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PubMed1996

Antagonists of integrin alpha v beta 3 inhibit retinal neovascularization in a murine model.

Integrin alpha v beta 3 is differentially expressed in angiogenic blood vessels in skin granulation tissue, and alpha v beta 3 antagonists inhibit angiogenesis in chick chorioallantoic membranes. In this study, we investigated the role of alpha v beta 3 in retinal neovascularization. There was no detectable signal for alpha v beta 3 by immunohistochemistry in normal human retina, but neovascular tissue removed from the surface of the retina of patients with diabetic retinopathy showed intense staining for alpha v beta 3 within the endothelial cells of new blood vessels. In a murine model of oxygen-induced ischemic retinopathy, there was intense staining for alpha v beta 3 in endothelial cells participating in neovascularization but no detectable staining in normal retinal blood vessels of adult mice. Synthetic peptides that bind alpha v beta 3 and perturb alpha v beta 3-mediated adhesion in vitro inhibited retinal neovascularization in the murine model when given by intraperitoneal or periocular injections. These data suggest that alpha v beta 3 antagonists may provide a useful adjunct for the treatment of retinal neovascularization.

Animals↗
PubMed2005

Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor.

PURPOSE: To investigate the anti-inflammatory and anti-angiogenic effects of telmisartan, an angiotensin II type 1 receptor (AT1-R) antagonist, on ischemia-induced retinal neovascularization. METHODS: C57BL/6 neonatal mice were reared in an 80% concentration of oxygen from postnatal day (P)7 to P12, followed by room-air breathing until P17, to induce ischemia-initiated retinal neovascularization (i.e., a murine model of ischemic retinopathy). Tissue localization of AT1-R was examined by immunohistochemistry for murine retinal wholemounts and human fibrovascular tissues excised at vitrectomy for proliferative diabetic retinopathy. Animals received intraperitoneal injection of telmisartan or vehicle. A concanavalin A lectin perfusion-labeling technique was used to evaluate the areas of physiological and pathologic retinal new vessels and the number of leukocytes adhering to the vasculature. Retinal mRNA and protein levels of intercellular adhesion molecule (ICAM)-1, vascular endothelial growth factor receptor (VEGFR)-1, and VEGFR-2 were examined by RT-PCR and ELISA. RESULTS: Vessels in human fibrovascular tissues and the murine retinas were positive for AT1-R. Pathologic (P < 0.01), but not physiologic (P > 0.05), retinal neovascularization was significantly suppressed in telmisartan-treated mice compared with vehicle-treated animals. The number of adherent leukocytes (P < 0.01) was also significantly reduced, together with retinal ICAM-1 levels (P < 0.01) in the telmisartan-treated group compared with the control group. No significant difference was detected in retinal VEGFR-2 levels between the two groups, whereas retinal VEGFR-1 levels in the telmisartan-treated group were significantly (P < 0.05) lower than in the vehicle-treated group. CONCLUSIONS: The present findings suggest that the AT1-R signaling blockade leads to the selective suppression of pathologic, but not physiological, retinal neovascularization through the inhibition of the inflammatory processes related to pathologic neovascularization.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2000

Octreotide, a somatostatin analogue, fails to inhibit hypoxia-induced retinal neovascularization in the neonatal rat.

OBJECTIVE: Octreotide, a somatostatin analogue, has been shown to prevent angiogenesis in diverse in vitro models. We evaluated its effect on retinal neovascularization in vivo, using a neonatal rat retinopathy model. METHODS: We used, on alternating days, hypoxia (10% O2) and hyperoxia (50% O2) during the first 14 days of neonatal rats, to induce retinal neovascularization. Half of the rats were injected subcutaneously with octreotide 0.7 microg/g BW twice daily. At day 18 the eyes were evaluated for the presence of epiretinal and vitreal hemorrhage, neovascularization and epiretinal proliferation. Octreotide pharmacokinetics and its effect on serum growth hormone (GH) and insulin-like growth factor I (IGF-I) were examined in 28 rats. RESULTS: Serum octreotide levels were 667 microg/l two hours after injection, 26.4 microg/l after nine hours and 3.2 microg/l after 14 hours. GH levels were decreased by 40% (p = 0.002) two hours after injection but thereafter returned to baseline. IGF-I levels were unchanged two hours after injection and were elevated by 26% 14 hours after injection (p = 0.02). Epiretinal membranes were highly associated with epiretinal hemorrhages (p < 0.001), while retinal neovascularization was notably associated with vitreal hemorrhages (p < 0.001). CONCLUSIONS: Twice-daily injections of octreotide failed to produce sustained decrease in serum GH, but produced rebound elevation of serum IGF-I. Accordingly, no statistically significant effect of injections on retinal pathology was noted. This finding, however, does not contradict our assumption that GH suppression may decrease the severity of retinopathy.

Animals↗
PubMed2001

Captopril improves retinal neovascularization via endothelin-1.

PURPOSE: The purpose of this study was to determine the effect of an angiotensin converting enzyme inhibitor, captopril, on oxygen-induced retinopathy (OIR) in the mouse. Endothelin-1 (ET-1) expression is assessed in a mouse model of OIR. METHODS: OIR was produced in C57BL6 mice. Captopril (0.5mg/kg/d SC) was given from P7 (post natal day 7) for 5 days. Retinopathy was assessed by a retinal scoring system and by quantification of extra retinal neovascular nuclei on retinal sections at P17 to P20. The expression of ET-1 was determined using a reverse transcriptase polymerase chain reaction. RESULTS: Pups treated with captopril during hyperoxia had a lower median retinopathy score of 4.5 (25th, 75th quartile: 3, 6.4) compared with animals exposed to hyperoxia alone with median score 9.5 (25th, 75th quartile: 7.1, 10.4; P < 0.001). The pups treated with captopril during hyperoxia had significant reduction in number of nuclei extending beyond the inner limiting membrane (15.8 +/- 16.7, mean +/- SD) when compared with the animals exposed to hyperoxia only (50.4 +/- 28.0; P < 0.01). ET-1 expression in the retina increased 4.1-fold from P7 to P12 and a 1.9-fold increase from P12 to P17. Overall, there was an 8-fold increase in ET-1 expression from P7 to P17. Hyperoxia increased ET-1 expression by 2.1-fold at P12 over room air-reared animals. At P17, there was a 2.9-fold increase in retinal ET-1 expression when compared with room air. At P17, there was a 6.2-fold suppression in ET-1 expression in captopril-treated animals when compared with the oxygen only-treated animals. CONCLUSIONS: Captopril reduces retinal neovascularization in a mouse model of oxygen-induced retinopathy. ET-1 expression is increased from P7 to P17, altered by hyperoxic exposure and relative hypoxic recovery and modulated by captopril in a mouse model of OIR.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates.

Vascular endothelial growth factor (VEGF) has been identified as a possible mediator of retinal neovascularisation (NV), but it is not certain if VEGF alone is sufficient to cause retinal NV. We sought to investigate this issue by implanting ethylene-vinyl acetate copolymer pellets that slowly release VEGF into the vitreous cavity of rabbits and primates. Eyes were examined by indirect ophthalmoscopy, fundus photography, and fluorescein angiography and then animals were killed at various time points and immunocytochemical and ultrastructural evaluations were carried out. Seven days after implantation of a pellet containing 30 micrograms of human recombinant VEGF into the vitreous cavity of rabbits, retinal blood vessels became dilated and tortuous, and between days 14 and 21, retinal NV was noted in all eyes. Fluorescein angiography showed profuse leakage of dye from the anomalous vessels. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA) showed positively staining nuclei in many of the endothelial cells of new blood vessels on the surface of the retina. Six eyes implanted with control pellets containing vehicle and two eyes implanted with pellets containing 30 micrograms of human serum albumin alone showed no retinal vascular abnormalities. Implantation of pellets containing 100 micrograms of VEGF into the vitreous cavity of primates resulted in iris NV and retinal vascular dilation and tortuosity very much like that seen in humans with ischemic retinopathies. Immunohistochemical staining for serum albumin showed widespread severe breakdown of the blood-retinal barrier (BRB). Histology showed dilated thin-walled retinal vessels, but unequivocal retinal NV could not be identified and staining for PCNA was negative. These findings indicate that sustained intravitreal release of VEGF causes widespread retinal vascular dilation and breakdown of the BRB. Retinal NV seems to require persistent high levels of VEGF at the retinal surface and can be achieved in rabbits providing a potentially useful model of retinal NV, but is difficult to achieve in primates. The extensive VEGF-induced disruption of the blood-retinal barrier suggests that VEGF antagonists may provide a new therapy for patients with ischemic retinopathies and macular edema.

Animals↗
PubMed2003

In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy.

Diabetic retinopathy and retinopathy of prematurity are among the leading causes of vision impairment throughout the world. Both diseases are characterized by pathological angiogenesis, which severely impairs vision. Extracellular proteinases play important roles in endothelial cell migration during angiogenesis. Amino-terminal fragment (ATF) is an angiostatic molecule that targets the uPA/uPAR system and inhibits endothelial cell migration. The angiostatic effect of ATF has been demonstrated in models of cancer, but has never been assessed in pathological retinal neovascularization. Endostatin also has angiostatic effects on tumor growth and retinal neovascularization. We used an adenoviral vector carrying the murine ATF (AdATFHSA) or endostatin gene coupled to human serum albumin (HSA) (AdEndoHSA) to increase the half-life of the therapeutic protein in the circulation. We induced retinopathy by exposing 7-day-old mice to high levels of oxygen. They were intravitreally injected with the vectors. Local injection of AdATFHSA or AdEndoHSA reduced retinal neovascularization by 78.1 and 79.2%, respectively. Thus, the adenovirus-mediated delivery of ATFHSA or EndoHSA reduces retinal neovascularization in a mouse model of hypoxia-induced neovascularization.

Adenoviruses, Human↗
PubMed1984

Retinitis pigmentosa and retinal neovascularization: a case report.

A 21-year-old white man with retinitis pigmentosa was found to have an isolated patch of retinal neovascularization. Ocular and systemic evaluation failed to reveal a recognized cause for the neovascularization. This case is felt to represent the unusual association of retinitis pigmentosa and retinal neovascularization.

Adult↗
PubMed1995

Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization.

Neovascular diseases of the retina are a major cause of blindness worldwide. Hypoxia is thought to be a common precursor to neovascularization in many retinal diseases, but the factors involved in the hypoxic neovascular response have not been fully identified. To investigate the role of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in retinal neovascularization, the expression of VEGF/VPF mRNA and protein were studied in a mouse model of proliferative retinopathy. RNA (Northern) blot analysis revealed that retinal VEGF/VPF mRNA expression increased 3-fold between 6 and 12 hr of relative retinal hypoxia and remained elevated during the development of neovascularization. In situ hybridization localized VEGF/VPF mRNA to cells bodies in the inner nuclear layer of the retina. Immunohistochemical confocal microscopy demonstrated that VEGF/VPF protein levels increase with a time course similar to that of the mRNA. The cells in the inner nuclear layer of the retina that produce VEGF/VPF were identified morphologically as Müller cells. These data suggest that VEGF/VPF expression in the retina plays a central role in the development of retinal ischemia-induced ocular neovascularization.

Animals↗
PubMed2001

Intravitreal injection of plasminogen kringle 5, an endogenous angiogenic inhibitor, arrests retinal neovascularization in rats.

AIMS/HYPOTHESIS: Plasminogen kringle 5 is an endogenous angiogenic inhibitor. The purpose of the present study was to explore the potential application of kringle 5 in the treatment of retinal neovascularization. METHODS: Plasminogen kringle 5 was expressed in E. coli and affinity-purified. Its anti-angiogenic activity was determined in cultured primary human capillary endothelial cells. Retinal neovascularization was induced in newborn rats by exposure to hyperoxia and then normoxia. Kringle 5 was intravitreally injected into the rat model. Retinal neovascularization was visualized by fluorescein angiography on flat-mounted retina and quantified by counting preretinal vascular cells. RESULTS: Plasminogen kringle 5 inhibited primary endothelial cells but not retinal neuronal cells, suggesting cell type-specific inhibition. The oxygen-induced retinopathy rat model showed an over-expression of vascular endothelial growth factor, preretinal neovascularization and haemorrhage. Intravitreal injection of kringle 5 before the development of neovascularization resulted in fewer neovascular tufts and pre-retinal vascular cells than in control rats with PBS injection (p < 0.01). Moreover, injection of kringle 5 after the development of neovascularization inhibited the increase in the preretinal vascular cells (p < 0.05). These results suggest that kringle 5 both prevents the development and arrests the progression of retinal neovascularization. The injection of kringle 5 did not result in any detectable inflammatory response in the retina or histological toxicity to retina neurons and pre-existing vessels. CONCLUSION/INTERPRETATION: These observations suggest that intravitreal delivery of angiogenic inhibitors could have therapeutic benefits in neovascular diseases of the retina.

Angiogenesis Inhibitors↗
PubMedDate not supplied

A case of diabetic retinopathy with both retinal neovascularization and complete posterior vitreous detachment.

PURPOSE: Report of a case with retinal neovascularization developing in the setting of diabetic retinopathy despite complete posterior vitreous detachment (PVD). CASE REPORT: A 76-year-old man had had type II diabetes mellitus for more than 30 years. Weiss' ring was detected by direct and indirect ophthalmoscopy. PVD was thus considered to be complete. On the other hand, fluorescein angiography showed two areas of hyperfluorescence at the margin of the retinal nonperfusion area. CONCLUSIONS: The present case underscores the importance of periodic follow-up using fluorescein angiography, given the probability of retinal neovascularization development and proliferative changes for many years even in diabetic retinopathy associated with complete PVD.

Aged↗
PubMed2004

Induction of IL-8, MCP-1, and bFGF by TNF-alpha in retinal glial cells: implications for retinal neovascularization during post-ischemic inflammation.

BACKGROUND: We have demonstrated that macrophages/microglia were activated during post-ischemic inflammation in a mouse model of ischemic retinal neovascularization, and that the angiogenesis induced by tumor necrosis factor-alpha (TNF-alpha) appeared to be modulated through such angiogenic factors as interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in microvascular endothelial cells. We have extended these studies, and investigated whether TNF-alpha is localized in macrophages/microglia in the mouse model of retinal neovascularization, and whether TNF-alpha can induce angiogenic factors in retinal glial cells. METHODS: C57BL/6 J pups were placed in a 75% oxygen environment on postnatal day 7 (P7) for 5 days and then returned to room air. The co-localization of TNF-alpha with macrophages/microglia in the ischemic retina was examined by fluorescent immunohistochemistry. Bovine retinal glial cells were isolated for Northern blot analysis to quantify the expression levels of monocyte chemotactic protein-1 (MCP-1), IL-8, bFGF, and VEGF. RESULTS: Double staining of retinas revealed that the TNF-alpha expression level was enhanced in macrophages/microglia 4 days after the hypoxia. Cellular mRNA levels of MCP-1, IL-8, and bFGF, but not VEGF, were increased after treating retinal glial cells with TNF-alpha (100 U/ml). CONCLUSIONS: The results indicate that TNF-alpha is produced by activated macrophages/microglia and may participate in retinal neovascularization during post-ischemic inflammation through the induction of potent angiogenic factors in an autocrine or paracrine manner.

Animals↗
PubMed2004

Involvement of protein kinase CK2 in angiogenesis and retinal neovascularization.

PURPOSE: The purpose of the study was to characterize signaling intermediates involved in angiogenic responses of retinal endothelial cells (RECs) to the extracellular matrix and growth factors, by using specific inhibitors. METHODS: Tubelike structure formation and the development of secondary sprouts on a basement membrane (BM) matrix, cell proliferation, and cell migration were studied in cultures of bovine and human RECs. Specific inhibitors were tested for inhibition of retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). RESULTS: In initial experiments, the broad-spectrum protein kinase inhibitors, H7 and H89, stabilized REC tubes on BM matrix and inhibited secondary sprouting, cell migration, and cell proliferation. Among more specific kinase inhibitors tested, only inhibitors of protein kinase CK2 (formerly, casein kinase II), such as emodin and DRB, were able to duplicate the effects of H7 and H89. Actinomycin D caused only minor changes in angiogenic assays, suggesting that CK2's effects on REC did not involve its known impact on transcription. The extent of retinal neovascularization in a mouse OIR model was reduced >70% (versus untreated or vehicle-treated groups) after treatment with emodin (6 days at 60 mg/kg per day) and by approximately 60% after treatment at the same dose with TBB, the most specific CK2 inhibitor known. In the treated retinas, the main vascular tree had minimal changes, but the neovascular tufts were greatly reduced in number or absent. CONCLUSIONS: This is the first demonstration of the involvement of ubiquitous protein kinase CK2 in angiogenesis. Naturally derived CK2 inhibitors may be useful for treatment of proliferative retinopathies.

Animals↗
PubMed2003

Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization.

PURPOSE: Ischemia-induced neovascularization can cause catastrophic loss of vision in retinal disorders such as diabetic retinopathy. Recent studies have shown that the angiopoietin-Tie2 system is a major regulator of vascular integrity and is involved in pathologic angiogenesis. In the study described herein, the role of these molecules in ischemic retinal disorders was investigated. METHODS: Human epiretinal membranes were examined by immunohistochemistry, In situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Effects of angiopoietins on tube formation were studied in vitro in bovine retinal capillary endothelial cells (BRECs) and in a murine model of ischemia-induced retinal neovascularization. RESULTS: In human epiretinal membranes surgically obtained from eyes with ischemic retinal disorders, substantial upregulation of angiopoietin 2 (Ang2) and the receptor Tie2 was recorded than in those from eyes with nonischemic diseases, whereas expression of Ang1 was constant in all membranes. Both Ang1 and Ang2 promoted tube-forming activity and enhanced the effects of vascular endothelial growth factor (VEGF) in cultured BRECs. Soluble Tie2 fusion protein (sTie2-Fc), which precluded modulation of VEGF-dependent tube formation by the angiopoietins, suppressed both VEGF and hypoxia-conditioned, medium-induced tube-forming activity in BRECs. Intravitreal injection of sTie2-Fc, soluble Flt-1 fusion protein (sFlt-1-Fc), and both chimeric proteins suppressed retinal angiogenesis in a murine model of retinal ischemia in the order of sTie2-Fc < sFlt-1-Fc < sTie2-Fc+sFlt-1-Fc. CONCLUSIONS: These results reinforce the substantial role of the angiopoietins/Tie2 system in ischemia-induced angiogenesis as well as the VEGF system and suggest that combined inhibition of Tie2 and VEGF signaling may be more effective in halting or preventing pathologic angiogenesis in ischemic retinal disorders.

Adult↗
PubMed2006

TNF-alpha is critical for ischemia-induced leukostasis, but not retinal neovascularization nor VEGF-induced leakage.

Vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) show significant overlap with regard to their effects in the eye. It has been postulated that VEGF-induced leukostasis, breakdown of the blood-retinal barrier, and ischemia-induced retinal neovascularization may be mediated, at least in part, through TNF-alpha. In this study, we used mice deficient in TNF-alpha to test our hypothesis. Compared to wild type mice, TNF-alpha-deficient mice showed an 80% reduction in leukocyte accumulation in retinal vessels after intravitreous injection of VEGF, and 100% reductions after intravitreous injections of interleukin-1beta (IL-1beta) or platelet-activating factor (PAF). The increase in retinal vascular permeability induced by injection of PAF was significantly reduced in mice lacking TNF-alpha, but VEGF- and IL-1beta-induced leakage was unaffected. Compared to wild type mice with oxygen-induced ischemic retinopathy, TNF-alpha-deficient mice with ischemic retinopathy showed significantly reduced leukostasis and mild reduction in vascular leakage, but no significant difference in retinal neovascularization. These data suggest that TNF-alpha mediates VEGF-, IL-1beta-, and PAF-induced leukostasis and vascular leakage mediated by PAF, but not leakage caused by VEGF or IL-1beta. Ischemia-induced retinal neovascularization, which has previously been shown to require VEGF, does not require TNF-alpha and is unaffected by attenuation of leukostasis.

Animals↗
PubMed1998

Peripheral retinal neovascularization (Eales disease) associated with the factor V Leiden mutation.

PURPOSE: To illustrate a case of peripheral retinal neovascularization (Eales disease) in a patient who tested positive for the factor V Leiden mutation. METHODS: A 42-year-old woman had a 1-week history of blurred vision in her right eye. Her medical history was remarkable for a cerebrovascular accident. Ophthalmoscopy of the right eye disclosed a mild vitreous hemorrhage and a ridge of retinal neovascularization in the temporal periphery. The left fundus showed evidence of temporal retinal ischemia. A laboratory evaluation for hypercoagulability was positive for factor V Leiden mutation. RESULTS: Peripheral scatter laser photocoagulation was applied to the ischemic retina, and the neovascularization regressed. The patient began taking warfarin sodium to prevent further thrombotic events. CONCLUSION: A laboratory evaluation for coagulopathy, including the factor V Leiden mutation, should be added to the examination of patients with Eales disease, especially individuals with a history of a previous thrombotic event.

Adult↗
PubMed1976

The role of lactic acid in retinal neovascularization.

In order to gain information on the possible role of lactate in the development of neovascularization following retinal malperfusion, the lactate content in vitreous-retina-choroid specimens of 02-treated kittens and streptozotocin-diabetic rats was determined. In both experiments there was no significant difference of lactate content between the diseased eyes and healthy controls.

Animals↗
PubMed1995

Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.

The majority of severe visual loss in the United States results from complications associated with retinal neovascularization in patients with ischemic ocular diseases such as diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. Intraocular expression of the angiogenic protein vascular endothelial growth factor (VEGF) is closely correlated with neovascularization in these human disorders and with ischemia-induced retinal neovascularization in mice. In this study, we evaluated whether in vivo inhibition of VEGF action could suppress retinal neovascularization in a murine model of ischemic retinopathy. VEGF-neutralizing chimeric proteins were constructed by joining the extracellular domain of either human (Flt) or mouse (Flk) high-affinity VEGF receptors with IgG. Control chimeric proteins that did not bind VEGF were also used. VEGF-receptor chimeric proteins eliminated in vitro retinal endothelial cell growth stimulation by either VEGF (P < 0.006) or hypoxic conditioned medium (P < 0.005) without affecting growth under nonstimulated conditions. Control proteins had no effect. To assess in vivo response, animals with bilateral retinal ischemia received intravitreal injections of VEGF antagonist in one eye and control protein in the contralateral eye. Retinal neovascularization was quantitated histologically by a masked protocol. Retinal neovascularization in the eye injected with human Flt or murine Flk chimeric protein was reduced in 100% (25/25; P < 0.0001) and 95% (21/22; P < 0.0001) 0.0001) of animals, respectively, compared to the control treated eye. This response was evident after only a single intravitreal injection and was dose dependent with suppression of neovascularization noted after total delivery of 200 ng of protein (P < 0.002). Reduction of histologically evident neovascular nuclei per 6-microns section averaged 47% +/- 4% (P < 0.001) and 37% +/- 2% (P < 0.001) for Flt and Flk chimeric proteins with maximal inhibitory effects of 77% and 66%, respectively. No retinal toxicity was observed by light microscopy. These data demonstrate VEGF's causal role in retinal angiogenesis and prove the potential of VEGF inhibition as a specific therapy for ischemic retinal disease.

Animals↗
PubMed1998

The role of NF-kappaB in retinal neovascularization in the rat. Possible involvement of cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 family.

Hypoxia precedes neovascularization in many retinal diseases that can lead to irreversible vision loss. The transcription factor NF-kappaB is activated by hypoxia and regulates the expression of many genes, including angiogenic factors. The relation between the NF-kappaB activation and the cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 (IL-8) family, was investigated by immunohistochemistry in a rat model of proliferative retinopathy presumably caused by relative hypoxia. Activated NF-kappaB and CINC immunoreactivity was detected in retinal glial cells in the nonperfused retina and in neovascular cells. Activated NF-kappaB was detected before the CINC staining, and both of these events occurred before the development of neovascularization. The intensity of both activated NF-kappaB and CINC staining remained increased during the development of neovascularization and then declined as neovascularization regressed. In rat retinal glial cells in vitro, dexamethasone, an inhibitor of NF-kappaB activation, prevented the hypoxia-induced increase in the amount of CINC mRNA. Furthermore, CINC induced neovascularization in a rat corneal pocket model. These results suggest that hypoxia-induced activation of NF-kappaB results in CINC production and participates in the induction of retinal neovascularization.

Actins↗