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PURPOSE: To report retinal neovascularization associated with retinoblastoma in a 14-month-old infant. DESIGN: Observational case report. METHODS: Review of clinical and pathologic findings. RESULTS: A large frond of retinal neovascularization was present posterior to the lens in the right eye, which also contained a retinoblastoma. CONCLUSIONS: Retinal neovascularization is an unusual association with retinoblastoma.
OBJECTIVES: To determine the role of extracellular proteinases in ischemia-induced retinal neovascularization in an animal model and to examine the effect of proteinase inhibitors on retinal neovascularization. METHODS: Retinal neovascularization was induced in newborn mice exposed to 75% oxygen for 5 days, followed by room air. Retinal extracts underwent zymographic analysis to measure the activity of urokinase and matrix metalloproteinases (MMPs). Some animals under the same conditions also received intraperitoneal injections of an MMP inhibitor. Histological analysis was done to quantitate the neovascular response in these animals. RESULTS: Levels of urokinase and MMPs (MMP-2 and MMP-9) in retinas were significantly increased in animals with induced retinal neovascularization. Neovascularization was significantly inhibited with intraperitoneal administration of an MMP inhibitor. CONCLUSION: Systemic inhibition of MMPs may have therapeutic potential in preventing retinopathy associated with retinal neovascularization. CLINICAL RELEVANCE: Because up-regulation and activation of proteinases represents a final common pathway in the process of retinal neovascularization, pharmacological intervention of this pathway may be an alternative therapeutic approach to proliferative retinopathy.
OBJECTIVE: To determine the effect of thiazolidinediones (TZDs) on experimental retinal neovascularization. METHODS: The ability of the TZDs troglitazone and rosiglitazone maleate (1-20 micromol/L) to inhibit retinal endothelial cell (REC) proliferation, migration, tube formation, and signaling was determined in response to vascular endothelial growth factor (VEGF). In vivo studies were performed using the oxygen-induced ischemia model of retinal neovascularization. Neonatal mice were treated with intravitreous injection of 0.5 microL of troglitazone (100 micromol/L) or rosiglitazone maleate (100 micromol/L), or vehicle, and retinal neovascularization was assayed qualitatively and quantitatively by means of angiography and histological examination. RESULTS: Expression of the TZD receptor, peroxisome proliferator-activated receptor gamma, was confirmed in RECs by means of Western immunoblotting. Rosiglitazone and troglitazone inhibited VEGF-induced migration (P< .05), proliferation (P< .05), and tube formation (P< .01) by RECs in vitro beginning at 10 micromol/L. Rosiglitazone and troglitazone inhibited phosphorylation of extracellular signal-regulated mitogen-activated protein kinase 1 in RECs. Intravitreous injection of rosiglitazone or troglitazone inhibited development of retinal neovascularization (P< .01) but did not significantly inhibit VEGF overexpression in the ganglion cell layer of the ischemic retina. CONCLUSION: The TZDs inhibit experimental retinal neovascularization with an effect that is primarily downstream of VEGF expression. CLINICAL RELEVANCE: The TZDs are widely prescribed and should be evaluated for their potential to inhibit the progression of diabetic retinopathy.
PURPOSE: The objective of the study was to determine the role of urokinase (uPA) and the urokinase receptor (uPAR) in retinal angiogenesis, and whether loss of uPAR or the inhibition of uPA/uPAR interactions could suppress the extent of retinal neovascularization in an animal model of ischemic retinopathy. METHODS: Retinal neovascularization was induced by exposing newborn mice to 75% oxygen on postnatal day 7 for 5 days, followed by exposure to room air on days 12 to 17. The expression of uPAR in the retina was investigated by RT-PCR and immunohistochemistry. The role of uPAR in ischemic retinopathy was investigated by quantitating the extent of retinal neovascularization in the uPAR(-/-) mouse. The effects of inhibiting the uPA/uPAR interaction on the development of retinal neovascularization were studied in this animal model with a uPA-derived peptide, A6. Animals were treated with an intraperitoneal injection of A6 at a dose of 5, 10, or 100 mg/kg once a day on days 12 to 16. Control animals included oxygen-exposed mice treated with similar amounts of PBS only on days 12 to 16. The effect of A6 on the expression of uPAR in the retina was examined by real-time RT-PCR. RESULTS: The expression of uPAR mRNA was upregulated in experimental animals during the period of angiogenesis and was localized to endothelial cells in the superficial layers of the retina. The uPAR(-/-) mouse demonstrated normal retinal vascular development; however, the absence of functional uPAR resulted in a significant reduction in the extent of retinal neovascularization. Histologic analysis of mice treated with A6 peptide showed significant inhibition of retinal neovascularization, and the response was dose dependent. The RT-PCR analysis of the retinas of the A6-treated animals showed a greater than twofold decrease in uPAR expression. CONCLUSIONS: Expression of the urokinase receptor uPAR is essential to the development of retinal neovascularization. Inhibition of the activity of uPAR suppresses retinal neovascularization, possibly through a reduction in cell-associated proteolytic activity, cell signaling, or cell-matrix adhesion necessary for cell migration during angiogenesis. The uPA/uPAR interaction may be an important therapeutic target in the management of proliferative retinopathies.
OBJECTIVE: To study effects of intravitreal pegaptanib (Macugen) on retinal neovascularization. DESIGN: Retrospective analysis of a randomized clinical trial. PARTICIPANTS, INTERVENTION, AND MAIN OUTCOME MEASURES: Individuals with retinal neovascularization identified from a multicenter, randomized, controlled trial evaluating pegaptanib for treatment of diabetic macular edema, with a best-corrected visual acuity letter score between 68 and 25 (approximate Snellen equivalent between 20/50 and 20/320) and receiving a sham injection or intravitreal pegaptanib (0.3 mg, 1 mg, 3 mg) administered at study entry, week 6, and week 12, with additional injections and/or focal photocoagulation as needed during the ensuing 18 weeks, up to a maximum of 6 pegaptanib/sham therapies, were evaluated. Scatter panretinal photocoagulation before study enrollment was permitted, but not within 6 months of randomization and study entry. Changes in retinal neovascularization were assessed on fundus photographs and fluorescein angiograms graded at a reading center in a masked fashion. RESULTS: Of 172 participants, 19 had retinal neovascularization in the study eye at baseline. Excluding 1 who had scatter photocoagulation 13 days before randomization and 2 with no follow-up photographs, 1 of the remaining 16 subjects had panretinal photocoagulation during study follow-up. Of these 16 subjects, 8 of 13 (62%) in a pegaptanib treatment group (including the one receiving panretinal photocoagulation), 0 of 3 in the sham group, and 0 of 4 fellow (nonstudy) eyes showed either regression of neovascularization on fundus photographs or regression or absence of fluorescein leakage from neovascularization (or both) at 36 weeks. In 3 of 8 with regression, neovascularization progressed at week 52 after cessation of pegaptanib at week 30. CONCLUSIONS: Most subjects with retinal neovascularization at baseline assigned to pegaptanib showed regression of neovascularization by week 36. These findings suggest a direct effect of pegaptanib upon retinal neovascularization in patients with diabetes mellitus.
Thrombospondin-1 is an extracellular matrix protein that inhibits endothelial cell proliferation, migration, and angiogenesis. This study was performed to investigate the role of thrombospondin-1 in ischemic retinal neovascularization. In a murine model of retinal neovascularization, thrombospondin-1 mRNA was increased from postnatal day 13 (P13), with a threefold peak response observed on P15, corresponding to the time of development of retinal neovascularization. Prominent expression of thrombospondin-1 was observed in neovascular cells, specifically, cells adjacent to the area of nonperfusion. It has been suggested that vascular endothelial growth factor (VEGF) plays a major role in ischemia-induced retinal neovascularization of this model, so we studied the effects of VEGF on thrombospondin-1 expression. In bovine retinal microcapillary endothelial cells, VEGF induced a biphasic response of thrombospondin-1 expression; VEGF decreased thrombospondin-1 mRNA 0.41-fold after 4 hours, whereas it increased, with a threefold peak response, after 24 hours. VEGF-induced endothelial cell proliferation was completely inhibited by exogenous thrombospondin-1 and increased by 37.5% with anti-thrombospondin-1 antibody. The present findings suggest that, in the ischemic retina, retinal neovascular cells increase thrombospondin-1 expression, and VEGF may stimulate endogenous thrombospondin-1 induction, which inhibits endothelial cell growth. VEGF-mediated thrombospondin-1 induction in ischemia-induced angiogenesis may be a negative feedback mechanism.
Peripheral retinal neovascularization occurs in approximately 10% of cases of sarcoidosis. Its pathogenesis is unknown, but it probably results from retinal ischemia and/or inflammation. In cases of peripheral retinal neovascularization associated with sarcoidosis, sickle cell disease should be considered, even if sarcoidosis is histologically proved: new vessels seen in sickle cell disease and sarcoidosis may have a very similar pattern. We present two cases with histologically proven sarcoidosis who developed peripheral neovascularization: the first one had no associated disease and new vessels were likely to be related to sarcoidosis; in the second case, hemoglobin electrophoresis revealed hemoglobin SC, and provided diagnosis of sickle cell hemoglobinopathy.
PURPOSE: Hypoxia and growth factors are postulated to be involved in the development of retinal neovascularization through the regulation of extracellular proteinase production. It has been shown that matrix metalloproteinases (MMPs) are elevated in the retina during the neovascularization process. However, the factors and mechanisms that regulate the expression of these enzymes are not well characterized. The present study examines the potential role of tumor necrosis factor (TNF)-alpha as a regulator of MMPs in the retinal neovascularization process. METHODS: C57/Bl6 mice were treated with 75% oxygen (experimental) or room air (control) from postnatal days (P)7 through P12, followed by room air until P17. Retinas were collected at P13, P15, or P17 and total RNA analyzed for the relative level of TNFalpha, TNF receptor (p55), and TNFalpha-converting enzyme (TACE). Immunostaining was used to identify changes in TNF protein expression as well as to localize TNFalpha within specific retinal cell types. The role of TNFalpha in stimulating retinal microvascular endothelial cell (RMVEC) proteinase production was evaluated using isolated murine RMVECs grown in normoxic or hypoxic conditions. Message expression was analyzed by RT-PCR and protein expression by zymographic analysis. RESULTS: TNFalpha mRNA was increased in the retinas of experimental animals on P13 and P15, during the early stages of retinal neovascularization. In addition to being expressed by Müller glial cells and the inner nuclear layer, additional expression was noted in the outer nuclear layer of experimental animals. No significant level of apoptosis was detected in the retina of experimental animals with retinal neovascularization. Isolated RMVECs did not significantly increase MMP production directly in response to a hypoxic stimulus, but required the presence of exogenous TNFalpha. TNFalpha increased the expression of MT1-MMP, MMP-3, and MMP-9 in these cells. The levels of TACE and p55, proteins important in mediating the response of cells to TNFalpha, were found to be increased by the angiogenic protein, vascular endothelial growth factor (VEGF), which was also elevated in the experimental retinas. CONCLUSIONS: TNFalpha levels increase in experimental mouse retinas exposed to hypoxic stimuli. Increased production of MMPs by RMVECs does not occur directly in response to a hypoxic stimulus. These cells are responsive, however, to stimulation by TNFalpha, which enhances the production of specific members of the MMP family. VEGF also plays a role in this process through its regulation of TACE and p55 mRNA in the vascular endothelial cells. These findings support the hypothesis that these two growth factors have a role in the regulation of extracellular proteinase expression during retinal neovascularization.
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.
Basic fibroblast growth factor (FGF2) is constitutively expressed in the retina and its expression is increased by a number of insults, but its role in the retina is still uncertain. This study was designed to test the hypothesis that altered expression of FGF2 in the retina affects the development of retinal neovascularization. Mice with targeted disruption of the Fgf2 gene had no detectable expression of FGF2 in the retina by Western blot, but retinal vessels were not different in appearance or total area from wild-type mice. When FGF2-deficient mice were compared with wild-type mice in a murine model of oxygen-induced ischemic retinopathy, they developed the same amount of retinal neovascularization. Transgenic mice with a rhodopsin promoter/Fgf2 gene fusion expressed high levels of FGF2 in retinal photoreceptors but developed no retinal neovascularization or other abnormalities of retinal vessels; in the ischemic retinopathy model, they showed no significant difference in the amount of retinal neovascularization compared with wild-type mice. These data indicate that FGF2 expression is not necessary nor sufficient for the development of retinal neovascularization. This suggests that agents that specifically antagonize FGF2 are not likely to be useful adjuncts in the treatment of retinal neovascularization and therapies designed to increase FGF2 expression are not likely to be complicated by retinal neovascularization.
Retinal neovascularization is central to the pathogenesis of proliferative diabetic retinopathy, the leading cause of blindness among the middle-aged population. Angiostatin, a proteolytic fragment of plasminogen is one of the most promising inhibitors of angiogenesis currently in clinical trials. Here we show that recombinant angiostatin can inhibit retinal neovascularization in a mouse model of proliferative retinopathy. Because proliferative diabetic retinopathy is a recurrent disease, effective therapy will need to be sustained. Recombinant adeno-associated viruses permit long-term expression of transfected genes; however, they can only accommodate a small insert sequence. Thus, we engineered and tested a shortened recombinant angiostatin derivative containing a signal sequence to permit secretion. Recombinant protein was purified from the medium of transfected HEK293 cells and injected subcutaneously into treated animals. The retinal vasculature was analyzed in retinal flat mounts and using immunohistochemically stained sections. Both methods demonstrate that this short, secreted form of angiostatin is effective in reducing the development of blood vessels in a nontumor environment and has therapeutic potential for neovascular retinopathies such as diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion and, possibly, age-related macular degeneration.
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.
PURPOSE: The role of adenosine receptor (AdoR) antagonists in human retinal endothelial cell function in vitro has previously been determined. In this study, efficacy of AdoR antagonist administration in reducing retinal neovascularization was examined in a mouse pup model of oxygen-induced retinopathy. METHODS: A previously described model of oxygen-induced retinal neovascularization in newborn mouse pups was used to examine the effect of various AdoR antagonists on neovascularization. The nonselective AdoR antagonist xanthine amine congener (XAC), the A(2A)-selective antagonist ZM241385, the A(2B)-selective antagonists 3-N-propylxanthine (enprofylline) and 3-isobutyl-8-pyrrolidinoxanthine (IPDX), and the A(1)-selective antagonist cyclopentyl-1,3-dipropylxanthine (CPX) were used. After the hyperoxia exposure the animals received daily intraperitoneal injections of pharmacologically relevant doses of AdoR antagonists for 5 days. Control animals received vehicle (0.1% dimethyl sulfoxide [DMSO]) alone. The animals were then killed and perfused with fluorescein-dextran. Wholemounts of retinas from one eye were prepared and examined, whereas the retinas of the contralateral eye were embedded, sectioned, and stained for counting neovascular nuclei extending beyond the internal limiting membrane into the vitreous. RESULTS: Angiography of wholemount retinas showed reduction of neovascular tufts in animals treated with selective A(2B) AdoR antagonists. Quantification of the extraretinal neovascular nuclei showed that only animals treated with XAC, enprofylline, or IPDX showed a significant reduction in retinal neovascularization. By contrast, neither CPX nor ZM241385 had an effect on neovascularization. CONCLUSIONS: The A(2B)-selective AdoR antagonists inhibited oxygen-induced retinal neovascularization in vivo and may provide a basis for developing pharmacologic therapies for the treatment of proliferative retinopathies.
PURPOSE: To determine the effects of tetrathiomolybdate (TM), a copper-chelating agent, on retinal angiogenesis and vascular endothelial growth factor (VEGF) in a mouse model of retinal neovascularization. METHODS: Postnatal day (P)7 C57BL/6N mice were exposed to 75% +/- 2% oxygen for 5 days (P7-P11) and then returned to room air for 5 days (P12-P17) to induce retinal neovascularization. Beginning on P10 or P12, mice received daily intraperitoneal injections of TM or phosphate-buffered saline (PBS; control) through P17. Retinal neovascularization was examined by fluorescein dextran angiography after 5 days in room air and was quantitated histologically by counting the neovascular endothelial cell nuclei anterior to the inner limiting membrane. TM's effects on VEGF expression were measured by ELISA. RESULTS: TM-treated and control animals demonstrated comparable regions of retinal nonperfusion. Retinas from control mice at P17 contained neovascular tufts at the junction between perfused and nonperfused retina. The tufts contained numerous neovascular nuclei. Retinas from mice treated with TM beginning on P10 (2 days before returning to room air), but not P12, demonstrated a 41% reduction in neovascular cell nuclei compared with control mice (P <0.01). The P10-treated mice also demonstrated a 24% reduction of VEGF compared with control animals (P=0.01). CONCLUSIONS: TM significantly inhibits retinal neovascularization and VEGF production in a mouse model of retinal neovascularization.
OBJECTIVE: To study the effect and therapeutically role of octreotide on retinal neovascularization. METHOD: (1) Forty one-week-old mice were randomly divided into five groups, in which four groups were exposed to 75% oxygen to establish a model of retinal neovascularization, the other group were fed in the normal environment. Mice in control group did not receive any treatment. The two experimental groups were given acetate octreotide by subcutaneous injection at the dose of 20 microg.kg(-1) and 50 microg.kg(-1) respectively twice a day for five days while the control group was given sterile PBS subcutaneously. (2) The mice were sacrificed on 17-day, the eyes were enucleated for histological examination using light and electron microscopy. (3) The effect of acetate octreotide on retinal vessels formation was assessed by counting the number of endothelial cells of new vessels extending from retina to vitreous of 4 microm sagittal retinal cross sections under the light microscope. The expression of SSTR2 in the mice retina was determined by situ hybridization. The change of retinal ultrastructure was observed under the electron microscopy. RESULTS: (1) HE staining: The numbers of endothelial cells of new vessels extending form retina to vitreous in the experimental groups were much less than the control and hyperoxia group (P < 0.01). (2) Situ hybridization showed that SSTR2 expressed in the nurtroganglion layer, endothelial cells and inner nuclear layer in the normal, control and hyperoxia group while the octreotide treated retina showed only light positive staining of SSTR2 in the nurtroganglion layer. (3) Electron microscopy showed hypoxia caused the damage of photoreceptor cells but the damage abated considerably after the mice were treated by the octreotide. CONCLUSION: Subcutaneous injection of octreotide may suppress the retinal neovascularization in the mice oxygen model and provide some of protection from the damage of retinal ultrastructure.
Retinal neovascularization (NVR) is a common complication of diabetes, which can cause legal blindness. This article presents the results of a study on 32 diabetic patients with NVR treated by DIODE LASER panretinal fotocoagulation.
PURPOSE: Perforation injury to the eye can protect against retinal degeneration and pigment epithelial derived factor (PEDF) may play a role in this neuro-protective effect. PEDF has also been shown to possess potent anti-angiogenic properties. The current study has investigated a possible anti-angiogenic effect of penetrating ocular injury in a murine model of oxygen induced proliferative retinopathy (OIR) and determined if such a procedure alters PEDF expression in the retina. METHODS: OIR was produced by exposure of neonatal mice to 75% oxygen between postnatal days 7 and 12 (P7-P12). Mice were separated into various groups, with one group receiving a penetrating injury in a single eye. Pre-retinal neovascularization and intra-retinal ischaemia was quantified at P17 and PEDF protein expression was determined using immunofluorescence in retinal flatmounts and sections. PEDF mRNA was quantified using real-time RT-PCR. RESULTS: Punctured eyes showed less pre-retinal neovascularization at P17 when compared to the non-punctured eyes (p<0.001) although there was no effect on retinal ischaemia. PEDF immunreactivity was strongest in the ganglion cells of the retina, and intensity increased in punctured eyes at P13. There was more immunoreactive PEDF in ganglion cells adjacent to retinal venules than arterioles. At P13, retinal PEDF mRNA was also increased in punctured eyes compared to non-punctured controls (p<0.05), although there was no differential at P17. CONCLUSIONS: Penetrating ocular injury suppresses retinal neovascularization and modulates expression of PEDF. These findings have implications for intra-vitreal delivery of angiostatic agents since ocular perforation may provoke an acute, endogenous anti-angiogenic response that should be taken into account.
Retinal neovascularization is a serious complication of the retinopathy associated with diabetes, branch vein occlusion, sickle cell anemia, and retrolental fibroplasia. Retinal capillary nonperfusion, demonstrated on fluorescein angiography, precedes the development of neovascularization in each of these conditions. Our working hypothesis is that the nonperfused (ischemic or hypoxic) retina liberates a vasoproliferative or angiogenic substance. Although I have delineated the clinical and experimental observations relating to the hypothesis of an ischemic-mediated angiogenesis substance, other postulated mechanisms for the development of retinal neovascularization may be involved. Recent observations on the experimental model of retrolental fibroplasia have demonstrated the markedly abnormal persistence and apparent proliferation of the hyaloid vessels in mice following oxygen-induced retinal vascular closure.