1438–1440.
Arroyo JG, Dastgheib K, Hatchell DL. Antithrombotic effect of ticlopidine in an experimental model of retinal vein occlusion. Jpn J Ophthalmol. 2001; 45: 359–362.
Ameri H, Kim JG, Ratanapakorn T, Chader GJ, Humayun MS. Intravitreal and subretinal injection of tissue plasminogen activator (tPA) in the treatment of experimentally created retinal vein occlusion in rabbits. Retina. 2008; 28: 350–355.
Abdallah WF, Patel H, Grant EG, Diniz B, Chader GJ, Humayun MS. Evaluation of ultrasound-assisted thrombolysis using custom liposomes in a model of retinal vein occlusion. Invest Ophthalmol Visual Sci. 2012; 53: 6920–6927.
Jaime GRL, Kashani AH, Saati S, Martin G, Chader G, Humayun MS. Acute variations in retinal vascular oxygen content in a rabbit model of retinal venous occlusion. PLoS One. 2012; 7: e50179.
Jiang CH, Zhang MN, Kamei M. Injection of tissue plasminogen activator into the optic nerve in an animal model of retinal vein occlusion. Int J Ophthalmol. 2009; 9: 1020–1025.
Zhou X, Wu J, Song Y, Zhao Y. Induction of branch retinal vein occlusion by photodynamic therapy with rose bengal in a rabbit model. In: Rumelt S, ed. Advances in Ophthalmology. 1st ed. Rijeka: INTECH Open Access Publisher; 2012: 399.
Takei K, Sato T, Nonoyama T, Miyauchi T, Goto K, Hommura S. A new model of transient complete obstruction of retinal vessels induced by endothelin-1 injection into the posterior vitreous body in rabbits. Graefes Arch Clin Exp Ophthalmol. 1993; 231: 476–481.
Huang W, Yang AH, Matsumoto D, et al. PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. J Ocul Pharmacol Ther. 2009; 25: 519–530.
Hill DW, Young S. Retinal vascular occlusion in the cat by photocoagulation: trial of a new instrument. Exp Eye Res. 1973; 16: 467–473.
Zauberman H, Levinger S, Burde RM. Perfusion of occluded retinal veins in the cat's eye. Br J Ophthalmol. 1984; 68: 58–61.
Levinger S, Zauberman H, Eldor A, Zelikovitch A, Rosenmann E. Prevention of clot formation in cat retinal vein by systemic and subconjunctival urokinase. Arch Ophthalmol. 1987; 105: 554–558.
Attariwala R, Jensen PS, Glucksberg MR. The effect of acute experimental retinal vein occlusion on cat retinal vein pressures. Invest Ophthalmol Vis Sci. 1997; 38: 2742–2749.
Ben-nun J. Capillary blood flow in acute branch retinal vein occlusion. Retina. 2001; 21: 509–512.
Chan CC, Green WR, Rice TA. Experimental occlusion of the retinal vein. Graefes Arch Clin Exp Ophthalmol. 1986; 224: 507–512.
De Juan E, Stefansson E, Dickson JS. Capillary endothelial-cell mitogenic activity in experimental branch vein occlusion. Graefe's Arch Clin Exp Ophthalmol. 1990; 228: 191–194.
De Juan E, Stefansson E, Ohira A. Basic fibroblast growth factor stimulates 3H-thymidine uptake in retinal venular and capillary endothelial cells in vivo. Invest Ophthalmol Vis Sci. 1990; 31: 1238–1244.
Stefansson E, Novack RL, Hatchell DL. Vitrectomy prevents retinal hypoxia in branch retinal vein occlusion. Invest Ophthalmol Vis Sci. 1990; 31: 284–289.
Hayashi A, Imai K, Kim HC, de Juan EJr. Activation of protein tyrosine phosphorylation after retinal branch vein occlusion in cats. Invest Ophthalmol Vis Sci. 1997; 38: 372–380.
Okun E, Collins EM. Histopathology of experimental photocoagulation in the dog eye. Part III. Microaneurysmlike formations following branch vein occlusion. Am J Ophthalmol. 1963; 56: 40–45.
McAllister IL, Yu DY, Vijayasekaran S, Barry C, Constable I. Induced chorioretinal venous anastomosis in experimental retinal branch vein occlusion. Br J Ophthalmol. 1992; 75: 615–620.
Tameesh MK, Lakhanpal RR, Fujii GY, et al. Retinal vein cannulation with prolonged infusion of tissue plasminogen activator (t-PA) for the treatment of experimental retinal vein occlusion in dogs. Am J Ophthalmol. 2004; 138: 829–839.
Mahmoud TH, Peng YW, Proia AD, Davidson M, Deramo VA, Fekrat S. Recombinant tissue plasminogen activator injected into the vitreous cavity may penetrate the retinal veins of a porcine model of vascular occlusion. Br J Ophthalmol. 2006; 90: 911–915.
Kohner EM, Dollery CT, Shakib M, et al. Experimental retinal branch vein occlusion. Am J Ophthalmol. 1970; 69: 778–825.
Pournaras CJ, Tsacopoulos M, Riva CE, Roth A. Diffusion of O2 in normal and ischemic retinas of anesthetized miniature pigs in normoxia and hyperoxia. Graefe's Arch Clin Exp Ophthalmol. 1990; 228: 138–142.
Pournaras CJ, Tsacopoulos M, Strommer K, Gilodi N, Leuenberger PM. Scatter photocoagulation restores tissue hypoxia in experimental vasoproliferative microangiopathy in miniature pigs. Ophthalmology. 1990; 97: 1329–1333.
Danis RP, Yang Y, Massicotte SJ, Boldt HC. Preretinal and optic nerve head neovascularization induced by photodynamic venous thrombosis in domestic pigs. Arch Ophthalmol. 1993; 111: 539–543.
Pournaras CJ. Retinal oxygen distribution: its role in the physiopathology of vasoproliferative microangiopathies. Retina. 1995; 15: 332–347.
Danis RP, Bingaman DP, Yang Y, Ladd B. Inhibition of preretinal and optic nerve head neovascularization in pigs by intravitreal triamcinolone acetonide. Ophthalmology. 1996; 103: 2099–2104.
Danis RP, Bingaman DP, Jirousek M, Yang Y. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531. Invest Ophthalmol Vis Sci. 1998; 39: 171–179.
Donati G, Poimiaras C, Tsacoponlos M. Effect of nitroprusside on arteriolar constriction after retinal branch vein occlusion. Invest Ophthalmol Visual Sci. 1998; 39: 1910–1917.
Danis RP, Criswell MH, Orge F, et al. Intravitreous anti-raf-1 kinase antisense oligonucleotide as an angioinhibitory agent in porcine preretinal neovascularization. Curr Eye Res. 2003; 26: 45–54.
Pournaras JAC, Petropoulos IK, Munoz JL, Pournaras CJ. Experimental retinal vein occlusion: Effect of acetazolamide and carbogen (95% O2/5% CO2) on preretinal PO2. Invest Ophthalmol Visual Sci. 2004; 45: 3669–3677.
McAllister IL, Vijayasekaran S, Chen SD, Yu DY. Effect of triamcinolone acetonide on vascular endothelial growth factor and occludin levels in branch retinal vein occlusion. Am J Ophthalmol. 2009; 147: 838–846.
Mendrinos E, Petropoulos IK, Mangioris G, et al. Vasomotor effect of intravitreal juxta-arteriolar injection of L-lactate on the retinal arterioles after acute branch retinal vein occlusion in minipigs. Invest Ophthalmol Vis Sci. 2011; 52: 3215–3220.
Vijayasekaran S, McAllister IL, Morgan WH, et al. Intravitreal triamcinolone acetonide induced changes in the anterior segment in a pig model of branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2011; 249: 215–222.
Pournaras CJ, Petropoulos IK, Pournaras JAC, Stangos AN, Gilodi N, Rungger-Brandle E. The rationale of retinal endovascular fibrinolysis in the treatment of retinal vein occlusion: From experimental data to clinical application. Retina. 2012; 32: 1566–1573.
McAllister IL, Vijayasekaran S, Xia W, Yu D. Evaluation of the ability of a photocoagulator to rupture the retinal vein and Bruch's membrane for potential vein bypass in retinal vein occlusion. Ophthalmic Surg Lasers Imaging Retina. 2013; 44: 268–273.
Cehofski LJ, Kruse A, Kjærgaard B, Stensballe A, Honoré B, Vorum H. Proteins involved in focal adhesion signaling pathways are differentially regulated in experimental branch retinal vein occlusion. Exp Eye Res. 2015; 138: 87–95.
Cehofski LJ, Kruse A, Bøgsted M, et al. Retinal proteome changes following experimental branch retinal vein occlusion and intervention with ranibizumab. Exp Eye Res. 2016; 152: 49–56.
De Smet MD, Stassen JM, Meenink TCM, et al. Release of experimental retinal vein occlusions by direct intraluminal injection of ocriplasmin. Br J Ophthalmol. 2016; 100: 1742–1746.
Willekens K, Gijbels A, Schoevaerdts L, et al. Robot-assisted retinal vein cannulation in an in vivo porcine retinal vein occlusion model. Acta Ophthalmol. 2017; 95: 270–275.
Zhang X, Ma Z, Hu Y, Fan J. Direct tissue plasminogen activator administration through a microinjection device in a pig model of retinal vein thrombosis. Curr Eye Res. 2002; 24: 263–267.
Tao Y, Li XX, Bai XB, Wu BD, Dong JQ. Diffusion of macromolecule through retina after experimental branch retinal vein occlusion and estimate of intraretinal barrier. Curr Drug Metab. 2007; 8: 151–156.
Noergaard MH, Bach-Holm D, Scherfig E, et al. Dorzolamide increases retinal oxygen tension after branch retinal vein occlusion. Invest Ophthalmol Visual Sci. 2008; 49: 1136–1141.
Ejstrup R, la Cour M, Kyhn MV, Heegaard S, Kiilgaard JF. Effect of glial cell line-derived neurotrophic factor on retinal function after experimental branch retinal vein occlusion. Invest Ophthalmol Vis Sci. 2012; 53: 6207–6213.
Ejstrup R, Scherfig E, la Cour M. Electrophysiological consequences of experimental branch retinal vein occlusion in pigs and the effect of dorzolamide. Invest Ophthalmol Visual Sci. 2011; 52: 952–958.
Shen LJ, Chen YQ, Cheng D, et al. In vivo retinal vein bypass surgery in a porcine model. Curr Eye Res. 2016; 41: 79–87.
Danis RP, Bingaman DP, Jirousek M, Yang Y. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531. Invest Ophthalmol Vis Sci. 1998; 39: 171–179.
McAllister IL, Vijayasekaran S, Yu DY. Intravitreal tenecteplase (Metalyse) for acute management of retinal vein occlusions. Invest Ophthalmol Vis Sci. 2013; 54: 4910–4918.
Cehofski LJ, Kruse A, Kjaergaard B, Stensballe A, Honore B, Vorum H. Dye-free porcine model of experimental branch retinal vein occlusion: a suitable approach for retinal proteomics. J Ophthalmol. 2015; 2015: 1–7.
Virdi PS, Hayreh SS. Ocular neovascularization with retinal vascular occlusion: I. Association with experimental retinal vein occlusion. Arch Ophthalmol. 1982; 100: 331–341.
Qing X, Fry GL, Lata GF, et al. Ocular neovascularization: tissue culture studies. Arch Ophthalmol. 1985; 103: 111–117.
Miller JW, Stinson WG, Gregory WA, El-Koumy HA, Puliafito CA. Phthalocyanine photodynamic therapy of experimental iris neovascularization. Ophthalmology. 1991; 98: 1711–1719.
Miller JW, Stinson WG, Folkman J. Regression of experimental iris neovascularization with systemic alpha- interferon. Ophthalmology. 1993; 100: 9–14.
Miller JW, Adamis AP, Shima DT, et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol. 1994; 145: 574–584.
Shima DT, Gougos A, Miller JW, et al. Cloning and mRNA expression of vascular endothelial growth factor in ischemic retinas of Macaca fascicularis. Invest Ophthalmol Vis Sci. 1996; 37: 1334–1340.
Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996; 114: 66–71.
Husain D, Miller JW, Kenney AG, Michaud N, Flotte TJ, Gragoudas ES. Photodynamic therapy and digital angiography of experimental iris neovascularization using liposomal benzoporphyrin derivative. Ophthalmology. 1997; 104: 1242–1250.
Bhisitkul RB, Robinson GS, Moulton RS, Claffey KP, Gragoudas ES, Miller JW. An antisense oligodeoxynucleotide against vascular endothelial growth factor in a nonhuman primate model of iris neovascularization. Arch Ophthalmol. 2005; 123: 214–219.
Genaidy M, Kazi AA, Peyman GA, et al. Effect of squalamine on iris neovascularization in monkeys. Retina. 2002; 22: 772–778.
Zhao T, Lu Q, Tao Y, Liang XY, Wang K, Jiang YR. Effects of apelin and vascular endothelial growth factor on central retinal vein occlusion in monkey eyes intravitreally injected with bevacizumab: a preliminary study. Mol Vis. 2011; 17: 1044–1055.
Hayreh SS. Occlusion of the central retinal vessels. Ophthalmologica. 1965; 49: 626–645.
Agarwal LP, Bawa J, Khosla PK. Central retinal vascular occlusion. Fluorescein angiography & histopathological correlation: (an experimental study). Indian J Ophthalmol. 1973; 1: 298–309.
Van Heuven WAJ, Hayreh MS, Hayreh SS. Experimental central retinal vascular occlusion. Blood-retinal barrier alterations and retinal lesions. Br J Ophthalmol. 1977; 97: 588–618.
Hayreh SS, March W, Phelps CD. Ocular hypotony following retinal vein occlusion. Arch Ophthalmol. 1978; 96: 827–833.
Gilliland MGF, Folberg R, Hayreh SS. Age of retinal hemorrhages by iron detection: an animal model. Am J Forensic Med Pathol. 2005; 26: 1–4.
Juarez CP, Tso MOM, van Heuven WAJ, Hayreh MS, Hayreh SS. Experimental retinal vascular occlusion II: a clinico-pathologic correlative study of simultaneous occlusion of central retinal vein and artery. Int Ophthalmol. 1986; 9: 77–87.
Fujino T, Curtin VT, Norton EWD. Experimental central retinal vein occlusion: a comparison of intraocular and extraocular occlusion. Trans Am Ophthalmol Soc. 1969; 81: 395–406.
Hamilton AM, Kohner EM, Bird AC. Experimental occlusion of retinal veins. Trans Ophthalmol Soc U K. 1976; 96: 197.
Hayreh SS, Lata GF. Ocular neovascularization: experimental animal model and studies on angiogenic factor(s). Int Ophthalmol. 1986; 9: 109–120.
Morgan KM, Bruner WE, Lata GF, Hayreh SS. Beta-N-acetyl-glucosaminidase: possible role in ocular neovascularization. Int Ophthalmol. 1986; 9: 129–137.
Packer AJ, Gu XQ, Servais EG, Hayreh SS. Primate model of neovascular glaucoma. Int Ophthalmol. 1986; 9: 121–127.
Danis RP, Wallow IHL. Microvascular changes in experimental branch retinal vein occlusion. Ophthalmology. 1987; 94: 1213–1221.
Wallow IHL, Danis RP, Bindley C, Neider M. Cystoid macular degeneration in experimental branch retinal vein occlusion. Ophthalmology. 1988; 95: 1371–1379.
Nork TM, Tso MO, Duvall J, Hayreh SS. Cellular mechanisms of iris neovascularization secondary to retinal vein occlusion. Arch Ophthalmol. 1989; 107: 581–586.
Khoobehi B, Aly OM, Schuele KM, Stradtmann MO, Peyman GA. Determination of retinal blood velocity with respect to the cardiac cycle using laser-triggered release of liposome-encapsulated dye. Lasers Surg Med. 1990; 10: 469–475.
Wallow IHL, Bindley CD, Linton KLP, Rastegar D. Pericyte changes in branch retinal vein occlusion. Invest Ophthalmol Vis Sci. 1991; 32: 1455–1463.
Pournaras CJ, Miller JW, Gragoudas ES, et al. Systemic hyperoxia decreases vascular endothelial growth factor gene expression in ischemic primate retina. Arch Ophthalmol. 1997; 115: 1553–1558.
Peyman GA, Khoobehi B, Moshfeghi A, Moshfeghi D. Reversal of blood flow in experimental branch retinal vein occlusion. Ophthalmic Surg Lasers. 1998; 29: 595–597.
Ieki Y, Nishiwaki H, Miura S, et al. Experimental macular edema induced by macular venule occlusion in monkey. Curr Eye Res. 2002; 25: 123–131.
Hamilton AM, Marshall J, Kohner EM, Bowbyes JA. Retinal new vessel formation following experimental vein occlusion. Exp Eye Res. 1975; 20: 493–497.
Archer DB. The nature of 'new retinal vessels'. Trans Ophthalmol Soc U K. 1976; 96: 210.
Ernest JT, Archer DB. Vitreous body oxygen tension following experimental branch retinal vein obstruction. Invest Ophthalmol Vis Sci. 1979; 18: 1025–1029.
Hockley DJ, Tripathi RC, Ashton N. Experimental retinal branch vein occlusion in the monkey. Histopathological and ultrastructural studies. Trans Ophthalmol Soc U K. 1976; 96: 202–209.
Rosen DA, Marshall J, Kohner EM, Hamilton AM, Dollery CT. Experimental retinal vein occlusion in the rhesus monkey. Radioactive microsphere and radioautographic studies. Trans Ophthalmol Soc U K. 1976; 96: 198.
Hamilton AM, Kohner EM, Rosen D, Bird AC, Dollery CT. Experimental retinal branch vein occlusion in rhesus monkeys. I. Clinical appearances. Br J Ophthalmol. 1979; 63: 377–387.
Hockley DJ, Tripathi RC, Ashton N. Experimental retinal branch vein occlusion in rhesus monkeys. III. Histopathological and electron microscopical studies. Br J Ophthalmol. 1979; 63: 393–411.
Rosen DA, Marshall J, Kohner EM, Hamilton AM, Dollery CT. Experimental retinal branch vein occlusion in rhesus monkeys. II. Retinal blood flow studies. Br J Ophthalmol. 1979; 63: 388–392.
Hayreh SS, Van Heuven WAJ, Hayreh MS. Experimental retinal vascular occlusion: I. Pathogenesis of central retinal vein occlusion. Arch Ophthalmol. 1978; 96: 311–323.
Akiyama H, Tanaka T, Itakura H, et al. Inhibition of ocular angiogenesis by an adenovirus carrying the human von Hippel-Lindau tumor-suppressor gene in vivo. Invest Ophthalmol Vis Sci. 2004; 45: 1289–1296.
Guex-Crosier Y. The pathogenesis and clinical presentation of macular edema in inflammatory diseases. Doc Ophthalmol. 1999; 97: 297–309.
Hebel R. Distribution of retinal ganglion cells in five mammalian species (pig, sheep, ox, horse, dog). Anat Embryol. 1976; 150: 45–51.
Chandler M, Smith P, Samuelson D, MacKay E. Photoreceptor density of the domestic pig retina. Vet Ophthalmol. 1999; 2: 179–184.
Olsen TW, Sanderson S, Feng X, Hubbard WC. Porcine sclera: thickness and surface area. Invest Ophthalmol Vis Sci. 2002; 43: 2529–2532.
Mitrofanis J, Vigny A, Stone J. Distribution of catecholaminergic cells in the retina of the rat, guinea pig, cat, and rabbit: independence from ganglion cell distribution. J Comp Neurol. 1988; 267: 1–14.
Beattie JR, Brockbank S, McGarvey JJ, Curry WJ. Raman microscopy of porcine inner retinal layers from the area centralis. Mol Vis. 2007; 13: 1106–1113.
Rapaport DH, Stone J. The area centralis of the retina in the cat and other mammals: focal point for function and development of the visual system. Neuroscience. 1984; 11: 289–301.
Mowat FM, Petersen-Jones SM, Williamson H, et al. Topographical characterization of cone photoreceptors and the area centralis of the canine retina. Mol Vis. 2008; 14: 2518–2527.
Coles JA. Some reflective properties of the tapetum lucidum of the cat's eye. J Physiol. 1971; 212: 393–409.
Bernstein MH, Pease DC. Electron microscopy of the tapetum lucidum of the cat. J Biophys Biochem Cytol. 1959; 5: 35–40.
Ollivier F, Samuelson D, Brooks D, Lewis P, Kallberg M, Komáromy A. Comparative morphology of the tapetum lucidum (among selected species). Vet Ophthalmol. 2004; 7: 11–22.
Albrecht May C. Comparative anatomy of the optic nerve head and inner retina in non-primate animal models used for glaucoma research. Open Ophthalmol J. 2008; 2: 94–101.
Beltran WA, Cideciyan AV, Guziewicz KE, et al. Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations. PLoS One. 2014; 9: e90390.
Mutlu F, Leopold IH. Structure of the retinal vascular system: of the dog, monkey, rat, mouse and cow. Am J Ophthalmol. 1964; 58: 261–270.
Mutlu F, Leopold IH. Structure of retinal vascular system of cat and rabbit. Am J Ophthalmol. 1964; 57: 804–814.
Bloodworth J, Gutgesell H, Engerman R. Retinal vasculature of the pig: light and electron microscope studies. Exp Eye Res. 1965; 4: 174–178.
Rootman J. Vascular system of the optic nerve head and retina in the pig. Br J Ophthalmol. 1971; 55: 808–819.
De Juan E, Chandler D, Hida T, Machemer R. Glio-vascular architecture in the rabbit retina. Invest Ophthalmol Vis Sci. 1986; 27: 1602–1608.
Ninomiya H, Inomata T, Kanemaki N. Microvascular architecture of the rabbit eye: a scanning electron microscopic study of vascular corrosion casts. J Vet Med Sci. 2008; 70: 887–892.
Cehofski LJ, Kruse A, Kjaergaard B, Stensballe A, Honore B, Vorum H. Proteins involved in focal adhesion signaling pathways are differentially regulated in experimental branch retinal vein occlusion. Exp Eye Res. 2015; 138: 87–95.
Chuang LH, Wu WC, Yeung L, et al. Serum concentration of bevacizumab after intravitreal injection in experimental branch retinal vein occlusion. Ophthalmic Res. 2010; 45: 31–35.
Rehak J, Dusek L, Chrapek O, Fric E, Rehak M. Initial visual acuity is an important prognostic factor in patients with branch retinal vein occlusion. Ophthalmic Res. 2011; 45: 204–209.
Tamura M. Neovascularization in experimental retinal venous obstruction in rabbit. Jpn J Ophthalmol. 1994; 98: 175–182.
Chang K, Chung H. Preretinal neovascularization induced by experimental retinal vein occlusion in albino rats. Korean J Ophthalmol. 1997; 11: 60–64.
Pournaras CJ, Tsacopoulos M, Strommer K, Gilodi N, Leuenberger PM. Experimental retinal branch vein occlusion in miniature pigs induces local tissue hypoxia and vasoproliferative microangiopathy. Ophthalmology. 1990; 97: 1321–1328.
Pournaras CJ, Roth A, Munoz JL, Abdesselem R. Experimental venous branch occlusion: change in the preretinal oxygen pressure pO2 by dexamethasone. Klin Monatsbl Augenheilkd. 1990; 196: 475–480.
Figure
 
Fundus fluorescein angiogram obtained in a mouse eye immediately following induction of RVO with laser photocoagulation. Note an area of thinning in a retinal vein at the site of the attempted occlusion, but still presence of flow through the vein (arrow). An area of retinal edema blocking the view of the vein itself, which remains perfused, is also seen (arrowhead). Achieving a full occlusion of the vein is challenging in mice given that appropriate focusing of the laser beam, even the smallest available, on the very small retinal vein is difficult.
Figure
 
Fundus fluorescein angiogram obtained in a mouse eye immediately following induction of RVO with laser photocoagulation. Note an area of thinning in a retinal vein at the site of the attempted occlusion, but still presence of flow through the vein (arrow). An area of retinal edema blocking the view of the vein itself, which remains perfused, is also seen (arrowhead). Achieving a full occlusion of the vein is challenging in mice given that appropriate focusing of the laser beam, even the smallest available, on the very small retinal vein is difficult.
Table 1
 
Animal Species and Techniques Used to Induce BRVO
Table 1
 
Animal Species and Techniques Used to Induce BRVO
Table 2
 
Animal Species and Techniques Used to Induce CRVO
Table 2
 
Animal Species and Techniques Used to Induce CRVO
Table 3
 
Advantages and Inconveniences of Species Used as Animal Models of RVO
Table 3
 
Advantages and Inconveniences of Species Used as Animal Models of RVO
Table 4
 
Similarities and Differences of Retina and Retinal Vasculature of the Different Animal Species Used in RVO Studies
Table 4
 
Similarities and Differences of Retina and Retinal Vasculature of the Different Animal Species Used in RVO Studies
Table 5
 
Advantages and Disadvantages of the Different Methods Used to Induce RVO
Table 5
 
Advantages and Disadvantages of the Different Methods Used to Induce RVO
Table 6
 
Parameters of Laser Photocoagulation Used in the Different Animal Models
Table 6
 
Parameters of Laser Photocoagulation Used in the Different Animal Models
Table 7
 
Clinical and Histopathologic Features of BRVO Animal Models
Table 7
 
Clinical and Histopathologic Features of BRVO Animal Models
Table 8
 
Clinical and Histopathologic Features of CRVO Animal Models
Table 8
 
Clinical and Histopathologic Features of CRVO Animal Models
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