Resveratrol Inhibits Pathologic Retinal Neovascularization inVldlr−/−Mice
| Autor: | David A. Sinclair, Jing Chen, Molly R. Seaward, Aimee M. Juan, Jing Hua, Roberta J. Dennison, Shaday Michan, Przemyslaw Sapieha, Colman J. Hatton, Andreas Stahl, Lois E.H. Smith, Karen I. Guerin, Nathan M. Krah |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Retinal degeneration Pathology medicine.medical_specialty genetic structures Angiogenesis Blotting Western Administration Oral Angiogenesis Inhibitors Nerve Tissue Proteins Retinal Neovascularization Biology Resveratrol Antioxidants Retina Mice chemistry.chemical_compound Glial Fibrillary Acidic Protein Stilbenes medicine Animals RNA Messenger Fluorescent Antibody Technique Indirect Mice Knockout Retinal pigment epithelium Reverse Transcriptase Polymerase Chain Reaction food and beverages Retinal Articles Anatomy Macular degeneration medicine.disease eye diseases Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Receptors LDL chemistry Retinal Telangiectasis Female Endothelium Vascular sense organs |
| Zdroj: | Investigative Opthalmology & Visual Science. 52:2809 |
| ISSN: | 1552-5783 |
| Popis: | Abnormal retinal angiogenesis and choroidal angiogenesis are common causes of vision loss.1 Macular telangiectasia (MacTel), also known as idiopathic parafoveal telangiectasia, is a retinal neovascular disease in which there is abnormal retinal neovascular proliferation in the perimacular area2–4 associated with photoreceptor degeneration.1,4 The pathogenesis of MacTel is not yet understood, though aging might be a contributing factor because MacTel is typically diagnosed in patients in their 50s or 60s. Regrettably, there is no recognized treatment for MacTel to date. Preclinical studies using animal models that mimic MacTel would significantly help to evaluate novel potential therapeutic strategies. Similar to MacTel and retinal angiomatous proliferation (RAP),5,6 the very low-density lipoprotein receptor (VLDLR) mutant mouse (Vldlr−/−) shows patchy retinal neovascularization (NV) arising from the deep retinal vascular layer. These changes become visible by the end of the second postnatal week, and by 4 weeks of age the NV lesions extend through the normally avascular photoreceptor layer toward the surface of the retinal pigment epithelium (RPE). NV lesions form subretinal clusters of abnormal microvessels reminiscent of those observed in patients with MacTel.6,7 Vegf-A (Vegf) is elevated in Vldlr−/− retinas and is likely one of the primary causes of the proliferation of subretinal neovascular lesions and their leakiness.6,8 Vldlr−/− mouse retinas also show photoreceptor degeneration and Muller glial activation9 associated with subretinal neovascular lesions, indicating a focal increase of retinal neuronal stress. Importantly, the NV lesions in both MacTel patients and Vldlr−/− mice originate from the retinal vessels without initial RPE damage, in contrast to wet age-related macular degeneration, in which NV grows from the choroid through defects in Bruch's membrane into the subretinal space.6 Although the molecular mechanisms leading to these vascular and neuronal lesions in Vldlr−/− mice are not fully understood, hypoxia, inflammation,9 and Wnt signaling10 may play a role in NV development. Antioxidants ameliorate both the retinal degeneration and the vascular pathology in Vldlr−/− retinas.6 In this study we evaluated the therapeutic potential of resveratrol, a plant polyphenol, for the treatment of subretinal NV using Vldlr−/− mice as a model for MacTel. Resveratrol is found in grapes, peanuts, pines, and red wines, and its intake has been associated with a reduced risk of cardiovascular disease.11 In animal models, resveratrol also inhibits angiogenesis in cancer,12,13 in development and wound healing through downregulation of the MAPK pathway in endothelial cells, leading to reduced endothelial proliferation and migration.14 Yet in other conditions such as stroke, myocardial infarction, and ischemia-reperfusion injuries, resveratrol can be proangiogenic while at the same time exerting neuroprotective properties.15–17 Our results show that the oral administration of resveratrol significantly suppresses pathologic NV formation in Vldlr−/− mice when treated after the onset of neovascular lesions but also when started before the lesions fully form. The antiangiogenic and antimigratory effects of resveratrol are seen in an ex vivo aortic ring assay and in cell culture experiments. Additionally, resveratrol treatment significantly reduces Vegf transcription in Vldlr−/− retinas and diminishes VEGF-induced phosphorylation of MAPK in vitro. Together these results suggest resveratrol reduces neovascular lesions in Vldlr−/− retinas through the downregulation of VEGF and an attenuated response of retinal endothelial cells to angiogenic stimulation. |
| Databáze: | OpenAIRE |
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