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PubMed1987

Foveal neovascularization in diabetic retinopathy.

Retinal neovascularization in diabetes mellitus almost always occurs at the optic disc and/or near the major nasal and temporal vascular arcades, sparing the foveal area. We examined seven eyes of seven patients with long-standing insulin-dependent diabetes mellitus who had unilateral foveal retinal neovascularization. The neovascularization originated from the perifoveal capillaries and demonstrated typical leakage on fluorescein angiography.

Adult↗
PubMed2006

[Quantification of oxygen-induced retinopathy in the mouse].

PURPOSE: To establish a quantifying model of retinal neovascularization suitable for examining pathogenesis and therapeutic intervention for the retinal neovascularization. METHODS: Sixty 7-day-old C57BL/6J mice were divided into oxygen-induced retinopathy group and control group. In oxygen-induced retinopathy group, 32 mice were exposed to (75 +/- 2)% oxygen for 5 days and then to room air; in control group, 32 mice were raised in room air. The retinal frozen sections were stained with griffonia simplicifolia lectin B4 (GSA) which selectively stained vascular cells; or the retinal preparation perfused with fluorescein-dextran were used to test the areas of the retinal neovascularization. RESULTS: After 5 days of exposure to hyperoxia at postnatal day 12 (P12), the larger central radial vessels became tortuous and constricted and central perfusion became obviously decreased. After returning to room air for 2 days at P14, neovascularization was seen. This response was maximal at P17. CONCLUSION: The reproducible and quantifiable mouse model of retinal neovascularization is useful for the study of pathogenesis of retinal neovascularization and therapeutic intervention.

Animals↗
PubMed1999

Transpupillary thermotherapy for choroidal melanoma.

The management of choroidal melanomas depends on many factors, most importantly, tumor size and location. Small choroidal melanoma in the posterior fundus is amenable to treatment options such as enucleation, radiotherapy, laser photocoagulation, and transpupillary thermotherapy or a combination of these methods. Transpupillary thermotherapy is a technique of tumor heating by infrared radiation delivered through the pupil into the tumor. This method causes dramatic tumor necrosis in choroidal melanomas up to 4 mm in thickness. With properly selected small choroidal melanomas, tumor control is approximately 94%. The heat induces cellular damage at the site of treatment with few remote side effects; therefore, complications are generally limited to the site of treatment and include retinal vascular obstruction (23%), retinal traction (20%), retinal neovascularization (6%), and retinal hole with detachment (< 1%). Tumors located temporal to the foveola demonstrate a statistically higher risk for retinal traction than those located in other quadrants. Tumors near the optic disk demonstrate a higher incidence of retinal neovascularization due to heat-induced obstruction of a major retinal vascular arcade. Overall, vision preservation is satisfactory after thermotherapy for choroidal melanoma, with more than 50% of patients maintaining the same or better vision after treatment, depending primarily on tumor location. In summary, small choroidal melanomas can be controlled with transpupillary thermotherapy, especially those near the optic disk and foveola in areas that are otherwise difficult to irradiate. Longer follow-up is necessary to assess for local recurrence and the impact of treatment on life prognosis.

Animals↗
PubMed1994

Oxygen-induced retinopathy in the mouse.

PURPOSE: To develop oxygen-induced retinopathy in the mouse with reproducible and quantifiable proliferative retinal neovascularization suitable for examining pathogenesis and therapeutic intervention for retinal neovascularization in retinopathy of prematurity (ROP) and other vasculopathologies. METHODS: One-week-old C57BL/6J mice were exposed to 75% oxygen for 5 days and then to room air. A novel fluorescein-dextran perfusion method has been developed to assess the vascular pattern. The proliferative neovascular response was quantified by counting the nuclei of new vessels extending from the retina into the vitreous in 6 microns sagittal cross-sections. Cross-sections were also stained for glial fibrillary acidic protein (GFAP). RESULTS: Fluorescein-dextran angiography delineated the entire vascular pattern, including neovascular tufts in flat-mounted retinas. Hyperoxia-induced neovascularization occurred at the junction between the vascularized and avascular retina in the mid-periphery. Retinal neovascularization occurred in all the pups between postnatal day 17 and postnatal day 21. There was a mean of 89 neovascular nuclei per cross-section of 9 eyes in hyperoxia compared to less than 1 nucleus per cross-section of 8 eyes in the normoxia control (P < 0.0001). Proliferative vessels were not associated with GFAP-positive astrocyte processes. CONCLUSIONS: The authors have described a reproducible and quantifiable mouse model of oxygen-induced retinal neovascularization that should prove useful for the study of pathogenesis of retinal neovascularization as well as for the study of medical intervention for ROP and other retinal angiopathies.

Animals↗
PubMedDate not supplied

Retinal fibrovascular proliferation associated with Nocardia subretinal abscess.

PURPOSE: To report the development of extensive fibrovascular proliferation in association with Nocardia subretinal abscess. METHOD: Case report. RESULTS: Extensive retinal neovascularization with tractional retinal detachment developed soon after ocular involvement in a 61-year-old patient with systemic nocardiosis. Fundus fluorescein angiography showed extensive area of capillary nonperfusion and severe leakage from the neovascular complex. The Nocardia subretinal abscess responded to systemic antibiotics, and the retinal neovascularization and tractional retinal detachment stabilized after 3 months. CONCLUSIONS: Retinal ischemia and severe retinal neovascularization may complicate intraocular nocardiosis. The authors propose secondary retinal vasculitis as a contributing factor towards the development of retinal ischemia in this setting.

Abscess↗
PubMed2004

Herbimycin A inhibits angiogenic activity in endothelial cells and reduces neovascularization in a rat model of retinopathy of prematurity.

The pathogenesis of retinopathy of prematurity involves dysregulated angiogenesis resulting in pre-retinal growth of new vessels. Inhibition of tyrosine kinase-dependent pro-angiogenic signals may provide a rational therapeutic approach to the reduction of pre-retinal neovascularization. Vascular endothelial growth factor stimulates endothelial cell mitogenesis, differentiation and migration, by binding and activating the receptor tyrosine kinases vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2. One of the vascular endothelial growth factor receptor substrates implicated in vascular endothelial growth factor signal transduction is c-Src. The ability of herbimycin A, a c-Src-selective tyrosine kinase inhibitor, to inhibit vascular endothelial growth factor-induced bovine retinal microvascular endothelial cell proliferation and tube formation was investigated. The ability of the compound to inhibit pathologic angiogenesis was tested in a rat model of retinopathy of prematurity. Exposure of neonatal rats to oxygen concentrations cycling between 10 and 50% induced severe pre-retinal neovascularization in all rats. Some of the eyes of these variable oxygen-exposed rats were herbimycin A-injected or vehicle-injected 1 or 3 days post-oxygen exposure while some eyes were non-injected. All rats were sacrificed for assessment 6 days post-exposure. Herbimycin A inhibited both vascular endothelial growth factor-induced bovine retinal microvascular endothelial cell proliferation and capillary tube formation in a dose-dependent manner. Injection of herbimycin A into oxygen-treated rats 1 day post-oxygen exposure produced a 63% decrease in pre-retinal neovascularization relative to vehicle (P = 0.0029). There was a 41% decrease in pre-retinal neovascularization in herbimycin-injected eyes relative to vehicle-injected eyes 3 days post-oxygen (P = 0.031). Pre-retinal neovascularization was reduced in vehicle-injected eyes relative to non-injected eyes at both injection times. There were no significant differences in retinal vascular area between any of the experimental groups. Based on the results of this study, herbimycin A inhibits endothelial cell proliferation and tube formation at non-toxic concentrations and reduces pre-retinal neovascularization in a rat model of retinopathy of prematurity. Reduction of angiogenesis by the inhibition of tyrosine kinase activity may be a viable route to the development of effective chemotherapies applicable to eye disease.

Animals↗
PubMed2002

Familial amyloidotic polyneuropathy presenting with rubeotic glaucoma.

A 78-year-old man with familial amyloidotic polyneuropathy type I (Met30), presented with rubeotic glaucoma 9 months following an uncomplicated vitrectomy for vitreous amyloidosis. There was retinal neovascularization and extensive retinal vascular closure. In the preceding 9 months, episodes of 'uveitis' and high intraocular pressure are thought to be due to amyloid protein released into the aqueous leading to trabecular meshwork obstruction and high intraocular pressures, thus compounding the ocular ischaemia created by amyloid vascular closure. The patient underwent pan-retinal photocoagulation and Molteno implant surgery. The rubeosis regressed and pressure control was gained but sight was lost.

Aged↗
PubMed2003

Reduced retinal angiogenesis in MMP-2-deficient mice.

PURPOSE: To study the putative role of endogenous matrix metalloproteinases (MMPs) in retinal neovascularization, an established mouse model was used to compare the retinal neovascularization observed in wild-type mice with that in mice without the MMP-2 or -9 genes. METHODS: C57Bl/6 (MMP-2(+/+) and -9(+/+)), MMP-2-deficient (MMP-2(-/-)), and MMP-9-deficient (MMP-9(-/-)) mice were used. After oxygen-induced retinopathy was induced in the mice, their eyes were rapidly removed and frozen in optimal cutting temperature embedding compound. Sections were histochemically stained with specific markers for vascular cells and angiogenesis-related factors. The area of new retinal vessels was measured using image-analysis software and compared between groups. RESULTS: Retinal neovascularization was not significantly different between wild-type and MMP-9(-/-) mice. The MMP-2(-/-) mice had significantly less extraretinal neovascularization than did wild-type mice. The mean number of extraretinal neovascular buds per cross section was significantly lower in MMP-2(-/-) mice than in wild-type mice (P < 0.05). The expression of other angiogenesis-related factors, vascular endothelial growth factor and pigment epithelium-derived factor, was not different between wild-type and MMP-2(-/-) mice. CONCLUSIONS: MMP-2 may be essential in the regulation of retinal neovascularization. Pharmacologic intervention using MMP inhibitors may be a future therapeutic approach for angiogenic retinal diseases.

Animals↗
PubMed2005

Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy.

Because oxidative stress has been strongly implicated in up-regulation of vascular endothelial growth factor (VEGF) expression in ischemic retinopathy, we evaluated the role of NAD(P)H oxidase in causing VEGF overexpression and retinal neovascularization. Dihydroethidium imaging analyses showed increased superoxide formation in areas of retinal neovascularization associated with relative retinal hypoxia in a mouse model for oxygen-induced retinopathy. The effect of hypoxia in stimulating superoxide formation in retinal vascular endothelial cells was confirmed by in vitro chemiluminescence assays. The superoxide formation was blocked by specific inhibitors of NAD(P)H oxidase activity (apocynin, gp91ds-tat) indicating that NAD(P)H oxidase is a major source of superoxide formation. Western blot and immunolocalization analyses showed that retinal ischemia increased expression of the NAD(P)H oxidase catalytic subunit gp91phox, which localized primarily within vascular endothelial cells. Treatment of mice with apocynin blocked ischemia-induced increases in oxidative stress, normalized VEGF expression, and prevented retinal neovascularization. Apocynin and gp91ds-tat also blocked the action of hypoxia in causing increased VEGF expression in vitro, confirming the specific role of NAD(P)H oxidase in hypoxia-induced increases in VEGF expression. In conclusion, NAD(P)H oxidase activity is required for hypoxia-stimulated increases in VEGF expression and retinal neovascularization. Inhibition of NAD(P)H oxidase offers a new therapeutic target for the treatment of retinopathy.

Acetophenones↗
PubMed2006

[Transfer of endostatin gene for inhibition of retinal angiogenesis in mice].

OBJECTIVE: To evaluate the effect of liposome mediated plasmids encoding endostatin (ES) injected into the vitreous to inhibit experimental retinal neovascularization. METHODS: Cationic liposome mediated ES expression plasmid PCDNA(3)-ES was constructed. One-week-old C57Bl/6N mice were exposed to (75 +/- 2)% oxygen for 5 days, then returned to the room air to induce retinal neovascularization. Cationic liposome mediated ES complex (2 microl) was injected into the vitreous in the treatment group. PBS 2 microl or liposome with carrier DNA complex were injected in the control group. The ES protein expression in the retina was tested with immunohistological methods at 1, 3, 7 and 14 days after injection. Retinal neovascularization was evaluated by angiography with injection of fluorescein dextran and quantification of neovascular proliferative retinopathy after 5 days in room air. To examine the toxicity of the liposome and plasmid PCDNA(3)-ES complex, the histological changes in the retina were examined by light and electron microscopy. RESULTS: ES protein was expressed in the retina 24 hours after injection. Most of them presented in the retinal ganglion layer. This could last for 2 weeks at least. Retina of the PBS-injected eyes of retinal neovascular animal model showed prominent neovascular tuft and fluorescein leakage. Fewer neovascular tufts could be seen after ES injection. Retinal neovascularization in the eyes injected with ES plasmids complex was reduced as compared with the control group. No side effect on the retina was observed by light and electron microscopy. CONCLUSIONS: Liposome mediated plasmids encoding ES can be transferred to retinal cells by vitreous injection and can suppress retinal neovascularization, no side or toxic effects are presented in the retina. Further studies should be done to improve the treatment results.

Angiogenesis Inhibitors↗
PubMed2006

Tubedown-1 (Tbdn-1) suppression in oxygen-induced retinopathy and in retinopathy of prematurity.

PURPOSE: Identification of unique proteins involved in retinopathy of prematurity (ROP) may facilitate new and more effective diagnostic tools and molecular-based treatments for ROP. Tubedown-1 (Tbdn-1), a novel homeostatic protein which copurifies with an acetyltransferase activity, is expressed in normal retinal endothelium and is specifically suppressed in retinal endothelial cells from patients with proliferative diabetic retinopathy. Furthermore, recent in vivo knockdown studies in mice have revealed that Tbdn-1 is important for retinal blood vessel homeostasis and for preventing retinal neovascularization in adults. The purpose of the present study was to determine if the expression pattern of Tbdn-1 is altered during oxygen-induced retinal neovascularization in mice and in a specimen of stage 3 human ROP. METHODS: Specimens of oxygen-induced retinal neovascularization in mice, and a single specimen of active stage 3 ROP were studied by immunohistochemistry and digital image analysis using antibodies raised against Tbdn-1 and other blood vessel markers. RESULTS: The pattern of Tbdn-1 expression during the course of oxygen-induced retinal neovascularization in mice suggests a regulating role in neonatal retinopathy. Retinal lesions from oxygen-induced retinal neovascularization in mice display suppression of retinal endothelial Tbdn-1 protein expression in conjunction with an increase in expression of proliferating cell nuclear antigen (a marker of proliferation) and alpha smooth muscle actin (a marker of myofibroblastic cells). Abnormal blood vessels within vitreoretinal neovascular lesions in a human specimen of active stage 3 ROP did not show Tbdn-1 protein expression. CONCLUSIONS: These results suggest that the loss of retinal endothelial Tbdn-1 expression may be a contributing factor in retinal blood vessel proliferation in ROP.

Acetyltransferases↗
PubMed2006

Vascular endothelial growth factor upregulates expression of ADAMTS1 in endothelial cells through protein kinase C signaling.

PURPOSE: ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs) has been demonstrated to inhibit angiogenesis in vivo and to suppress endothelial cell proliferation in vitro. The purpose of this study was to investigate the expression of ADAMTS1 in endothelial cells and in a mouse model of ischemia-induced retinal neovascularization and to study the regulation of ADAMTS1 expression in endothelial cells by vascular endothelial growth factor (VEGF). In addition, the potential function of endothelial cell-derived ADAMTS1 on cell proliferation was investigated. METHODS: Expression of ADAMTS1 in human retinal endothelial cells (HRECs), human umbilical vein endothelial cells (HUVECs), and the mouse model of ischemia-induced retinal neovascularization was assayed by real-time PCR and Western blot analysis. The effect of ADAMTS1 on endothelial cell proliferation was evaluated using siRNA knockdown and [3H] thymidine incorporation. RESULTS: ADAMTS1 mRNA and protein levels were increased in a mouse model of ischemia-induced retinal neovascularization, and VEGF induced time- and dose-dependent increases in ADAMTS1 mRNA and protein expression in endothelial cells. This upregulation was inhibited by the VEGF receptor (VEGFR)2 inhibitor SU1498, anti-VEGFR2 neutralizing antibody, and the phospholipase C (PLC)-gamma inhibitor U73122. VEGF upregulation of ADAMTS1 expression was completely abolished by the inhibition of protein kinase C by calphostin C and largely blocked by the specific inhibition of PKCbeta. Knockdown of endogenous ADAMTS1 resulted in increased proliferation of endothelial cells. CONCLUSIONS: These results indicate that VEGF significantly induces ADAMTS1 expression in endothelial cells in a PKC-dependent fashion. ADAMTS1 expression is also increased, along with VEGF expression, in vivo in ischemia-induced retinal neovascularization. In addition, ADAMTS1 appears to be an endogenous regulator of endothelial cell proliferation. Therefore, VEGF upregulation of ADAMTS1, a potent angiogenesis inhibitor, may represent a mechanism for feedback inhibition of angiogenesis and retinal neovascularization.

ADAM Proteins↗
PubMed2006

Expression of protein kinase CK2 in astroglial cells of normal and neovascularized retina.

We previously documented protein kinase CK2 involvement in retinal neovascularization. Here we describe retinal CK2 expression and combined effects of CK2 inhibitors with the somatostatin analog octreotide in a mouse model of oxygen-induced retinopathy (OIR). CK2 expression in human and rodent retinas with and without retinopathy and in astrocytic and endothelial cultures was examined by immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction. A combination of CK2 inhibitors, emodin or 4,5,6,7-tetrabromobenzotriazole, with octreotide was injected intraperitoneally from postnatal (P) day P11 to P17 to block mouse OIR. All CK2 subunits (alpha, alpha', beta) were expressed in retina, and a novel CK2alpha splice variant was detected by reverse transcriptase-polymerase chain reaction. CK2 antibodies primarily reacted with retinal astrocytes, and staining was increased around new intraretinal vessels in mouse OIR and rat retinopathy of prematurity, whereas preretinal vessels were negative. Cultured astrocytes showed increased perinuclear CK2 staining compared to endothelial cells. In the OIR model, CK2 mRNA expression increased modestly on P13 but not on P17. Octreotide combined with emodin or 4,5,6,7-tetrabromobenzotriazole blocked mouse retinal neovascularization more efficiently than either compound alone. Based on its retinal localization, CK2 may be considered a new immunohistochemical astrocytic marker, and combination of CK2 inhibitors and octreotide may be a promising future treatment for proliferative retinopathies.

Angiogenesis Inhibitors↗
PubMed2005

Expression and activation of STAT3 in ischemia-induced retinopathy.

PURPOSE: Signal transducer and activator of transcription protein-3 (STAT3) is a transcription factor that participates in many biological processes, including tumor angiogenesis. The expression and activation of Stat3 in the mouse model of ischemia-induced retinal neovascularization was investigated to evaluate the possible role of STAT3 in retinal vascular disease. METHODS: Retinal neovascularization was induced in mice pups by exposure to hyperoxia. Gene microarrays were used to identify genes whose expression in the retina is altered at postnatal day (P)12 and P18. The relative levels of Stat3 mRNA were determined by semiquantitative RT-PCR. Stat3 protein levels and the levels of the activated form of Stat3 (pStat3) at P12, P15, P18, and P22 were determined by immunoblot analysis. Stat3 and pStat3 were demonstrated by immunofluorescence in retinal sections at P12, P15, and P18. RESULTS: In a series of microarray experiments, increased Stat3 mRNA levels in the retina were detected at P18. This result was validated by RT-PCR and demonstrated that Stat3 and pStat3 protein levels also increase during the development of neovascularization. Stat3 partially colocalized with blood vessels at the peak of neovascularization. pStat3 colocalized completely with blood vessels in both experimental samples and age-matched controls. pStat3 staining increased notably in the neovascular vessels at P15 and P18 and was more strongly associated with the epiretinal vessels than with inner retinal vessels. It was not detected in larger blood vessels, such as those of the optic nerve. CONCLUSIONS: The level of Stat3 expression increased, and pStat3 was observed in association with retinal neovascularization. Activated Stat3 was preferentially localized to neovascular retinal vessels. These data suggest that STAT3 may have a role in proliferative retinopathy.

Animals↗
PubMed1995

Dye laser treatment in proliferative diabetic retinopathy and maculopathy.

The aim of this study was to compare the efficacy of various dye laser wavelengths in different forms of retinopathies. The study material consisted of 292 eyes of 210 diabetic retinopathy patients treated with dye laser photocoagulation between 1990 and 1992. All the patients were followed for at least 6 months after photocoagulation. Non-proliferative changes (maculopathy and/or preproliferative retinopathy) were present in 135 (46.3%) and proliferative retinopathy in 157 (53.7%) of the eyes undergoing photocoagulation. Of the 157 eyes with proliferative retinopathy, 60 (20.5%) had disc neovascularization, 71 (24.3%) had retinal neovascularization and 26 (8.9%) had retinitis proliferans. Yellow dye laser (580 nm) was applied in 92 (31.5%) eyes, red dye laser (630 nm) in 120 (41.1%) eyes and both yellow and red dye lasers in 80 (27.4%) eyes. There was no significant difference between the different wavelength groups with regard to visual acuity changes before and after treatment (p < 0.01). Overall, the visual acuity was maintained in 56.2% and improved in 25.0% of the eyes. After panretinal photocoagulation, disc neovascularization regressed partially or completely in 47 (78.3%) of the eyes. There was no significant difference among the various laser wavelengths with regard to treatment efficacy judged by the disappearance or regression of disc neovascularization (p < 0.01). All retinal neovascularizations regressed completely with laser treatment, but in 7 eyes (9.9%) new retinal neovascularizations in previously untreated areas developed. Dye laser has not resulted in any complications. It requires lower power settings compared to argon laser and thus facilitates photocoagulation. Another advantage of dye laser is the ability to use yellow and red wavelengths sequentially.

Adult↗
PubMed2001

An anti-angiogenic state in mice and humans with retinal photoreceptor cell degeneration.

Abnormal angiogenesis accompanies many pathological conditions including cancer, inflammation, and eye diseases. Proliferative retinopathy because of retinal neovascularization is a leading cause of blindness in developed countries. Another major cause of irreversible vision loss is retinitis pigmentosa, a group of diseases characterized by progressive photoreceptor cell degeneration. Interestingly, anecdotal evidence has long suggested that proliferative diabetic retinopathy is rarely associated clinically with retinitis pigmentosa. Here we show that neonatal mice with classic inherited retinal degeneration (Pdeb(rd1)/Pdeb(rd1)) fail to mount reactive retinal neovascularization in a mouse model of oxygen-induced proliferative retinopathy. We also present a comparable human paradigm: spontaneous regression of retinal neovascularization associated with long-standing diabetes mellitus occurs when retinitis pigmentosa becomes clinically evident. Both mouse and human data indicate that reactive retinal neovascularization either fails to develop or regresses when the number of photoreceptor cells is markedly reduced. Our findings support the hypothesis that a functional mechanism underlying this anti-angiogenic state is failure of the predicted up-regulation of vascular endothelial growth factor, although other growth factors may also be involved. Preventive and therapeutic strategies against both proliferative and degenerative retinopathies may emerge from this work.

Animals↗
PubMed1990

Oxygen and diabetic eye disease.

In 1956, Wise suggested that retinal hypoxia stimulated retinal neovascularization in the ischemic proliferative retinopathies. Although not directly proven, this theory is strongly supported by a wealth of circumstantial information. Two treatment modalities, vitrectomy and panretinal photocoagulation, have been shown to be effective against retinal neovascularization in diabetics. Both of these treatment modalities improve retinal oxygenation, and we propose that this is the mechanism through which they halt retinal neovascularization. The mechanism for improving retinal oxygenation is different for the two treatment modalities. In the case of panretinal photocoagulation, the new oxygen supply comes from the choroid through the laser scar in the outer retina. In the case of vitrectomy, it comes from the vitreous cavity itself, but the end result is the same. We have expanded Wise's hypothesis to include these two treatment modalities, which were not known at the time of Wise's original paper.

Animals↗
PubMed1976

The blood-retinal barriers.

The Blood-Retinal Barrier (BRB) is a situation of restricted permeability which is present between the blood and the retina. This barrier has a well defined anatomic substrate, particular permeability characteristics and appears to play a role of major importance in the pathophysiology and therapeutics of retinal disease. The BRB phenomenon operates fundamentally at two levels, retinal vessels and chorioepithelial interface, forming which may be better called an inner BRB and an outer BRB. The main structures involved are, for the inner BRB, the endothelial membrane of the retinal vessels, and for the outer BRB, the retinal pigment epithelium. 'Zonulae occludentes' are present in these membranes forming complete belts around the cells, sealing off the spaces between them. Other structures appear to play an accessory role. Both barriers show an apparent predominance of processes of active transport over mechanisms of passive transfer, these being extremely restricted. Much information on the pathophysiology of the BRB mechanism has been obtained from studies of its experimental breakdown. In this way, a breakdown of the inner BRB may be induced by acute distension of the vessel walls, ischaemia, chemical influences, defects in the endothelial cells and failure of the active transport system, whereas experimental ischaemia, mechanical distension of the pigment epithelial membrane, defects in the pigment epithelium and failure of the active transport systems can cause a breakdown of the outer BRB. The increased permeability of the inner BRB, and of the outer BRB, appears to be related to changes in the vascular endothelial membrane and retinal pigment epithelium, respectively. In clinical ophthalmology there are two methods for the diagnosis of breakdown of the BRB, fundus fluorescein angiography and vitreous fluorophotometry. Vitreous fluorophotometry being capable of detecting functional alterations of the barrier before any pathological changes are apparent. There is evidence of an intimate relationship between breakdown of the BRB and almost every retinal disease, particularly the vascular retinopathies and the pigment epitheliopathies. Diabetic retinopathy, hypertensive retinopathy, retinal vein obstruction, blood diseases, trauma or surgery to the eye, temporary arterial obstruction, perivasculitis, Behçet's and Coats' diseases, retinoblastoma, hemangioblastoma and retinal neovascularization are examples of situations where a breakdown of the inner BRB has been demonstrated. On the other hand, examples of breakdown of the outer BRB include situations of choroidal ischaemia, detachment of the pigment epithelium, choroidal neovascularization, photocoagulation, retinal detachment, Koyanagi's disease, central serous choroidopathy, multifocal inner choroiditis and acute placoid pigment epitheliopathy.

Animals↗