An apelin receptor antagonist inhibits pathological retinal angiogenesis in a mouse model of ischemic retinopathy

Abstract

Vision loss associated with ischemic retinopathy, such as retinopathy of prematurity and proliferative diabetic retinopathy, is caused by pathological retinal angiogenesis. Currently, anti-vascular endothelial growth factor (VEGF) antibody is widely used for the treatment of pathological retinal angiogenesis. However, anti-VEGF therapy is ineffective in some patients with ischemic retinopathy, and its efficacy is not long-lasting. We have previously demonstrated that apelin and its receptor APJ are markedly elevated during pathological angiogenesis in the retina of a mouse model of oxygen-induced retinopathy (OIR), an ischemic retinopathy model. In this study, we investigated whether ML221, an APJ antagonist, inhibited pathological retinal angiogenesis in the OIR model mice. ML221 (10 mg/kg/day) and SU1498 (9 mg/kg/day), a selective inhibitor of VEGF receptor (VEGFR2), was administered intraperitoneally daily from postnatal day (P) 12 to P16 in the OIR model mice. The retinal vascular endothelial cells were stained with FITC-conjugated isolectin B4. Immunohistochemistry was performed to determine the distribution of APJ and VEGFR2 in the retina. Isolectin B4 staining revealed that abundant neovascular tufts and avascular regions emerged in the retina of OIR model mice at P17. Intraperitoneal injection of ML221 markedly reduced the formation of neovascular tufts and the avascular regions in the retina. In contrast, intraperitoneal injection of SU1498 suppressed the formation of neovascular tufts, but did not affect the avascular regions. Abundant APJ immunoreactivity was observed in the endothelial cells within neovascular tufts in the retina of the OIR model mice at P17. On the other hand, VEGFR2 immunoreactivities were observed in the endothelial cells within not only neovascular tufts but also sprouting edge in the retina. These results suggest that APJ antagonists efficiently prevent pathological angiogenesis in the retina of ischemic retinopathy.