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PubMed2006

Low-density lipoprotein receptor-related protein-1 (LRP-1) expression in a rat model of oxygen-induced retinal neovascularization.

The low-density lipoprotein receptor-related protein-1 (LRP-1) is a high-molecular weight receptor of the LDL receptor gene family. Its ability to bind and internalize both proteinases and proteinase-inhibitor complexes from the extracellular space suggests that it has a major role in modulating uncontrolled retinal cell proliferation. In order to test this assumption, we investigated the expression of LRP-1 and receptor-associated ligands in a rat model of oxygen-induced retinal neovascularization. Wistar albino rats were placed into incubators at birth and exposed to an atmosphere alternating between 50% and 10% of oxygen every 24 h. After 14 days, the animals were allowed to recover in room air and sacrificed at postnatal day 20 (P20). The protein expression of LRP-1 and alpha2-macroglobulin (alpha2M) in the retina from unexposed and hyperoxia-exposed rats was investigated by Western blot. The localization of LRP-1 after neovascularization was assessed by immunohistochemical staining. The activity of metalloproteinases (MMPs) was determined by zymography. Histological analysis was done to quantitate the neovascular response in these animals. Western blot analysis showed that LRP-1 was expressed, along with alpha2M, in the retina of rats with oxygen-induced neovascularization at P20. By immunohistochemical analysis, positive staining for LRP-1 appeared in cells extending from the inner limiting membrane (ILM) to the outer limiting membrane (OLM). The cells of the retina that expressed LRP-1 were identified by immunofluorescence as Müller cells. Zymographic analysis demonstrated increased activity of MMP-2 and MMP-9 under neovascular conditions. This is the first demonstration of the involvement of LRP-1 in retinal neovascularization. In retinas of rats with oxygen-induced neovascularization, the expression of LRP-1 and alpha2M was increased along with an enhanced activity of MMPs, suggesting that LRP-1 expression may play a role in modulating retinal neovascularization by regulating proteolytic activity.

Animals↗
PubMedDate not supplied

[Pathogenesis of retinal neovascularization].

Presented are the causes and actual opinions on the pathogenesis of retinal neovascularization. The ischaemic hypothesis of neovascularization is particularly discussed; it is commonly accepted to day as the most probable hypothesis.

Arteriovenous Malformations↗
PubMed2005

[Remodel retinal neovascularization by overexpression of HESR-1 in vitro].

OBJECTIVE: To remodel retinal neovascularization by overexpression of HESR-1 in vitro. METHODS: Human retinal capillary endothelial cell (HRCEC) was isolated, then HRCECs were transfected with pcDNA3.1+HESR-1. The changes of expression of KDR and occluding in HRCECs were analyzed using ELISA assay, the regulation of occluding in HRCECs by HESR-1 was evaluated by western blot. RESULTS: Over-expression of HESR-1 down-regulated KDR expression, but occludin expression was up-regulated in HRECEs, the result also showed that the vessels permeability was reduced by HESR-1. CONCLUSIONS: Overexpression of HESR-1 in HRCECs can inhibit the neovascularization and decrease the permeability of new vessels. It may be a promising gene therapy for intraocular neovascularization.

Basic Helix-Loop-Helix Proteins↗
PubMed2003

Kallikrein-binding protein inhibits retinal neovascularization and decreases vascular leakage.

AIMS/HYPOTHESIS: Kallikrein-binding protein (KBP) is a serine proteinase inhibitor (serpin). It specifically binds to tissue kallikrein and inhibits kallikrein activity. Our study was designed to test its effects on retinal neovascularization and vascular permeability. METHODS: Endothelial cell proliferation was determined by [(3)H] thymidine incorporation assay and apoptosis quantified by Annexin V staining and flow cytometry. Effect on retinal neovascularization was determined by fluorescein angiography and count of pre-retinal vascular cells in an oxygen-induced retinopathy (OIR) model. Vascular permeability was assayed by the Evans blue method. Vascular endothelial growth factor (VEGF) was measured by Western blot analysis and ELISA. RESULTS: Kallikrein-binding protein specifically inhibited proliferation and induced apoptosis in retinal capillary endothelial cells. Intravitreal injection of KBP inhibited retinal neovascularization in an OIR model. Moreover, KBP decreased vascular leakage in the retina, iris and choroid in rats with OIR. Blockade of kinin receptors by specific antagonists showed significantly weaker inhibition of endothelial cells, when compared to that of KBP, suggesting that the anti-angiogenic activity of KBP is not through inhibiting kallikrein activity or kinin production. KBP competed with (125)I-VEGF for binding to endothelial cells and down-regulated VEGF production in endothelial cells and in the retina of the OIR rat model. CONCLUSION/INTERPRETATION: Kallikrein-binding protein is a multi-functional serpin, and its vascular activities are independent of its interactions with the kallikrein-kinin system. Inhibition of VEGF binding to its receptors and down-regulation of VEGF expression could represent a mechanism for the vascular activities of KBP.

Animals↗
PubMed2002

Synthetic peptides interacting with the 67-kd laminin receptor can reduce retinal ischemia and inhibit hypoxia-induced retinal neovascularization.

The high-affinity 67-kd laminin receptor (67LR) is expressed by proliferating endothelial cells during retinal neovascularization. The role of 67LR has been further examined experimentally by administration of selective 67LR agonists and antagonists in a murine model of proliferative retinopathy. These synthetic 67LR ligands have been previously shown to stimulate or inhibit endothelial cell motility in vitro without any direct effect on proliferation. In the present study, a fluorescently labeled 67LR antagonist (EGF(33-42)) was injected intraperitoneally into mice and its distribution in the retina was assessed by confocal scanning laser microscopy. Within 2 hours this peptide was localized to the retinal vasculature, including preretinal neovascular complexes, and a significant amount had crossed the blood retinal barrier. For up to 24 hours postinjection, the peptide was still present in the retinal vascular walls and, to a lesser extent, in the neural retina. Non-labeled EGF(33-42) significantly inhibited pre-retinal neovascularization in comparison to controls treated with phosphate-buffered saline or scrambled peptide (P < 0.0001). The agonist peptide (Lam beta 1(925-933)) also significantly inhibited proliferative retinopathy; however, it caused a concomitant reduction in retinal ischemia in this model by promoting significant revascularization of the central retina (P < 0.001). Thus, 67LR appears to be an important target receptor for the modulation of retinal neovascularization. Agonism of this receptor may be valuable in reducing the hypoxia-stimulated release of angiogenic growth factors which drives retinal angiogenesis.

Animals↗
PubMed2002

[Bilateral peripheral retinal neovascularization in a patient with multiple sclerosis].

We present the case of a 32-year-old man suffering from multiple sclerosis who had developed bilateral peripheral neovascularization of the retina. The main disease had been diagnosed 10 years before, whereas in his ophthalmic history the patient reported an incident of retrobulbar optic neuritis in his left eye occurring 3 years before. The patient was referred to our clinic in order to investigate the cause of a sudden loss of vision in his left eye. Ophthalmic examination and fluorescein angiography revealed the presence of a bilateral peripheral retinal neovascularization with an intravitreous hemorrhage in the left eye. Systemic clinical and laboratory investigation were negative for other causes of retinal neovascularization except multiple sclerosis, which is associated with periphlebitis in 10% of cases. Chronic retinal ischemia may lead to retinal neovascularization.

Adult↗
PubMed1998

Two cases of unilateral retinal neovascularization in Turner syndrome.

PURPOSE: To report two cases of unilateral retinal neovascularization in Turner syndrome. METHOD: We examined two female infants, born at 34 weeks' and 33 weeks' gestation, who had received oxygen for 9 days and 3 days, respectively, after birth. Both infants had the 45,XO karyotype of Turner syndrome. RESULTS: In each patient, the fundus of one eye showed an avascular area, neovascularization, and multiple branchings with anastomosis of retinal vessels in the temporal periphery. Fellow eyes showed no abnormalities in the fundi. Both infants were treated with argon laser photocoagulation to the avascular area and the neovascularization in the temporal periphery. The neovascularization regressed completely after retinal photocoagulation. CONCLUSION: Abnormalities of retinal vessels may be one of the ocular findings associated with Turner syndrome.

Female↗
PubMed1998

Increased expression of KDR/Flk-1 (VEGFR-2) in murine model of ischemia-induced retinal neovascularization.

Although the vascular endothelial growth factor (VEGF)/VEGF receptor system plays a critical role in the pathogenesis of ischemic retinal neovascular diseases such as diabetic retinopathy, regulation of VEGF receptor expression in ischemic retina has not been fully investigated in vivo. Accordingly, we studied the regulation of Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2) expression in a mouse model of ischemia-induced retinal neovascularization. Immunohistochemistry for Flt-1 and KDR/Flk-1 revealed that, in hypoxic retina, the immunoreactivity of KDR/Flk-1 was increased in both intensity and extent of involvement in the vessels near the avascular area, particularly at the neovascular tufts, but that the pattern of Flt-1 expression in hypoxic retina was almost the same as that of control animals. The number of KDR/Flk-1-positive vessels was significantly increased in hypoxic retina (P < 0.01). In addition, expression of both Flt-1 and KDR/Flk-1 was observed in nonvascular cells of the neural retina. Northern blot analysis demonstrated that the mRNA levels of KDR/Flk-1 were greater in the neovascular retina of hypoxic animals than in control animals. We suggest that the increased expression of KDR/Flk-1 in vascular cells might potentiate the VEGF-mediated angiogenesis that accompanies many ischemic retinal diseases.

Animals↗
PubMed1994

Occlusive microvascular retinopathy with optic disc and retinal neovascularization in acute lymphocytic leukemia.

BACKGROUND: Acute lymphocytic leukemia can be associated with an occlusive microvascular retinopathy. There is a potential for worsening of this occlusive microvascular retinopathy by radiation damage to the retinal vasculature (radiation retinopathy) and by the toxic effects of chemotherapy. METHODS: An 18-year-old woman with T-cell acute lymphocytic leukemia received low-dose irradiation to the brain and subsequent chemotherapy, which included cytosine arabinoside. RESULTS: During the chemotherapy, she developed severe bilateral occlusive microvascular retinopathy that progressed despite extensive panretinal photocoagulation to bilateral optic disc and retinal neovascularization and eventual traction retinal detachment involving the macula. CONCLUSION: The toxic effect of a chemotherapeutic agent such as cytosine arabinoside when combined with radiation retinopathy may be additive, leading to a much more severe ischemic retinal vasculopathy than one would encounter with acute lymphocytic leukemia alone. This must be kept in mind when planning combined radiation and chemotherapy for T-cell acute lymphocytic leukemia.

Adolescent↗
PubMed1993

Case report: associated retinal neovascularization and choroidal hemangioma.

Choroidal hemangiomas are vascular hamartomas that may be associated with secondary changes. Although subretinal fluid and associated neurosensory retina and retinal pigment epithelial changes are well documented, two cases in which retinal neovascularization was felt to be secondary to choroidal hemangiomas are presented. Long term follow-up reveals mild changes of the retinal neovascularization in both cases. The neovascularization did not affect the visual prognosis of the involved eyes.

Adult↗
PubMed2004

Neuropeptide Y and Y2-receptor are involved in development of diabetic retinopathy and retinal neovascularization.

BACKGROUND: Neuropeptide Y is a sympathetic neurotransmitter, a potent endothelium-derived angiogenic factor and a vascular mitogen. We have studied the role of the functional leucine7 to proline7 polymorphism of the signal peptide region of preproneuropeptide Y (prepro-NPY) as a genetic susceptibility factor for diabetic retinopathy. In addition, we investigated the role of the NPY Y2-receptor as a putative mediator of angiogenic NPY signaling in the retina. METHODS: Frequencies of proline7 (Pro7) carriers in the prepro-NPY were determined in type 1 and type 2 diabetes patients having retinopathy, in type 2 diabetes patients without retinopathy and in healthy control subjects. The role of Y2-receptor in hyperoxemia-induced retinal neovascularization was investigated in Y2-receptor knockout mice (Y2-/-) and in rats administered Y2-receptor mRNA antisense oligonucleotide. RESULTS: The carriers having Pro7 in the preproNPY are markedly over-represented among type 2 diabetes patients with retinopathy compared to type 2 diabetes patients without retinopathy and to the population control. Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide. CONCLUSIONS: NPY and Y2-receptor play important roles in diabetic retinopathy and retinal neovascularization and are thus potential new targets for drug molecules for treatment of retinopathy.

Adult↗
PubMed2006

VEGF165b, an endogenous C-terminal splice variant of VEGF, inhibits retinal neovascularization in mice.

PURPOSE: Hypoxia driven ocular angiogenesis occurs in a range of ischemic retinopathies including proliferative diabetic retinopathy and retinopathy of prematurity. These conditions are initiated and sustained by hypoxia dependent vascular endothelial growth factor (VEGF) expression in the eye. There are two families of VEGF isoforms formed by differential splicing, the pro-angiogenic VEGF family, known to contribute to ocular neovascularization, and the anti-angiogenic VEGF family, which are downregulated in diabetic retinopathy in humans. The first member of the VEGF family to be isolated was VEGF165b. To determine whether VEGF165b could inhibit hypoxia driven angiogenesis in the eye, the oxygen induced retinopathy mouse model of ocular neovascularization was used. METHODS: 1 ng of recombinant human VEGF165b peptide was injected intraocularly upon return to normoxia after 5 days exposure to 95% oxygen, and neovascularization assessed. RESULTS: VEGF165b significantly inhibited the percentage area of retinal neovascularization from 23+/-3% to 12+/-3.3%, and significantly increased normal vascular areas from 62+/-4% to 74+/-4%. The percentage area of residual ischemic retina was not affected. CONCLUSIONS: These results show that a single injection of VEGF165b can significantly reduce preretinal neovascularization without inhibition of physiological intraretinal angiogenesis. Controlling the balance of VEGF(xxx) to VEGF(xxx) isoforms may therefore be therapeutically valuable in the treatment of proliferative eye diseases such as diabetic retinopathy and age related macular degeneration. The regulation of splicing between these two families of isoforms may provide a novel therapeutic strategy for proliferative eye disease.

Animals↗
PubMed1984

Argon laser treatment of retinal neovascularization associated with sarcoidosis.

A 22-year-old Japanese woman with systemic sarcoidosis had retinal neovascularizations at seven loci with repeated vitreous hemorrhage in her right eye. Oral administration of prednisone was not effective. However, argon laser photocoagulation to the neovascularizations obliterated the neovascular fronds except at the optic nerve head; three months from the treatment, the neovascularization at the optic nerve head regressed spontaneously. No serious complications have occurred, and the vitreous hemorrhage has not recurred for the past two years. From these results, argon laser photocoagulation was thought to be effective for the treatment of retinal neovascularization in sarcoidosis.

Adult↗
PubMed2004

Intraocular gutless adenoviral-vectored VEGF stimulates anterior segment but not retinal neovascularization.

Vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) have been implicated as important stimulatory factors for retinal neovascularization. In this study, we used intraocular gene transfer with gutless adenoviral (AGV) vectors to determine the effect of increased intraocular expression of VEGF, IGF-1, or sphingosine kinase (SPK), which produces sphingosine-1-phosphate, another angiogenic factor. Retinal neovascularization did not occur from intravitreous AGV-vectored VEGF, IGF-1, SPK, or combined VEGF and IGF-1, except occasionally adjacent to the retinal penetration site from the injection. However, corneal and iris neovascularization occurred after 2 weeks in all eyes injected with AGV.VEGF, but not those injected with only AGV.IGF-1 or AGV.SPK. These data suggest that the superficial capillary bed of the retina is relatively insensitive to VEGF, IGF-1, or SPK in adult mice, except when combined with retinal trauma. However, AGV-vectored VEGF is sufficient to consistently cause severe corneal and iris neovascularization. This provides a model for anterior segment neovascularization, which unlike previous models is relatively inexpensive and is not plagued by spontaneous regression, and therefore, may be useful for identification of new treatments.

Adenoviridae↗
PubMed1989

[Treatment of retinal neovascularization secondary to branch vein occlusion with argon laser photocoagulation].

20 cases (22 eyes) of retinal neovascularization (RNV) secondary to branch vein occlusion were treated with argon laser photocoagulation. The RNV and the area of nonperfusion in these eyes were detected by fluorescein angiography. The results showed that argon laser photo coagulation was a highly effective therapy for RNV which was refractory to treatment. Photocoagulation minimized or resolved RNV and prevented recurrent vitreous hemorrhage. The relationship of RNV with the area of nonperfusion, the selection of the direct or indirect modality, and the points of note for success and prevention of complications were discussed.

Adult↗
PubMed2005

Inhibition of retinal neovascularization by soluble EphA2 receptor.

Eph receptor tyrosine kinases (RTKs) and their ligands, known as ephrins, play an important role in vascular remodeling during embryogenesis, but their functions in adult angiogenesis are just beginning to be investigated. In this report, we investigated the effect of blocking EphA receptor activation on VEGF-induced angiogenic responses of cultured retinal endothelial cells and on retinal neovascularization in a rodent model of retinopathy of prematurity (ROP). Soluble EphA2-Fc receptors inhibited ephrin-A1 ligand or VEGF-induced BRMEC migration and tube formation without affecting proliferation in vitro. Since EphA2-Fc receptors can inhibit activation of multiple EphA receptors, the specific role of EphA2 receptor in angiogenesis was further investigated in EphA2-deficient endothelial cells. Loss of EphA2 in endothelial cells leads to defective cell migration and assembly in response to either ephrin-A1 or VEGF. Finally, a significant reduction in the severity of abnormal retinal neovascularization was observed in the eyes treated with soluble EphA2-Fc receptors, yet the normal total retinal vascular area was not significantly changed. Because soluble Eph receptor significantly inhibited pathologic retinal angiogenesis without affecting normal intraretinal vessels, it may be a promising agent for treatment of retinal angiogenesis in a number of human ocular diseases.

Animals↗
PubMed2005

Retinal neovascularization during treatment with IGF-1 for insulin resistance syndrome.

BACKGROUND: Leprechaunism is a rare congenital syndrome and the most severe form of insulin resistance syndrome, with mutations in the insulin receptor gene. Recombinant human insulin-like growth factor-1 (rhIGF-1) is currently applicable to the treatment for insulin resistance syndrome by its insulin-like effect. Although IGF-1 is thought to promote tissue proliferation and neovascularization, it is uncertain how it acts on the development of diabetic retinopathy. METHODS: Interventional case report. RESULTS: A 12-year-old girl with leprechaunism has been treated with IGF-1 since she was 6 months old. She presented with neovascular glaucoma in the left eye, but with no serious changes in the right fundus except for tortuosity and dilatation of retinal veins. Thereafter, retinal neovascularization in the right eye developed in 6 months to form a loop-shaped vascular network in the vitreous cavity despite panretinal photocoagulation. CONCLUSIONS: Characteristics of retinal neovascularization and clinical course suggest that IGF-1 treatment was closely associated with the development of diabetic retinopathy in this case.

Blindness↗
PubMed2003

Increased retinal neovascularization in Fas ligand-deficient mice.

PURPOSE: To investigate whether the absence of the Fas-Fas ligand system of apoptosis regulation affects hyperoxia-induced retinal vaso-obliteration and retinal neovascularization in a mouse model of oxygen-induced retinopathy. METHODS: C57BL/6 (B6) and congenic Fas ligand-deficient generalized lymphoproliferative disease (gld) mice were exposed to 75% oxygen from postnatal day (P)7 to P12 and then allowed to recover in room air. Eyes obtained from P7, P8, P10, P12, P14, P17, and P21, from both hyperoxia-injured and room air control animals were processed for histopathologic examination. Retinopathy was also qualitatively assessed in FITC-dextran perfused retinas by fluorescence microscopy. TUNEL assays were used to compare apoptosis in B6 and gld mice. Intraretinal blood vessel formation was quantitated by immunolabeling with an anti-type-IV collagen antibody. Retinopathy was further assessed by quantitation of preretinal neovascular nuclei on P17. RT-PCR was used to examine retinal expression of Fas and Fas ligand (FasL) over a time course of hyperoxia-induced retinopathy. RESULTS: In hyperoxia-injured mice, the same degree of vaso-obliteration was apparent on P8, P10, and P12 in B6 and gld mice. By P17, the hyperoxia-exposed FITC-perfused retinas of both strains exhibited preretinal neovascular tufts. However, P17 gld hyperoxia-exposed retinas exhibited approximately a 50% increase in preretinal neovascular nuclei compared with B6 mice. In addition, a subset of apoptotic cells located solely within the neovascular tufts on P17 were significantly decreased in hyperoxia-exposed gld retinas, compared with B6 control animals. RT-PCR showed an increase in the expression levels of Fas in both strains of mice as a result of hyperoxia-induced injury. CONCLUSIONS: These data suggest that the Fas-FasL interaction plays an important role in retinal neovascularization after hyperoxia-induced injury. The absence of functional FasL leads to an increased incidence of preretinal neovascular nuclei and decreased retinal apoptosis suggesting that this pathway may serve as a means of regulating endogenous endothelial cell populations in pathologic angiogenesis.

Animals↗