Effects of Dioxin on Vascular Endothelial Growth Factor (VEGF) Production in the Retina Associated with Choroidal Neovascularization
ABSTRACT Cigarette smoking is the most consistent risk factor for age-related macular degeneration (AMD), especially the choroidal neovascularization (CNV)-mediated exudative type. Dioxins and dioxin-like compounds have various effects on living organisms and are also contained in cigarette smoke. However, the effects of dioxins on the eye remain elusive. In this study, the authors examined the association between dioxins and neovascularization in the eye.
C57BL/6 mice were injected intraperitoneally with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every other day for 14 days. Messenger RNA expression of cytochrome P450 (CYP)1A1, CYP1B1, vascular endothelial growth factor (VEGF)-A and VEGF-B, and VEGF production were examined in the eyes of TCDD-treated mice and in human retinal pigment epithelial cell lines (ARPE-19) exposed to TCDD. In addition, CNV was induced by photocoagulation in mice injected with TCDD, and the volume of CNV was compared by fluorescence-labeled choroidal flat mount.
TCDD injected intraperitoneally increased CYP1A1 mRNA expression in the iris/ciliary body and retina, indicating that TCDD acts directly on ocular tissues through the aryl hydrocarbon receptor (AhR) to promote the transcription of target genes. TCDD also promoted VEGF-A mRNA expression in the retina and the retinal pigment epithelium. TCDD-induced VEGF production at the molecular level was also observed in vivo by immunohistochemistry and in vitro using ARPE-19. Moreover, the injection of TCDD significantly exacerbated photocoagulation-induced CNV in mice.
The authors demonstrate that dioxins are among the factors inducing abnormal vascularization in the eye through VEGF production mediated by AhR signaling.
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ABSTRACT: Purpose. To identify the predictors of visual response to the bevacizumab treatment of neovascular age-related macular degeneration (AMD). Design. A cohort study within the Neovascular AMD Treatment Trial Using Bevacizumab (NATTB). Methods. This was a multicenter trial including 144 participants from the NATTB study. Visual outcomes measured by change in visual acuity (VA) score, proportion gaining ≥15 letters, and change in central retinal thickness (CRT) were compared among groups according to the baseline, demographic, and ocular characteristics and genotypes. Results. Mean change in the VA score was 9.2 ± 2.3 SD letters with a total of 46 participants (31.9%) gaining ≥15 letters. Change in median CRT was -81.5 μ m. Younger age, lower baseline VA score, shorter duration of neovascular AMD, and TT genotype in rs10490924 were significantly associated with greater VA score improvement (P = 0.028, P < 0.001, P = 0.02, and P = 0.039, resp.). Lower baseline VA score and TT genotype in rs10490924 were significantly associated with a higher likelihood of gaining ≥15 letters (P = 0.028, and P = 0.021, resp.). Conclusions. Baseline VA and genotype of rs10490924 were both important predictors for visual response to bevacizumab at 6 months. This trial is registered with the Registration no. NCT01306591.Journal of Ophthalmology 08/2013; 2013:676049. DOI:10.1155/2013/676049 · 1.94 Impact Factor
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ABSTRACT: Age-related macular degeneration (AMD) is one of the main socioeconomical health issues worldwide. AMD has a multifactorial etiology with a variety of risk factors. Smoking is the most important modifiable risk factor for AMD development and progression. The present review summarizes the epidemiological studies evaluating the association between smoking and AMD, the mechanisms through which smoking induces damage to the chorioretinal tissues, and the relevance of advising patients to quit smoking for their visual health.Journal of Ophthalmology 12/2013; 2013:895147. DOI:10.1155/2013/895147 · 1.94 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease with high morbidity and mortality. Within the inflammatory milieu, resident fibroblast-like synoviocytes (FLS) in the synovial tissue undergo hyperplasia, which leads to joint destruction. Epidemiological studies and our previous research suggest activation of Ah receptor (AHR) pathway plays an instrumental role in the inflammatory and destructive RA phenotype. In addition, our recent studies implicate the AHR in the regulation of the expression of several growth factors in established tumor cell lines. Thus, under inflammatory conditions, we hypothesized that the AHR is involved in the constitutive and inducible expression of several growth factors, FLS proliferation and migration, along with protease-dependent invasion in RA-FLS. Treatment with AHR antagonist GNF351 inhibits cytokine-induced expression of vascular endothelial growth factor-A, epiregulin, amphiregulin and basic fibroblast growth factor mRNA expression through an AHR-dependent mechanism in both RA-FLS and FLS. Secretion of vascular endothelial growth factor-A and epiregulin from RA-FLS was also inhibited upon GNF351 treatment. RA-FLS cell migration, along with cytokine-induced RA-FLS cell proliferation, was significantly attenuated by GNF351 exposure. Treatment of RA-FLS with GNF351 mitigated cytokine-mediated expression of matrix metalloproteinases (MMP) -2 and -9 mRNA levels and diminished the RA-FLS invasive phenotype. These findings indicate that inhibition of AHR activity may be a viable therapeutic target in amelioration of disease progression in RA by attenuating growth factor release, FLS proliferation, migration and invasion, along with our previously described anti-inflammatory activity.Journal of Pharmacology and Experimental Therapeutics 12/2013; 348(2). DOI:10.1124/jpet.113.209726 · 3.86 Impact Factor