| Structures of eye are precise. Pathological changes of ocular tissues will damage the function of these tissues, which result in visual impairment.Vision loss in pathological ocular diseases such as retinopathy of prematurity (ROP), proliferative diabetic retinopathy (DR), Vogt-Koyanagi-Harada disease (VKH), age-related macular degeneration (AMD) ischaracterized by the extensive proliferation of new blood vessels in the choroid and retina. The initial pathogenies of these diseases are different, but this abnormal and disproportionate hype-vascularization is compensatory mechanism to overcome the earlier phase of ischemia of tissues induced by hypoxia. Studies have shown that pro-angiogenec factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), pigment-epithelium-derived factor (PEDF), insulin-like growth factors (IGFs) increased by hypoxia in retina, choroid and pigment epithelial cells. Pro-angiogenic factors are over-expressed in the ocular tissues prior to the pathogenesis of neovascularization of proliferative oculopathy. Recently, it is widely accepted that VEGF plays a primary role in angiogenic processes. VEGF not only change character of extracellular matrix change,enhance permeability of blood vessels, but also induce cell proliferation, migration, differentiation and survival. It is an essential factor for pathological angiogenesis. Specific receptors of endothelial cells phosphorylatedby binding of VEGF, stimulate the phosphorylation of the downstream moleculars, such as PI3K/AKT, ERK1/2, and activated signaling pathways induce the expression of several transcription factors and cytokines. Finnaly, these factors affect angiogenesis by promoting the proliferation, migration, tube formation and differentiation of endothelial cells.Surgical treatment for ocular neovascularization is a high-risk procedure, it has uncertain therapeutic effect and neopathy postoperatively, but medication as a nondestruction modes of therapy could be benefit for patients with these blindness-cause disease. Application of corticosteroid drugs, antioxidant are limited by drug toxicity and delivery modes in clinical, but VEGF-related drugsare attractive.Chinese herbal monomers purified from herb medicines are valuable treasures of China. To discover small molecularsin these Chinese herb medicines which possess anti-angiogenesis activities is very important for future clinical drugs and healthy development of patients with blinding disease. Raddeanin A(RA) is received more attention with its attractive antitumor activity both in vitro and in vivo among all the identified oleanane-type saponins from A. raddeana(also known as "Liangtoujian" in China),however, there isno report about its antiangiogenesis activity. In this study, we investigated the functional role of Raddeanin A in angiogenesis and potential mechanism. We found that Raddeanin Asuppressed proliferation, migration and tube formation of endothelial cells in vitro. At lower doses, Raddeanin A inhibited micro-vessels of rat aortic ring formation and growth significantly. In the oxygen-induced retinopathymodel, Raddeanin A inhibited retinal angiogenesis. Moreover, we found that RaddeaninA inhibited angiogenesis and retinal neovascularization via VEGFR2 mediated AKTand ERK1/2 signaling pathway.In conclusion, we identified a herbal monomer Raddeanin A as inhibitor of angiogenesis in vivo and in vitro. Raddeanin A inhibited hypoxia-induced ocular neovascularization through suppressing VEGFR2 mediated AKT and ERK1/2 signaling pathway. In addition, we established hindlimb ischemia in STZ induced diabetic mice animal model, colon cancer liver metastaisis mice model and pulmonary metastasis mice model for correlation studies. |
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