Anti-angiogenic Effects of Mammalian Target of Rapamycin Inhibitors in a Mouse Model of Oxygen-Induced Retinopathy

Abstract

Ocular pathologic angiogenesis is a causative factor for retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. In the present study, we examined the effects of rapamycin and everolimus, inhibitors of mammalian target of rapamycin (mTOR), on retinal pathologic angiogenesis in mice with oxygen-induced retinopathy (OIR), an animal model of proliferative ischemic retinopathy. Mice were exposed to 80% oxygen from postnatal day (P) 7 to P10, and were then brought into room air and subcutaneously injected with rapamycin and everolimus. The neovascular tufts, the size of the central avascular zone, and the immunoreactivity for phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTOR activity, were evaluated in flat-mounted retinas. Retinal neovascular tufts and vascular growth in the avascular zone were observed in P15 mice with OIR. In addition, intense immunoreactivity for pS6 was detected in the neovascular tufts and in endothelial cells located at the vascular-avascular border. Both rapamycin and everolimus reduced the extent of retinal neovascular tufts and pS6 immunoreactivity, but they also increased the size of the avascular zone. Thus, activation of the mTOR pathway in endothelial cells contributes to retinal pathologic angiogenesis, and mTOR inhibitors that target proliferating endothelial cells are promising candidates as anti-angiogenic agents for the treatment of vasoproliferative retinal diseases.Key words mammalian target of rapamycin; pathologic angiogenesis; retina; vascular endothelial growth factor Ocular pathologic angiogenesis contributes to the pathogenesis of vision threatening eye diseases, such as retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration.

Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization

“…Building upon previous research targeting the mTOR signaling pathway as a therapeutic for various diseases, a number of studies have investigated the role of mTOR in the pathological conditions of the retina 15, 16, 17, 19, 29, 30. Using mTOR pathway inhibitors, recently it has been shown that blocking mTOR signaling conferred protection against the formation and progression of CNV 16, 18, 19, 30.…”

“…mTOR was shown to be a critical factor in the angiogenesis processes of various retinal pathologic conditions, including AMD, retinopathy of prematurity, and diabetic retinopathy 15, 16, 17. Other recent studies demonstrated that autophagy induced by mTOR inhibition promoted the survival of retinal pigment epithelial (RPE) cells under toxic conditions,18, 19, 20 indicating that the development of new therapeutic modalities for managing AMD may crucially include mTOR signaling pathway regulation.…”

Nogo‐A inhibits vascular regeneration in ischemic retinopathy

“…The level of phospho-VEGFR2 did not significantly vary between αBrdU and 11C7 treatments (Supporting Information Figure S6b) in P13 OIR retina. The activation of signaling cascades involved in pathological angiogenesis such as P-Stat3 (Sun et al, 2015), P-S6 (Yagasaki et al, 2014), and P-Erk1/2 (Yu et al, 2016) were also not influenced by 11C7 injection (Supporting Information Figure 6a,b). These results suggest that 11C7 may promote in part vascular growth by decreasing S1PR2 in endothelial cells.…”

Exposure to high‐concentration oxygen in the neonatal period induces abnormal retinal vascular patterning in mice

“…Therefore, in this study, newborn (P0) male and female mice (11∼14 mice) were placed in hyperoxic conditions (75% oxygen) in an oxygen-regulated chamber with their nursing mother. Oxygen concentrations were measured with a sensor placed inside the cage and regulated by an oxygen controller (ProOx110; Biospherix, Redfield, NY), as reported previously (Yagasaki et al, 2014a). After completing 48 or 96 hr of hyperoxia, mice were returned to normoxia (room air).…”