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Abstract
Pathological retinal angiogenesis is caused by the progression of ischemic retinal diseases and can result in retinal detachment and irreversible blindness. This neovascularization is initiated from the retinal veins and their associated capillaries and involves the overgrowth of vascular endothelial cells. Since expression of the apelin receptor (APJ) is restricted to the veins and proliferative endothelial cells during physiological retinal angiogenesis, in the present study, we investigated the effect of APJ inhibition on pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). In vitro experiments revealed that ML221, an APJ antagonist, suppressed cultured-endothelial cell proliferation in a dose-dependent manner. Intraperitoneal administration of ML221 inhibited pathological angiogenesis but enhanced the recovery of normal vessels into the ischemic regions in the retina of the OIR model mice. ML221 did not affect the expression levels of vascular endothelial growth factor (VEGF) and its receptor (VEGFR2) in the retina. APJ was highly expressed in the endothelial cells within abnormal vessels but was only detected in small amounts in morphologically normal vessels. These results suggest that APJ inhibitors selectively prevent pathological retinal angiogenesis and that the drugs targeting APJ may be new a candidate for treating ischemic retinopathy.
Highlights
Pathological retinal angiogenesis is caused by the progression of ischemic retinal diseases, such as proliferative diabetic retinopathy and retinopathy of prematurity, and can result in retinal detachment and irreversible blindness
Since overgrowth of endothelial cells is involved in pathological retinal angiogenesis, we first examined the effect of ML221, an APJ antagonist, on endothelial cell proliferation using mouse microvascular endothelial bEnd.[3] cells
These results suggest that ML221 inhibits endothelial cell proliferation by blocking apelin-APJ signaling without affecting the expression of vascular endothelial growth factor (VEGF) and VEGFR2
Summary
Pathological retinal angiogenesis is caused by the progression of ischemic retinal diseases, such as proliferative diabetic retinopathy and retinopathy of prematurity, and can result in retinal detachment and irreversible blindness. Vascular endothelial growth factor (VEGF) is a primary angiogenic factor that mediates such ischemia-induced retinal neovascularization. The formation of neovascular tufts is shown to be a consequence of the overgrowth of vascular endothelial cells induced by an overexpression of hypoxia-inducible growth factors[7,8]. These findings suggest that decreased proliferative signals in endothelial cells of the venules and their associated capillaries under hypoxic conditions could lead to specific inhibition of pathological retinal angiogenesis. Apelin expression is induced by hypoxia[13], and apelin and APJ expressions are increased in the endothelial cells in ischemia tissues[12]. We demonstrated that APJ inhibition suppressed pathological retinal angiogenesis in ischemic retinopathy
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