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Objective-To investigate the role of endogenous apelin in pathological retinal angiogenesis. Methods and Results-The progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis, mainly induced by vascular endothelial growth factor (VEGF) and erythropoietin. Although antiangiogenic therapies using anti-VEGF drugs are effective in treating retinal neovascularization, they show a transient efficacy and cause general adverse effects. New therapeutic target molecules are needed to resolve these issues. It was recently demonstrated that the apelin/APJ system, a newly deorphanized G protein-coupled receptor system, is involved in physiological retinal vascularization. Retinal angiography and mRNA expression were examined during hypoxia-induced retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Compared with age-matched control mice, retinal apelin expression was dramatically increased during the hypoxic phase in oxygen-induced retinopathy model mice. APJ was colocalized in proliferative cells, which were probably endothelial cells of the ectopic vessels in the vitreous body. Apelin deficiency hardly induced hypoxia-induced retinal angiogenesis despite the upregulation of VEGF and erythropoietin mRNA in oxygen-induced retinopathy model mice. Apelin small and interfering RNA suppressed the proliferation of endothelial cells independent of the VEGF/VEGF receptor 2 signaling pathway. Conclusion-These results suggest that apelin is a prerequisite factor for hypoxia-induced retinal angiogenesis. Key Words: angiogenesis Ⅲ VEGF Ⅲ apelin Ⅲ retinopathy T he progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis, which is mainly induced by vascular endothelial growth factor (VEGF) 1 and erythropoietin (Epo). 2 Antiangiogenic therapies targeting these factors are effective in treating proliferative diabetic retinopathy. 3,4 However, these therapies show a transient efficacy and cause the general adverse effects. 5 Furthermore, elevated VEGF levels do not necessarily correlate with pathological retinal angiogenesis in patients with diabetic maculopathy. 6 This suggests that the entire process of pathological retinal angiogenesis includes more than just upregulation of VEGF expression. Therefore, finding other factors involved in pathological retinal angiogenesis is important.The apelin/apelin receptor (APJ) system is a newly deorphanized G protein-coupled receptor system. 7 Recently, much attention has been focused on the possible roles of the apelin/APJ system in vascular pathophysiology. 8,9 APJ is expressed in endothelial cells at the leading edge of vessels during early embryogenesis; and apelin, in combination with VEGF, induces the proliferation and assembly of endothelial cells. 10 Moreover, we demonstrated a retardation of physiological retinal vascular development during the early postnatal period and a reduced angiogenic response to VEGF in apelin-knockout...

Elderly HCC patients, who have good performance status, should be treated in the same manner and with the same strategy as young HCC patients.

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