Molecular mechanisms of ocular angiogenesis and development of therpeutic agents

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In diabetic retinopathy, vascular barrier breakdown, obstruction and new vessel formation are caused by any cytokines and growth factors, including vascular endothelial growth factor(VEGF), transforming growth factor-beta(TGF-beta)superfamily and interleukin-6(IL-6). The purpose of this presentation is to clarify the roles and the interaction among factors in the pathogenesis of proliferative diabetic retinopathy(PDR).The Expressions of VEGF, PIGF, TGF-beta superfamily(TGF-beta, activin A), interleukin-6(IL-6)in the intraocular humor and the pathological fibrovascular tissues obtained from PDR eyes were investigated. The correlation between the expression of cytokines/growth factors and clinical characteristics was inquired to know the roles in the pathogenesis of diabetic retinopathy. The concentrations of VEGF, PIGE and IL-6 increased in the intraocular humor from diabetic retinopathy eyes. In the pathological preretinal proliferative tissues obtained from PDR eyes, VEGF, TGF-b2, and … More activin A were expressed. The concentration of VEGF, blood-ocular barrier function and pathological changes of iris vessels were correlated. VEGF is speculated to play important roles in the breakdown of vascular barrier functions and new vessel formation in diabetic retinopathy. Concentrations of PIGF and VEGF in PDR eyes were correlated, because both are induced by hypoxia. Activin A counteracted the growth stimulation by VEGF in the cultured endothelial cells.The angiogenesis process is regulated by many growth factors and cytokines including VEGF and TGF-beta. In the next step, to investigate the molecular mechanisms of regulation of angiogenesis, angiogenic activity in vivo and the effects on cultured endothelial cells in vitro of VEGF and TGF-beta superfamily.Angiogenesis in vivo (CAM assay) : VEGF and TGF-beta induced angiogenesis. Activin A did not induce the angiogenesis.Effects on endothelial cells in vitro : VEGF stimulated 4 steps of angiogenesis. However, TGF-beta and activin A inhibited the endothelial cell function in vitro. These results suggest that the angiogenis activity in vivo and that in vitro may be differetnt, so both experimental systems are mandatory to evaluate the angiogenic activity of various cytokines. Less