Effects of Dioxin on Vascular Endothelial Growth Factor (VEGF) Production in the Retina Associated with Choroidal Neovascularization

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 02/2009; 50(7):3410-6. DOI: 10.1167/iovs.08-2299
Source: PubMed


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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    • "The AhR localization induced not only cytochrome P450 family 1 member A1 (CYP1A1) and 1A2 expression but also Nrf2 expression. In addition, AhR mediates TCDD induced VEGF expression [19] and relates to angiogenesis in mouse [20]. In this study, we report a novel pathway that induces VEGF expression in HepG2 cells in response to glucose deprivation. "
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    ABSTRACT: Aryl hydrocarbon receptor (AhR) not only regulates drug-metabolizing enzyme expression but also regulates cancer malignancy. The steps to the development of malignancy include angiogenesis that is induced by tumor microenvironments, hypoxia, and nutrient deprivation. Vascular endothelial growth factor (VEGF) plays a central role in the angiogenesis of cancer cells, and it is induced by activating transcription factor 4 (ATF4). Recently, we identified that glucose deprivation induces AhR translocation into the nucleus and increases CYP1A1 and 1A2 expression in HepG2 cells. Here, we report that the AhR pathway induces VEGF expression in human hepatoblastoma HepG2 cells under glucose deprivation, which involves ATF4. ATF4 knockdown suppressed VEGF expression under glucose deprivation. Moreover, AhR knockdown suppressed VEGF and ATF4 expression under glucose deprivation at genetic and protein levels. The AhR-VEGF pathway through ATF4 is a novel pathway in glucose-deprived liver cancer cells that is related to the microenvironment within a cancer tissue affecting liver cancer malignancy.
    BMC Molecular Biology 12/2013; 14(1):27. DOI:10.1186/1471-2199-14-27 · 2.19 Impact Factor
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    • "Furthermore, dioxin which is present primarily in the gaseous phase of cigarette smoking promotes VEGF production in the retina of mice and human retinal pigment epithelium (RPE) cells and exacerbates the development of laser-induced CNV [36]. Cigarette smoking plays a role in the pathogenesis of neovascular AMD in more than one way, including causing oxidative damage [37, 38], as well as affecting choroidal blood flow [39, 40] and macular pigment optical density [41, 42]; therefore, smoking may have an antieffect of bevacizumab treatment on the pathological characteristics in the retina for neovascular AMD, and, as a distant factor for retina, smoking may cause the anatomical change at first and then lead to dysfunction of retina, which may explain why cigarette smoking showed no association with VA score change that was a measurement of visual function. "
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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 · 1.43 Impact Factor
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    ABSTRACT: Angiogenesis has key roles in development and in the progression of human diseases such as cancer. Consequently, identifying the novel markers and regulators of angiogenesis is a critical task. The dioxin receptor (AhR) contributes to vascular homeostasis and to the endothelial response to toxins, although the mechanisms involved are largely uncharacterized. Here, we show that AhR-null mice (AhR(-/-)) have impaired angiogenesis in vivo that compromises tumor xenograft growth. Aortic rings emigration experiments and RNA interference indicated that AhR(-/-) endothelial cells failed to branch and to form tube-like structures. Such a phenotype was found to be vascular endothelial growth factor (VEGF)-dependent, as AhR(-/-) aortic endothelial cells (MAECs) secreted lower amounts of active VEGF-A and their treatment with VEGF-A rescued angiogenesis in culture and in vivo. Further, the addition of anti-VEGF antibody to AhR(+/+) MAECs reduced angiogenesis. Treatment under hypoxic conditions with 2-methoxyestradiol suggested that HIF-1alpha modulates endothelial VEGF expression in an AhR-dependent manner. Importantly, AhR-null stromal myofibroblasts produced increased transforming growth factor-beta (TGFbeta) activity, which inhibited angiogenesis in human endothelial cells (HMECs) and AhR(-/-) mice, whereas the co-culture of HMECs with AhR(-/-) myofibroblasts or with their conditioned medium inhibited branching, which was restored by an anti-TGFbeta antibody. Moreover, VEGF and TGFbeta activities cooperated in modulating angiogenesis, as the addition of TGFbeta to AhR(-/-) MAECs further reduced their low basal VEGF-A activity. Thus, AhR modulates angiogenesis through a mechanism requiring VEGF activation in the endothelium and TGFbeta inactivation in the stroma. These data highlight the role of AhR in cardiovascular homeostasis and suggest that this receptor can be a novel regulator of angiogenesis during tumor development.
    Journal of Biological Chemistry 08/2009; 284(37):25135-48. DOI:10.1074/jbc.M109.013292 · 4.57 Impact Factor
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