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At least 991 records · Page 55Linked to original sources
PubMed2002

Localization of VEGF receptor-2 (KDR/Flk-1) and effects of blocking it in oxygen-induced retinopathy.

PURPOSE: Vascular endothelial cell growth factor (VEGF) has been implicated in vascular development and in proliferative retinopathies. The goal of this study was to examine the immunohistochemical localization and relative levels of VEGF receptor-2 (KDR) in canine retina during postnatal vasculogenesis and during angiogenesis in oxygen-induced retinopathy (OIR) and to investigate the effects of neutralizing KDR on these processes. METHODS: Eyes from normal dogs ranging from 1 to 22 days of age and age-matched oxygen-treated animals were snap frozen for immunohistochemical analysis with antibodies against human KDR. To examine the effects of blocking KDR, 6-day-old air-reared control and oxygen-treated animals were surgically implanted with slow release polymer pellets containing control IgG or anti-KDR. Material eluted from pellets was assessed using a binding assay (measures binding to soluble KDR) to determine the kinetics of anti-KDR release and endothelial cell proliferation to measure bioactivity. Animals were killed at 22 days of age and tissues examined with adenosine diphosphatase (ADPase) histochemical staining of blood vessels. RESULTS: KDR immunoreactivity was only weakly associated with developing retinal vessels and was not observed in angioblasts throughout normal postnatal development. Immunoreactivity was very strong in reforming retinal vessels and intravitreal neovascularization in oxygen-treated animals. Anti-KDR had no effect on vessel morphology or growth in air-reared control animals. In oxygen-treated animals, anti-KDR significantly inhibited revascularization of the retina (P = 0.005) and formation of intravitreal neovascularization compared with control IgG pellet eyes (P < 0.04). CONCLUSIONS: KDR/Flk-1 was only weakly associated with normal developing primary retinal vessels but was strongly expressed by proliferating endothelial cells in reforming retinal vessels and intravitreal neovascularization after hyperoxic insult. Anti-KDR antibody delivered by slow-release pellets had no effect on normal vasculogenesis, but it inhibited the formation of intravitreal neovascularization and retinal vessel development in OIR. The study suggests that blocking KDR may be beneficial for treating pathologic angiogenesis in adult tissue.

Animals↗
PubMed1999

[Cell biology of intraocular vascular diseases].

Diabetic retinopathy (DR) still remains the leading cause of blindness in the working population of Japan and western world, though therapies such as retinal photocoagulation and vitrectomy can be remarkably effective when administered at an appropriate stage in the disease process. Consequently, there is a need for further investigation of the pathogenesis of DR to develop better therapy. DR is characterized by gradually progressive alterations in the retinal microvasculature, leading to three fundamental morbidities: 1. vascular hyperpermeability, 2. vascular occlusion, and 3. neovascularization. Recent studies have revealed that hyperglycemia causes several metabolic disorders which cause DR directly or indirectly through the abnormal expression of cytokines including vascular endothelial growth factor (VEGF). In this study, we performed precise tests of the correlation between intraocular VEGF and the three fundamental changes in the diabetic retina mentioned above. Ultrastructural study of the human retina revealed that two major pathways are responsible for hyperpermeability of diabetic retinal vessels, i.e., intercellular or paracellular transport (opening of the tight junctions) and intracellular or transcellular transport (caveolae, intracytoplasmic vesicles, and fenestration). All these pathways were induced by intravitreal injection of VEGF. The major trigger of VEGF overexpression is tissue ischemia caused by vascular occlusion. However, the retinas from the eyes with background DR revealed increased expression of VEGF without apparent incidence of vascular occlusion. We have identified accumulation of advanced glycation end products (AGEs) in these retinas, and found that AGEs are a major stimulus for VEGF overexpression in background DR. Retinal vascular occlusion was caused by thrombus formation primarily in the capillary vessels. Thrombi mainly consisted of fibrin, platelets, and leucocytes in the early stage of their formation, and glial cells and macrophages were also involved in the later stage. The blood coagulation process plays an important role in fibrin formation in thrombi. The expression of tissue factor (TF), an initiator of extrinsic blood coagulation, was upregulated by VEGF in retinal vascular endothelial cells (REC). In addition, AGEs were also thrombogenic through the induction of TF expression and suppression of the expression of prostacyclin stimulating factor (PSF), which stimulate prostacyclin synthesis in vascular endothelial cells. These findings suggest that AGEs, VEGF, and TF could interact in a vicious circle because AGEs and VEGF could induce retinal vascular occlusion which results in further increase in VEGF expression. Intravitreal injection of VEGF could induce retinal neovascularization. VEGF stimulates vascular endothelial cell proliferation by binding to a specific receptor named kinase insert domain-containing receptor/fetal liver kinase (KDR/FIk-1, KDR). AGEs and basic fibroblast growth factor (bFGF) induced expression of KDR in REC, and a transcription factor Sp 1 was involved in this process. Since the expression of KDR as well as VEGF was already upregulated in the retinas with background DR, VEGF appeared to start to induce the proliferative changes long before the actual onset of proliferative DR. These findings indicated that VEGF and its receptor system plays a pivotal role all through the disease process of DR. We considered that amelioration of the activated VEGF and its receptor system could lead to the development of new therapy for DR. We have developed two novel methods to prevent retinal neovascularization by inhibiting VEGF and its receptor system. 1. An insulin sensitizing agent (troglitazone) inhibited proliferation, migration, and in vitro tube formation by REC as well as oxygen-induced retinal neovascularization in a mouse model. Thus, glycemic control by troglitazone could reduce the incidence of neovascularization in diabetic eyes. 2. (ABSTRACT TRUNCATED)

Animals↗
PubMed1983

A prospective follow-up study of panretinal photocoagulation in preventing neovascular glaucoma following ischaemic central retinal vein occlusion.

Fifteen consecutive eyes with central retinal vein occlusion (CRVO) and extensive capillary non-perfusion were treated by panretinal photocoagulation using argon laser. Of these eyes six had chronic glaucoma and one had acute angle-closure glaucoma when first seen. One developed neovascular glaucoma before treatment. After photocoagulation iris new vessels appeared in two eyes with pre-existing glaucoma. In one case the new vessels later regressed without further treatment. The prevalence of neovascular glaucoma was considerably less than has been reported in untreated eyes with ischaemic-type CRVO. Poor dilatation of the pupil due to pre-existing glaucoma, cataract and/or massive retinal oedema put a limit on the extent of treatment.

Aged↗
PubMed2000

Clinicopathological correlation in exudative age related macular degeneration: histological differentiation between classic and occult choroidal neovascularisation.

AIMS: To analyse the histopathology of classic and occult choroidal neovascular membrane surgical specimens in age related macular degeneration. METHODS: 35 membranes, from a consecutive series of surgically removed choroidal neovascular membranes in age related macular degeneration, were classified as classic or occult following the guidelines of the Macular Photocoagulation Study. Membranes with classic as well as occult components were considered as mixed membranes. The membranes were serially sectioned and stained with haematoxylin and eosin, Masson trichrome, periodic acid-Schiff, and phosphotungstic acid haematoxylin stain. The correlation has been made in a masked fashion. RESULTS: 31 membranes (19 classic, 10 occult, and two mixed membranes) could be analysed histologically. 18 classic choroidal neovascular membranes had a major subretinal fibrovascular component and 10 of these had an additional, minor fibrovascular component under the retinal pigment epithelium. The 10 occult membranes contained a fibrovascular component under the retinal pigment epithelium and the two mixed membranes contained fibrovascular tissue on both sides of the retinal pigment epithelium. Fibrin and remains of outer segments tended to occur at the lateral edges of classic membranes and to cover the inner surface of occult membranes. CONCLUSION: Classic choroidal neovascularisation in age related macular degeneration is predominantly composed of subretinal fibrovascular tissue while occult choroidal neovascularisation is composed of fibrovascular tissue at the choroidal side of the retinal pigment epithelium.

Aged↗
PubMed2002

Inducible nitric oxide synthase mediates retinal apoptosis in ischemic proliferative retinopathy.

Ischemic proliferative retinopathy (e.g., diabetes mellitus, retinopathy of prematurity, or retinal vein occlusion) is a major cause of blindness worldwide. Apart from neovascularization, ischemic proliferative retinopathy leads to retinal degeneration. Apoptosis has been ascribed to be the leading mechanism in ischemic retinal degeneration. We showed recently that inducible nitric oxide synthase (iNOS) is expressed in the avascular retina in proliferative retinopathy in vivo and that iNOS expression in retinal glial cells is responsible for retinal neuronal cell death in vitro. Here we show that retinal apoptosis and subsequent degeneration occur in the murine model of ischemic proliferative retinopathy. Furthermore, because NO can have beneficial or detrimental effects in the retina, we analyzed the role of iNOS on retinal apoptosis in ischemic proliferative retinopathy. Using iNOS knock-out mice and iNOS inhibitor 1400W, we demonstrate in vivo that iNOS expression induces apoptosis locally in the inner nuclear layer of the avascular retina and that protein nitration may be involved in this process. These findings are the first evidence for retinal apoptosis in an animal model of ischemic proliferative retinopathy, demonstrating that iNOS plays a crucial role not only in retinal neovascular disease but also in retinal degeneration. We show that it is an ideal target to protect the hypoxic retina from degeneration and to improve its vascularization.

Aging↗
PubMed2004

[Neovascularization in ocular tissues: mechanisms and role of proangiogenic and antiangiogenic factors].

Blood vessel growth and stability are under precise control of an array of pro- and anti-angiogenic factors. Under physiological conditions, actions of particular regulatory factors, as well as their mutual interactions are harmonized and balanced. Disruption of the balance between these pro- and anti-angiogenic factors is characteristic of many vascular diseases, including those occurring within the eye. Functional dominancy of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) over antiangiogenic ones (e.g., pigment epithelium-derived growth factor, PEDF), which may occur under ischemic conditions, may initiate the process of retinal or choroidal neovascularization, representing a major threat to the eyesight. This article presents and discusses current ideas concerning molecular and cellular processes underlying aberrant growth on new blood vessels in ocular tissues, in relation to microvascular ocular complications associated mainly (but not only), with diabetes mellitus, age-related macular degeneration (AMD), and retinopathy of prematurity (ROP). This review also surveys latest achievements in the field of clinically more effective future therapeutic strategies, including gene therapy applicable to the neovascular eye diseases.

Choroid↗
PubMed1990

Exudative retinal detachment following central and hemicentral retinal vein occlusions.

We describe five eyes of five patients that developed an exudative retinal detachment following a central retinal vein occlusion (including one eye with a hemicentral [hemispheric] retinal vein occlusion). The time interval between the occurrence of the vein occlusion and the appearance of the retinal detachment ranged from 7 to 36 weeks in the four cases seen in the acute period. Each detachment involved the posterior retina and was associated with the development of marked retinal ischemia. Neovascular glaucoma occurred in two cases. The subretinal fluid completely or partially resorbed in the four eyes that were treated with retinal photocoagulation, but the final visual acuity was poor in all cases. Exudative retinal detachment is a potential complication of central retinal vein occlusion and in this series was associated with a poor visual prognosis.

Adolescent↗
PubMed2002

Transplantation of autologous retinal pigment epithelium in eyes with foveal neovascularization resulting from age-related macular degeneration: a pilot study.

PURPOSE: To describe the indications, surgical technique, and clinical results of 14 eyes in 13 patients with age-related macular degeneration and foveal choroidal neovascularization, in which subretinal surgery was combined with simultaneous transplantation of autologous retinal pigment epithelial cells. METHODS: Between March 1999 and February 2000, in a prospective study, 14 eyes (13 patients) with age-related macular degeneration underwent subretinal surgery because of foveal choroidal neovascularization with simultaneous transplantation of retinal pigment epithelium harvested from the nasal subretinal area of the same eye. Preoperatively, 1 month postoperatively, 3 months postoperatively and at 3-month intervals thereafter, examinations were performed including best-corrected visual acuity, visual field, biomicroscopy of anterior and posterior segment, tonometry, fluorescein and indocyanine angiographies, autofluorescence, scotometry, and fixation tests. RESULTS: Postoperatively, after median observation of 17 months (range, 12 to 24 months) best-corrected visual acuity was improved 2 or more lines in eight eyes (57.1%), remained the same (+/- 1 line) in five eyes (35%), and decreased by more than 2 lines in one eye (7.1%). Pairwise t test showed significant improvement after 1 month (P = .0031, P = .0062) as well as 1 year (P = .0066, P = .0105). Satisfactory reading vision between Jaeger 1 and 4 was achieved in three eyes (21.2%). No significant intraoperative or postoperative complications occurred in any eye. No recurrence of choroidal neovascularization was observed during the observation period. CONCLUSIONS: In eyes with age-related macular degeneration and foveal choroidal neovascularization, autotransplantation of retinal pigment epithelium was performed in addition to conventional removal of the choroidal neovascularization without significant intraoperative or postoperative complications. Visual acuity improvement of 2 or more lines in 57% of the eyes was achieved. No recurrent choroidal neovascularization formation was observed during the observation period. The results of this pilot study suggest that autologous transplantation of retinal pigment epithelium combined with submacular surgery might be a reasonable treatment option for patients with foveal choroidal neovascularization secondary to age-related macular degeneration.

Aged↗
PubMedDate not supplied

[Treatment of neovascular age-related macular degeneration with antiangiogenic drugs].

Age-related macular degeneration (ARMD) remains a leading cause of blindness in the western world. Several clinical forms of the disease are recognized, whereas choroidal neovascularization (CNV) represents an important manifestation suitable for treatment. The treatment of CNV has been a major focus of research in the past decades, and the first evidence-based established therapy was laser photocoagulation, which reduces the risk of visual loss in extrafoveal lesions. In the late 90's photodynamic therapy has been established as an efficient method for the treatment of predominantly classic and occult CNV. Additional therapies such as macular translocation, submacular surgery, and indocyanine-mediated prothrombosis are currently under investigation in large-scale clinical trials. Molecular biology has recently provided a better comprehension of the pathogenesis of ARMD, and vascular endothelial growth factor (VEGF) was recognized as key mediator in the angiogenesis of CNV-formation. Therefore, the pharmacological approach rose as a key research area to treat CNV. The first FDA-approved agent for CNV-therapy is aptamer pegaptanib sodium (Macugen), which inactivates the key angiogenic isoform VEGF165. Additional VEGF-blockers such as ranibizumab RhuFab V2 (Lucentis) and bevacizumab (Avastin) are under evaluation in major clinical studies. Impressive results of intravitreal bevacizumab were released recently. Moreover, the steroid-derived anecortave acetate as well as the corticosteroid triamcinolone acetate have been proposed as methods for treatment of wet-ARMD. This paper presents the rationale and principles of the pharmacologic antiangiogenic therapy for CNV in ARMD.

Angiogenesis Inhibitors↗
PubMed2006

Pegaptanib (Macugen): treating neovascular age-related macular degeneration and current role in clinical practice.

Repeated Macugen intravitreal injections, well tolerated and safe when performed according to protocol, is the first successful pharmacotherapy for wet AMD. Macugen has already had a significant impact on neovascular AMD management, in regard to both individual patients with AMD lesions that would become amenable to treatment, and in its effects on visual function and its preservation in the aging United States population. Although results and delivery method are not optimal, the positive outcomes indicate the beginning, and not the limit, of pharmacotherapy for AMD. The benefits of Macugen therapy for AMD strongly outweigh the risks. It is pointed out by some that the overall magnitude of the efficacy results is very similar to the PDT trials and question why there is so much enthusiasm about a treatment that entails intravitreal injections every 6 weeks instead of PDT every 12 weeks. In all fairness, PDT is not equally efficacious across the lesion subtypes and sizes, whereas Macugen has effect with all lesion subtypes. In addition, these studies widen the armamentarium and open up the possibility of combination therapy in attacking neovascularization through multiple ways.

Aptamers, Nucleotide↗