PURPOSE: To investigate the effects of resveratrol on the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in human adult retinal pigment epithelial (ARPE-19) cells, and on experimental choroidal neovascularization (CNV) in mice. MATERIALS AND METHODS: ARPE-19 cells were treated with different concentrations of resveratrol and then incubated under hypoxic conditions with subsequent evaluation of cell viability, expression of HIF-1alpha, and expression of VEGF. The effects of resveratrol on the synthesis and degradation of hypoxia-induced HIF-1alpha were evaluated using inhibitors of the PI3K/Akt/mTOR and the ubiquitin proteasome pathways. In animal studies, CNV lesions were induced in C57BL/6 mice by laser photocoagulation. After 7 days of oral administration of resveratrol or vehicle, which began one day after CNV induction, image analysis was used to measure CNV areas on choroidal flat mounts stained with isolectin IB4. RESULTS: In ARPE-19 cells, resveratrol significantly inhibited HIF-1alpha and VEGF in a dose-dependent manner, by blocking the PI3K/Akt/mTOR signaling pathway and by promoting proteasomal HIF-1alpha degradation. In mice experiments, orally administered resveratrol significantly inhibited CNV growth in a dose-dependent manner. CONCLUSION: Resveratrol may have therapeutic value in the management of diseases involving pathological neovascularization.
Adult ; Animals ; Anoxia/metabolism/physiopathology ; Cell Survival/drug effects ; Choroidal Neovascularization/*metabolism/pathology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors/*physiology ; Proteasome Endopeptidase Complex ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*physiology ; Retinal Pigment Epithelium/*drug effects/metabolism ; Signal Transduction ; Stilbenes/administration & dosage/*pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*physiology ; Ubiquitin ; Vascular Endothelial Growth Factor A/*drug effects/metabolism

PURPOSE: To investigate which spectral domain optical coherence tomography (SD-OCT) findings predict visual outcome after anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (NV-AMD). METHODS: We reviewed the medical records of patients with treatment-naive NV-AMD who underwent three or more consecutive anti-VEGF injections. The patients were divided into three groups according to their changes of visual acuity (VA); improved (group I), static (group S), or worsened (group W). We assessed the incidences and values of all available SD-OCT findings of these groups, compared these findings between the three groups and compared the initial values with the post-treatment values. RESULTS: Better initial VA and longer external limiting membrane (ELM) length were associated with less change in VA after anti-VEGF treatment. The initial VA was mildly correlated with initial photoreceptor inner and outer segment junction (IS/OS) length and initial ELM length. The final VA was also mildly correlated with the final IS/OS length and the final ELM length. VA was significantly changed after anti-VEGF treatment in groups W and I. With regard to incidence, disruption of the IS/OS (IS/OS-D), disruption of the ELM (ELM-D) and ELM length differed significantly between the three groups, particularly ELM-D. The incidences of IS/OS-D and ELM-D in group I were significantly lower than those in groups S and W, and those in group S were also lower than those in group W. The ELM length in group I was significantly longer than it was in groups S and W, and the ELM length in group S was longer than that for group W. However, these three findings did not change after the anti-VEGF treatment. CONCLUSIONS: Initial IS/OS-D, ELM length and particularly ELM-D can be useful predictors of the visual outcome after anti-VEGF treatment in NV-AMD patients.
Aged ; Aged, 80 and over ; Angiogenesis Inhibitors/*therapeutic use ; Choroidal Neovascularization/*drug therapy/physiopathology ; Female ; Humans ; Intravitreal Injections ; Male ; Middle Aged ; Ranibizumab/*therapeutic use ; Retinal Photoreceptor Cell Inner Segment/pathology ; Retinal Photoreceptor Cell Outer Segment/pathology ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Visual Acuity/*physiology ; Wet Macular Degeneration/*drug therapy/physiopathology

CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angiogenic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout (CD146(EC-KO)) mice using the Tg(Tek-cre) system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146(EC-KO) mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells (ECs) of CD146(EC-KO) mice. Mechanistic studies further confirmed that VEGF-induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/NF-κB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146(EC-KO) mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis.
Animals ; CD146 Antigen ; genetics ; metabolism ; Cells, Cultured ; Endothelial Cells ; cytology ; metabolism ; Female ; Fibrosarcoma ; metabolism ; pathology ; Male ; Melanoma, Experimental ; metabolism ; pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B ; metabolism ; Neovascularization, Physiologic ; drug effects ; Phosphorylation ; drug effects ; Proto-Oncogene Proteins c-akt ; metabolism ; Retinal Vein ; growth & development ; pathology ; Signal Transduction ; drug effects ; Transplantation, Homologous ; Vascular Endothelial Growth Factor A ; pharmacology ; Vascular Endothelial Growth Factor Receptor-2 ; metabolism

PURPOSE: To identify the unique pathologic findings of retinal angiomatous proliferation (RAP) in optical coherence tomography (OCT). METHODS: Retrospectively, 29 eyes of 25 patients with age-related macular degeneration and complicated RAP were analyzed. All 29 eyes had choroidal neovascularization (CNV) in the area of pigment epithelial detachment (PED) or adjacent to it, which was visible with fluorescein angiography or indocyanine green angiography. Cross-sectional images were obtained by OCT scanning through the CNV lesions. RESULTS: Six distinctive findings of OCT included drusen (100%), inner retinal cyst (80%), outer retinal cyst (68%), fibrovascular PED (84%), serous retinal detachment (40%), and PED (68%). CONCLUSIONS: Through analysis of OCT findings, we revealed six different types of lesions distinctive of RAP which may provide helpful diagnostic information for subsequent treatment and predicting the prognosis of RAP.
Aged ; Aged, 80 and over ; Female ; Follow-Up Studies ; Humans ; Macular Degeneration/*complications/diagnosis ; Male ; Middle Aged ; Reproducibility of Results ; Retina/*pathology ; Retinal Neovascularization/*diagnosis/etiology ; Retrospective Studies ; Severity of Illness Index ; Tomography, Optical Coherence/*methods

We report here the records of 10 consecutive Korean patients (10 eyes) with ocular toxoplasmosis which showed the typical clinical manifestations with seropositivity for Toxoplasma gondii specific IgG antibodies by micro-ELISA between 2006 and 2010. Nine patients were males and 1 was female; their age was 50.5+/-13.8 years. The most common accompanying signs were vitritis (100%), anterior uveitis (70%), and scattered white deposit (80%). Pre-existing retinochoroidal scar was found in 1 (10%) patient. All patients received antiparasitic chemotherapy and systemic corticosteroid treatment, which resolved the presenting attack and recovered the visual acuity better than initial one in 9 patients and worse in 1. Optic atrophy, cataract, and retinal neovascularization were observed during the follow-up period and recurrence was detected in 3 eyes (30%) 6 to 20 months after the initial attack. In Korea, although rarely detected and reported, ocular toxoplasmosis needs more attention in clinical field of retinal diseases.
Adrenal Cortex Hormones/administration & dosage ; Adult ; Age Distribution ; Aged ; Anti-Inflammatory Agents/administration & dosage ; Antibodies, Protozoan/*blood ; Antiprotozoal Agents/administration & dosage ; Cataract/pathology ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Immunoglobulin G/blood ; Korea ; Male ; Middle Aged ; Optic Atrophy/pathology ; Retinal Neovascularization/pathology ; Sex Distribution ; Toxoplasma/immunology/*isolation & purification ; Toxoplasmosis, Ocular/complications/*diagnosis/drug therapy/*pathology ; Uveitis, Anterior/complications/drug therapy/parasitology/pathology

PURPOSE: The goal of the present research was to study post-treatment changes in polypoidal choroidal vasculopathy (PCV) shown by optical coherence tomography (OCT). METHODS: The study included 12 patients with naive PCV. Photodynamic therapy and 3 consecutive intravitreal bevacizumab injections at 6-week intervals were given. Best corrected visual acuity, subretinal fluid (SRF), pigment epithelium detachment (PED), central macular thickness (CMT), and total macular volume (TMV) were measured before and after treatment as assessed by Stratus OCT3. RESULTS: After treatment, the SRF height decreased earlier than the PED height. The SRF diameter decreased with statistical significance. However, the PED diameter did not show a statistically significant improvement, persisting at pre-treatment levels. Both CMT and TMV decreased significantly after treatment. CONCLUSIONS: After PCV treatment, SRF and PED stabilized, as shown by OCT. However, the PED treatment response was both delayed and refractory compared to the SRF response. The small change in post-treatment PED diameter may suggest the possibility of PCV recurrence.
Aged ; Choroid/*pathology ; Choroid Diseases ; Choroidal Neovascularization/diagnosis/*drug therapy ; Disease Progression ; Female ; Fluorescein Angiography ; Follow-Up Studies ; Fundus Oculi ; Humans ; Male ; Photochemotherapy/*adverse effects ; Prognosis ; Retinal Detachment/diagnosis/*etiology ; Retinal Pigment Epithelium/*pathology ; Retrospective Studies ; *Subretinal Fluid ; Time Factors ; Tomography, Optical Coherence ; Visual Acuity

BACKGROUNDNeovascularization can cause vision loss in proliferative diabetic retinopathy (PDR) and may be affected by many factors. Stromal cell-derived factor-1 (SDF-1) is a potent stimulator of angiogenesis. The study was aimed to investigate the expression of SDF-1 and its correlation with vascular endothelial growth factor (VEGF) in the eyes with diabetic retinopathy.

METHODSThe levels of SDF-1 and VEGF were measured by enzyme-linked immunosorbent assay in the vitreous of 41 eyes of 41 patients with PDR and 12 eyes of 12 patients with idiopathic macular hole (IMH). Vitreous fluid samples and fibrovascular preretinal membranes were obtained at vitrectomy. SDF-1 and VEGF were localized using immunohistochemistry.

RESULTSThe vitreous concentration of VEGF was significantly higher in eyes with PDR ((2143.7 +/- 1685.21) pg/ml) than in eyes with IMH ((142.42 +/- 72.83) pg/ml, P < 0.001). The vitreous level of SDF-1 was also significantly higher in eyes with PDR ((306.37 +/- 134.25) pg/ml) than in eyes with IMH ((86.91 +/- 55.05) pg/ml, P < 0.001). The concentrations of both VEGF and SDF-1 were higher in eyes with active PDR than in eyes with inactive PDR. Panretinal photocoagulation (PRP) could decrease the SDF-1 levels in the vitreous of PDR patients. The vitreous concentration of SDF-1 correlated with that of VEGF in eyes with PDR (r = 0.61, P < 0.001). The costaining of SDF-1 and VEGF was confined to the vascular components in preretinal membranes.

CONCLUSIONSSDF-1 protein is highly expressed in both the vitreous and preretinal membranes of PDR patients; SDF-1 may be correlated with VEGF in angiogenesis in PDR.

Chemokine CXCL12 ; metabolism ; Diabetic Retinopathy ; metabolism ; pathology ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunohistochemistry ; Neovascularization, Pathologic ; metabolism ; physiopathology ; Retinal Perforations ; metabolism ; Vascular Endothelial Growth Factor A ; metabolism ; Vitrectomy ; Vitreous Body ; metabolism

We report a case of serous retinal detachment following combined photodynamic therapy (PDT) and intravitreal bevacizumab injection in subfoveal choroidal neovascularization (CNV).
Administration, Oral ; Angiogenesis Inhibitors/administration & dosage/*adverse effects ; Antibodies, Monoclonal/administration & dosage/*adverse effects ; Choroidal Neovascularization/*drug therapy/pathology ; Diagnosis, Differential ; Female ; Fluorescein Angiography ; Fundus Oculi ; Glucocorticoids/administration & dosage ; Humans ; Injections ; Middle Aged ; Photochemotherapy/*adverse effects ; Retinal Detachment/*chemically induced/diagnosis/drug therapy ; Tomography, Optical Coherence ; Triamcinolone/administration & dosage ; Vascular Endothelial Growth Factor A ; Vitreous Body

Photodynamic therapy (PDT) involves the induction of endothelial cell death or occlusion of blood vessels. On the basis of this mechanism of action, PDT is used in the treatment of predominant classic choroidal neovascularization (CNV), if the classic component is over 50%, and in myopic CNV. This study describes 2 cases of distinctive, abnormal, large, subretinal new vessels that are thought to have originated from the choroids. Diminishment of the new vessels was observed following treatment with PDT.
Retinal Vessels/drug effects/*pathology ; Retinal Diseases/*drug therapy/pathology ; *Photochemotherapy ; Neovascularization, Pathologic/*drug therapy/pathology ; Middle Aged ; Male ; Humans ; Female ; Angiography

OBJECTIVETo examine the expression of mRNA of vascular endothelial growth factor (VEGF) in a rat model of hyperoxia-induced retinopathy and to investigate the role of VEGF in the process of neovascularization in retinopathy.

METHODSOne hundred fifty one-day-old neonatal Sprague-Dawley rats were randomly divided into hyperoxia-induced retinopathy and normal control groups. The rats in the retinopathy group were exposed to (80 +/- 2)% oxygen for 7 days and then replaced by room air. The rats in the control group were exposed to room air all the time of the experiment. The morphologic changes of retinal vessels were estimated by observing the vascular pattern in adenosine diphosphate ase (ADPase) stained retina flat mounts. The newborn vessels were quantified by haematoxylin and eosin staining. Reversal transcription-polymerase chain reaction (RT-PCR) was used to detect the VEGF mRNA expression.

RESULTSIn the retinopathy group at 7 days of age, most of central radial vessels became constricted and blocked, and central perfusion decreased obviously. After switching to room air exposure for 7 days (14 days of age), noticeable retinal neovascularization appeared. The expression of VEGF mRNA in the retinopathy group at 7 days of hyperoxia exposure was noticeably lower than in the control group, and increased gradually after switching to room air exposure. At 9 and 14 days of age, the expression of VEGF mRNA in the retinopathy group was noticeably higher than in the control group. The expression of retinal VEGF mRNA in the retinopathy group increased before neovascularization occurred, and decreased with regression of new vessels.

CONCLUSIONSHyperoxia exposure may decrease the transcription of VEGF mRNA and the growth of retinal blood vessels. The relative hypoxia after hyperxia withdrawal can up-regulate the transcription of VEGF mRNA, resulting in a significant retinal neovascularization. The abnormal expression of VEGF in the retina may play an important role in the development of neovascularization in retinopathy.

Animals ; Animals, Newborn ; Disease Models, Animal ; Female ; Humans ; Hyperoxia ; complications ; Infant, Newborn ; Male ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Retina ; pathology ; Retinal Neovascularization ; Retinopathy of Prematurity ; metabolism ; Vascular Endothelial Growth Factor A ; genetics