Treatment Of Retinal Neovascularization Research Articles

Suppression of retinal neovascularization by intravitreal injection of cryptotanshinone

Neovascular eye diseases, including proliferative diabetic retinopathy and retinopathy of prematurity, is a major cause of blindness. Laser ablation and intravitreal anti-VEGF injection have shown their limitations in treatment of retinal neovascularization. Identification of a new therapeutic strategies is in urgent need. Our study aims to assess the effects of Cryptotanshinone (CPT), a natural compound derived from Salvia miltiorrhiza Bunge, in retina neovascularization and explore its potential mechanism. Our study demonstrated that CPT did not cause retina tissue toxicity at the tested concentrations. Intravitreal injections of CPT reduced pathological angiogenesis and promoted physical angiogenesis in oxygen-induced retinopathy (OIR) model. CPT improve visual function in OIR mice and reduced cell apoptosis. Moreover, we also revealed that CPT diminishes the expression of inflammatory cytokines in the OIR retina. In vitro, the administration of CPT effectively inhibited endothelial cells proliferation, migration, sprouting, and tube formation induced by the stimulation of human retinal vascular endothelial cells (HRVECs) with VEGF165. Mechanistically, CPT blocking the phosphorylation of VEGFR2 and downstream targeting pathway. After all, the findings demonstrated that CPT exhibits potent anti-angiogenic and anti-inflammatory effects in OIR mice, and it has therapeutic potential for the treatment of neovascular retinal diseases.

PlGF silencing combined with PEDF overexpression: Modeling RPE secretionas potential therapy for retinalneovascularization.

Ocular neovascularization is a defining feature of several blinding diseases. We have previously described the effectiveness of long-term pigment epithelium-derived factor (PEDF) expression in the retina of diabetic mice in ameliorating some diabetic retinopathy hallmarks. In this study, we aimed to investigate if the antiangiogenic potential of PEDF overexpression was enhanced in combination with placental growth factor (PlGF) silencing. Human RPE cells were transfected with a self-replicating episomal vector (pEPito) for PEDF overexpression and/or a siRNA targeting PlGF gene. Conditioned media from PEDF overexpression, from PlGF inhibition and from their combination thereof were used to culture human umbilical vein endothelial cells, and their proliferation rate, migration capacity, apoptosis and ability to form tube-like structures were analyzed in vitro. We here demonstrate that pEPito-driven PEDF overexpression in combination with PlGF silencing in RPE cells does not affect their viability and results in an enhanced antiangiogenic activity in vitro. We observed a significant decrease in the migration and proliferation of endothelial cells, and an increase in apoptosis induction as well as a significant inhibitory effect on tube formation. Our findings demonstrate that simultaneous PEDF overexpression and PlGF silencing strongly impairs angiogenesis compared with the single approaches, providing a rationale for combining these therapies as a new treatment for retinal neovascularization.

Protective effects of different bile acids against pathological neovascularization

Emerging evidence suggest that the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine (TUDCA) conjugates, possess neuroprotective and vasculoprotective properties and may exert beneficial effects in a number of neovascular diseases including ischemic retinopathy such as retinopathy of prematurity (ROP). However, the direct activity of UDCA or TUDCA in the treatment of retinal neovascularization has not been previously investigated. Herein, we studied the effects of different bile acids on in vitro angiogenesis in human retinal endothelial cells (HuREC) and retinal vascularization in vivo using the mouse model of oxygen induced retinopathy (OIR), an experimental model of ROP. HuREC were treated with 20 ng/ml of VEGF and/or different doses (10–500 μM) of UDCA or TUDCA for different times. Angiogenic responses were evaluated using tube formation assay. Treatment of HuREC with VEGF significantly induced time dependent tube formation. UDCA dose‐dependently halted VEGF‐induced tube formation, whereas TUDCA had no effect. For the in vivo studies, mice were subjected to OIR and treated with UDCA and TUDCA (administered i.p.) from days P12–P17 (the neovascular stages). Isolectin B4 staining on flat mounted retinal preparations was performed at P17 to evaluate retinal vessel growth and distribution. The results of this analysis revealed that UDCA in the OIR mice halted pathological neovascularization, but did not alter normal vascularization. On the contrary, treatment of the mice with TUDCA failed to block retinal neovascularization, thus confirming the in vitro data. In summary, here we have shown that the bile acids UCDA and TUCDA possess differential ability to modulate VEGF‐mediated angiogenesis effects on HuREC and on retinal pathological neovascularization in vivo. The results of studies support the hypothesis that UDCA could be a potential therapeutic option for ROP as it exerts protection even by systemic administration and does not alter normal progression of vessel formation.Support or Funding InformationThis study is supported by R03HD097660‐01.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Anti-angiogenic effect of adiponectin in human primary microvascular and macrovascular endothelial cells

Neovascularization in retina and choroid involves interplay of many cytokines and growth factors. Vascular endothelial growth factor (VEGF) being a pro-angiogenic molecule has been found to be high in aqueous and vitreous humour of patients with proliferative diabetic retinopathy (PDR). VEGF is also found in the fibroblast and retinal pigment epithelial cells (RPE) of choroidal neovascular (CNV) membranes isolated from patients. Though anti-VEGF agents cause regression of clinically visible new vessels, there is evidence that they increase the occurrence of retinal tractional detachment and other adverse effects in PDR and CNV treatments. Adiponectin (APN) is a cytokine, found to be involved in the pathobiology of PDR. It is unclear whether APN plays a reparative or pathological role in the disease condition. In this study, we explored the effect of APN on tube formation in the primary culture of human umbilical vein macrovascular endothelial cells (HUVEC), human retinal microvascular endothelial cells (hREC) and human choroidal endothelial cells (hCEC). Anti-VEGF agent, bevacizumab (avastin) was used as a control. Full-length pAc-APN transfected in HUVEC, hRECs and hCECs inhibited basal tube formation and migration comparable to bevacizumab (Avastin™). In hRECs, full length pAc-APN reduced VEGF or PDR vitreous mediated migration. In a similar way, rAPN significantly disrupted VEGF and PDR vitreous induced tube formation in HUVEC and hREC. Moreover, rAPN significantly reduced VEGF influenced proliferation and phosphorylation of ERK1/2 in hREC. Altogether, our study suggests that APN may be effective in the treatment of retinal neovascularization.

Inhibition of integrin \u03b15\u03b21 ameliorates VEGF-induced retinal neovascularization and leakage by suppressing NLRP3 inflammasome signaling in a mouse model

PurposeTo assess the effect of inhibiting integrin α5β1 by ATN-161 on vascular endothelial growth factor (VEGF)-induced neovascularization (NV) and leakage causing retinal detachment in adult Tet/opsin/VEGF transgenic mice, and characterize the underlying mechanism of its function.MethodRetinas from adult Tet/opsin/VEGF transgenic mice and human retinal endothelial cells (HRECs) exposed to VEGF (treated with ATN-161 or PBS) were used to carry out immunofluorescence, RT-PCR and western blot to examine expression levels of integrin α5β1 and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome. Retinal frozen section analysis was used to assess NV and leakage causing retinal detachment.ResultsIn comparison to normal-treated mice, doxycycline-treated Tet/opsin/VEGF transgenic mice showed severe retinal detachment and higher integrin α5β1 expression. Furthermore, the retinal detachment was inhibited significantly by ATN-161. Additionally, ATN-161 treatment was associated with a conspicuous reduction in NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1, and mature interleukin-1β expression levels in the retinas of Tet/opsin/VEGF transgenic mice treated with doxycycline as well as in HRECs exposed to VEGF.ConclusionATN-161, an antagonist of integrin α5β1, is a promising treatment for retinal neovascularization (RNV), and its retinal protection role appears to take effect through inhibition of NLRP3 inflammasome activity.

Infliximab for the treatment of posterior uveitis with retinal neovascularization in Behet disease.

To report a case of posterior uveitis with retinal neovascularization in a patient with Behet disease treated with infliximab. A 50-year-old man with a history of recurrent relapses of ocular inflammation despite immunosuppressive therapy developed retinal neovascularization near the optic disk. The patient was treated with infliximab and followed up for 12 months. Retinal neovascularization regressed 8 months after the first antitumor necrosis factor (TNF) treatment and with six infusions of infliximab. The ocular inflammation resolved almost completely. The result suggests that anti-TNF therapy may be effective in the treatment of retinal neovascularization caused by panuveitis in Behet disease. (Eur J Ophthalmol 2004; 14: #-8).

Intravitreal bevacizumab in treatment of retinal neovascularization from tuberculous retinal vasculitis.

Intravitreal bevacizumab in treatment of retinal neovascularization from tuberculous retinal vasculitis.

MicroRNA-370 suppresses the retinal capillary endothelial cell growth by targeting KDR gene.

Ocular neovascularization (NV) is the one of the major causes of blindness in many ocular diseases. Currently, the administration of anti-VEGF agents has been widely accepted for the clinical management of these devastating diseases. However, the short effective duration and the non-responsive rate due to the protein nature of the anti-VEGF antibodies warrants further investigations to explore alternative angiogenic suppressants. Evidence suggested that microRNA-370 could inhibit the formation of vessels. However, the exact mechanism has not yet been clarified. To investigate the regulatory role of microRNA-370 in the growth and apoptosis of retinal capillary endothelial cells and association between microRNA-370 and kinase insert domain-containing receptor (KDR) gene. The effects of miRNA-370 on cell cycle and apoptosis, as well as the expression of cycle- and apoptosis-related genes, were determined using MTT, TUNEL assay, qRT-PCR, and Western blot. The direct target of miRNA-370 was confirmed using 3' untranslated region (UTR) luciferase reporter assay. The miRNA-370 induced growth inhibition and apoptosis of retinal capillary endothelial cell while the inhibition of miRNA-370 reversed these effects. miRNA-370 upregulated the expression of CyclinD1, p21, p27, FasL, and Bim. Furthermore, miR-370 directly reduced the expression of KDR by targeting its 3'untranslated region. MicroRNA-370 inhibits the expression of KDR gene resulting in retinal capillary endothelial cell growth inhibition and apoptosis, which could be of value in the treatment of retinal neovascularization (Tab. 1, Fig. 5, Ref. 27).

Planned Preterm Delivery and Treatment of Retinal Neovascularization in Norrie Disease

Planned Preterm Delivery and Treatment of Retinal Neovascularization in Norrie Disease

Small interference RNA targeting vascular endothelial growth factor gene effectively attenuates retinal neovascularization in mice model

Background The mechanism of retinal neovascularization is not understood completely. Many growth factors are involved in the process of retinal neovascularization, such as vascular endothelial growth factor (VEGF) and pigment epithelium-deprived factor (PEDF), which are the representatives of angiogenic and antiangiogenic molecules respectively. Oxygen induced retinopathy (OIR) is a useful model to investigate retinal neovascularization. The present study was conducted to investigate the feasibility of small interference RNA (siRNA) targeting VEGF gene in attenuating oxygen induced retinopathy (OIR) by regulating VEGF to PEDF ratio (VEGF/PEDF). Methods In vitro, cultured EOMA cells were transfected with VEGF-siRNA (psi-HITM/EGFP/VEGF siRNA) and LipofectamineTM 2000 for 24, 48, and 72 hours, respectively. Expression of VEGF mRNA was evaluated by real time polymerase chain reaction (PCR) and the level of VEGF protein was analyzed by Western blotting. In vivo, OIR model mice were established, the mice (C57BL/6J) received an intra-vitreal injection of 1 μl of mixture of psi-HITM/EGFP/VEGF siRNA and Lipofectamine 2000. Expressions of retinal VEGF and PEDF protein were measured by Western blotting, retinal neovascularization was observed by fluorescein angiography, and quantified. Results In vitro psi-HITM/EGFP/VEGF siRNA treatment significantly reduced VEGF mRNA and protein expression. In vivo, with decreased VEGF and VEGF-PEDF ratio, significant attenuation of neovascular tufts, avascular regions, tortuous, and dilated blood vessels were observed in the interfered animals. Conclusions VEGF plays an important role in OIR, and the transfection of VEGF-siRNA can effectively downregulate VEGF expression in vivo, accompanied by the downregulation of VEGF-PEDF ratio, and simultaneous attenuation of retinal neovascularization was also observed. These findings suggest that VEGF/PEDF may serve as a potential target in the treatment of retinal neovascularization and RNA interference targeting VEGF expression, which represents a possible therapeutic strategy.

Endothelial Tip Cells in Ocular Angiogenesis

Endothelial tip cells are leading cells at the tips of vascular sprouts coordinating multiple processes during angiogenesis. In the developing retina, tip cells play a tightly controlled, timely role in angiogenesis. In contrast, excessive numbers of tip cells are a characteristic of the chaotic pathological blood vessels in proliferative retinopathies. Tip cells control adjacent endothelial cells in a hierarchical manner to form the stalk of the sprouting vessel, using, among others, the VEGF-DLL-Notch signaling pathway, and recruit pericytes. Tip cells are guided toward avascular areas by signals from the local extracellular matrix that are released by cells from the neuroretina such as astrocytes. Recently, tip cells were identified in endothelial cell cultures, enabling identification of novel molecular markers and mechanisms involved in tip cell biology. These mechanisms are relevant for understanding proliferative retinopathies. Agents that primarily target tip cells can block pathological angiogenesis in the retina efficiently and safely without adverse effects. A striking example is platelet-derived growth factor, which was recently shown to be an efficacious additional target in the treatment of retinal neovascularization. Here we discuss these and other tip cell-based strategies with respect to their potential to treat patients with ocular diseases dominated by neovascularization.

Human Apolipoprotein(a) Kringle V Inhibits Ischemia-Induced Retinal Neovascularization via Suppression of Fibronectin-Mediated Angiogenesis

Retinal neovascularization is observed in progression of diabetic retinopathy. New vessels grow into the vitreous cavity in proliferative diabetic retinopathy, resulting in traction retinal detachment and vitreous hemorrhage. To overcome the catastrophic visual loss due to these complications, efforts have been focused on the treatment of retinal neovascularization. In this study, we demonstrated the inhibitory effect of recombinant human apolipoprotein(a) kringle V (rhLK8) in an animal model of ischemia-induced retinal neovascularization. rhLK8 induced no definite toxicity on endothelial cells and retinal tissues at the therapeutic dosage. Interestingly, rhLK8 showed antiangiogenic effect, particularly on fibronectin-mediated migration of endothelial cells. Further experiments demonstrated high binding affinity of rhLK8 to α3β1 integrin, and suppression of it might be the mechanism of antiangiogenic effect of rhLK8. Furthermore, rhLK8 inhibited phosphorylation of focal adhesion kinase, resulting in suppression of activation of consequent p130CAS-Jun NH2-terminal kinase. Taken together, our data suggested the possible application of rhLK8 in the treatment of retinal neovascularization by suppression of fibronectin-mediated angiogenesis.

RhoA Activation and Effect of Rho-kinase Inhibitor in the Development of Retinal Neovascularization in a Mouse Model of Oxygen-induced Retinopathy

Purpose: To study RhoA activation and the effect of the Rho-kinase inhibitor in the development of retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR).Methods: C57BL/6 mice at postnatal day (P7) were exposed to hyper-oxygen for 5 days and returned to room air for 5 days to induce OIR. RhoA-GTP, an active form of RhoA, in retinas at P12, P13 and P17 was detected. Mice received a single intravitreal injection of Y27632 (5 µM or 50 µM), a Rho-kinase inhibitor, in one eye during the transition from oxygen to room air at P12. Contralateral eyes were used as the control. Fluorescein-conjugated dextran angiography of retinal whole mount was prepared to score features of neovascular retinopathy at P17. The preretinal neovascular nuclei quantification was performed in frozen sections as well to evaluate the neovascularization.Results: The retinal RhoA-GTP in OIR mice significantly increased from 0.24 ± 0.06 at P12 to 0.38 ± 0.12 at P13 (p < 0.05). The median total retinopathy score of 5.7 was significantly lower in eyes treated with Y27632 than controls (p < 0.001). Significant improvement was found in the specific categories of vascular tufts (p < 0.01) and extraretinal neovascularization (p < 0.05) in treated eyes. Those treated eyes also had a significantly decreased number of neovascular nuclei (p < 0.01).Conclusions: These results suggest that Rho/Rho-kinase signaling pathways are involved in the early process of hypoxia-induced retinal neovascularization and Y27632 might have therapeutic potential for the treatment of retinal neovascularization.

Dual Targeting of Retinal Vasculature in the Mouse Model of Oxygen Induced Retinopathy

Hypoxia-inducible factor-1 (HIF-1) plays crucial roles in retinal neovascularization (NV) by upregulating its target genes, which are involved in anaerobic energy metabolism, angiogenesis, cell survival, cell invasion, and drug resistance. Therefore, it is apparent that the inhibition of HIF-1 activity may be a strategy for treating retinal angiopathies. Many efforts to develop new HIF-1-targeting agents have been made by both academic and pharmaceutical industry laboratories. The future success of these efforts will be a new class of HIF-1-targeting agents, which could be utilized in the treatment of several ocular pathologies. This review focuses on the potential of HIF-1 as a target molecule for the treatment of retinal NV, and on possible strategies to inhibit HIF-1 activity. In addition, we introduce YC-1 as a new anti- HIF-1, anti-neovascular agent in the retinal model. Although YC-1 was originally developed as a potential therapeutic agent for thrombosis and hypertension, recent studies demonstrated that YC-1 suppressed HIF-1 activity and vascular endothelial growth factor expression in retinal microvascular endothelial cells. Moreover, it inhibited retinal NV in the oxygen-induced retinopathy (OIR) mouse model without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anti-neovascular agents that could be used in the retinal pathologies.

Sorafenib protects human optic nerve head astrocytes from light-induced overexpression of vascular endothelial growth factor, platelet-derived growth factor, and placenta growth factor

Objectives: Growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and placenta growth factor (PlGF) are key players in the development of diabetic retinopathy, age-related macular degeneration, and other retinal neovascular diseases. Glial cells provide a significant source of retinal growth factor production under physiologic and pathologic conditions. Cumulative light exposure has been linked to increased retinal growth factor expression. Previous reports indicate that sorafenib, an oral multikinase inhibitor, might have a beneficial effect on retinal neovascularization. This study was designed to investigate the effects of sorafenib on light-induced overexpression of growth factors in human retinal glial cells.Methods: Primary human optic nerve head astrocytes (ONHAs) were exposed to white light and incubated with sorafenib. Viability, expression, and secretion of VEGF-A, PDGF-BB, and PlGF and their mRNA were determined by reverse transcription-polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay.Results: Light exposure decreased cell viability and increased VEGF-A, PDGF-BB, and PlGF expression and secretion. These light-induced effects were significantly reduced when cells were treated with sorafenib at a concentration of 1 μg/ml.Conclusion: Sorafenib significantly reduced light-induced overexpression of VEGF-A, PDGF-BB, and PlGF in primary human ONHAs. Sorafenib has promising properties as a potential supportive treatment for retinal neovascularization.

Plasminogen activator inhibitor-1 (PAI-1) facilitates retinal angiogenesis in a model of oxygen-induced retinopathy.

Angiogenesis, or the formation of new retinal blood vessels, is a key feature of many proliferative retinal diseases including diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. The aim of the present study was to investigate the role of the serine proteinase inhibitor plasminogen activator inhibitor -1 (PAI-1) in facilitating retinal angiogenesis. The temporal expression of PAI-1 was examined by real-time PCR, Western blot analysis, and immunohistochemistry in retinal tissues from mice with oxygen-induced retinopathy. The requirement for PAI-1 in facilitating the retinal angiogenic response in this model was examined by quantitating the angiogenic response with wild-type and PAI-1 null mice. The mechanism by which PAI-1 mediates angiogenesis was further investigated with isolated human retinal vascular endothelial cells. PAI-1 expression was upregulated in the retinas of mice with oxygen-induced retinopathy, which coincided with a significant increase in the expression of vitronectin in the retina of the experimental mice. There was significant reduction in the angiogenic response of PAI-1(-/-) mice compared with wild-type mice. PAI-1 promotes endothelial cell migration in vitro and facilitates the migration of cells on a vitronectin substrate by regulating alpha v integrin cell surface expression. These observations suggest a role for PAI-1 during retinal angiogenesis and point to a potential new therapeutic target in the prevention or treatment of retinal neovascularization seen in many ocular diseases.

Intravitreal Injection of Bevacizumab in Eales Disease

Purpose: To report a case of presumed Eales disease that showed regression of retinal neovascularization after the use of intravitreal bevacizumab. Design: Retrospective, interventional case report. Methods: Broad retinal neovascularization in a patient with presumed Eales disease did not regressed despite adequate photocoagulation treatment, and bevacizumab (1.25 mg) was injected intravitreally. The patient was followed up for 1 year. Results: One week after injection, fluorescein angiography demonstrated dramatic regression of retinal neovascularization. After 12-months, visual acuity was improved and no signs of recurrence were observed. Conclusion: Intravitreal bevacizumab may be effective as an adjunctive treatment of retinal neovascularization in patients with Eales disease.

Exploring the molecular mechanism of ocular angiogenesis inhibition by triamcinolone acetonide

Evaluation of: Ebrahem Q, Minamoto A, Hoppe G et al. Triamcinolone acetonide inhibits IL-6- and VEGF-induced angiogenesis downstream of the IL-6 and VEGF receptors. Invest. Ophthalmol. Vis. Sci. 47(11), 4935–4941 (2006).Ocular neovascularization (NV) is a disease characterized by uncontrolled new blood vessel formation from pre-existing vasculature that leads to vascular leakage and, eventually, vision loss. Pathological NV is closely associated with expression of cytokines and growth factors, such as vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). Administration of triamcinolone acetonide (TA) by intravitreal injection is a commonly used treatment for retinal NV. This paper demonstrates that TA blocks IL-6- and VEGF-mediated angiogenesis through the mifepristone-sensitive steroid receptor and that TA inhibits VEGF action downstream of VEGF receptors. Elucidation of molecular mechanisms of TA action may provide potential new therapeutic strategies for treating ocular NV.

Infliximab for the Treatment of Posterior Uveitis with Retinal Neovascularization in Behçet Disease

Purpose To report a case of posterior uveitis with retinal neovascularization in a patient with Behçet disease treated with infliximab. Methods A 50-year-old man with a history of recurrent relapses of ocular inflammation despite immunosuppressive therapy developed retinal neovascularization near the optic disk. The patient was treated with infliximab and followed up for 12 months. Results Retinal neovascularization regressed 8 months after the first anti–tumor necrosis factor (TNF) treatment and with six infusions of infliximab. The ocular inflammation resolved almost completely. Conclusions The result suggests that anti-TNF therapy may be effective in the treatment of retinal neovascularization caused by panuveitis in Behçet disease.

Efficacy of Prinomastat® (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization

Purpose. To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat ®) , a selective inhibitor of matrix metalloproteases, in an animal model of retinal neovascularization. Methods. C57BL/6J mice were used to produce oxygen-induced retinal neovascularization. Mice were exposed to room air from birth (P0) to postnatal 7 days (P7) and to hyperoxia (75% oxygen) for the next 5 days. On postnatal day 12 (P12) the animals were returned to the room air and were treated until postnatal day 16 (P16) with intraperitoneal injections of AG 3340. Four groups were assigned: no drug, 1.6 mg/kg/day, 16 mg/kg/day and 48 mg/kg/day. On day 17 (P17) the animals were sacrificed and the eyes prepared for histological sectioning. Preretinal neovascularization was assessed by counting neovascular nuclei of endothelial cells in the preretinal side of the internal limiting membrane (ILM). The use of animals for this study complies with the ARVO guidelines for animal research. Results. AG3340 administered systemically by intraperitoneal injections inhibited hypoxia-induced retinal neovascularization. The inhibition was dose dependent with highly significant decrease of neovascular nuclei counts among eyes treated with 0, 1.6 mg/kg, 16 mg/kg and 48 mg/kg doses. There appears to be a saturation effect of inhibition at the level of 70% at the two highest doses of 16 mg/kg and 48 mg/kg. Conclusions. AG3340 administered systemically significantly inhibits oxygen-induced retinal neovascularization in an animal model and appears to be a promising candidate for the treatment of neovascular retinal diseases.